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Scleroderma
Thetermsclerodermaencompassesaspectrumofcomplexandvariableconditionsprimarily
characterizedby3majorphenomenon:abnormal,excessformationofconnectivetissue
(fibrosis),vascularalterations,andanautoimmuneresponse(Gabrielli2009A.D.A.M.2013
Derk2003BalbirGurman2012Varga2008).Sclerodermaspectrumdisorderssharethe
commonfeatureofhardeningorthickeningoftheskin,butothermanifestationscanvary
greatlybetweenpatients.Althoughthecauseofsclerodermaisnotunderstood,thehallmarkof
sclerodermaisfibrosis,whichisaprocesssimilartotheformationofscartissuefibrosisis
primarilybroughtaboutbyinflammation.Nocurecurrentlyexistsforscleroderma(Gabrielli
2008Gomer2008).
Thereare2primarytypesofscleroderma:
Thelesssevereformiscalledlocalizedscleroderma.Itislimitedtotheskinand
underlyingmuscles,joints,andsometimesbonesitdoesnotaffectinternalorgans.In
somecases,localizedsclerodermamayresolveonitsown(MayoClinic2010NIAMS
2012Gabrielli2009Clemens2003KleinWeigel2011Hawk2001Takehara2005).
Thereareabout27newcasesoflocalizedsclerodermapermillionpeopleperyear
(Peterson1997).
Themorewidespreadandsevereformiscalledsystemicscleroderma(alsoknownas
systemicsclerosis).Thisformisprogressiveandoccursthroughoutthebody,affecting
internalorgansaswellastheskin(Chatterjee2010).Itmayaffecttheconnectivetissue
ofthelung,kidney,heart,andotherorgans,aswellasbloodvessels,muscles,andjoints
(Hawk2001Heinberg2007).Thereare2subtypesofsystemicsclerosis:limited
cutaneoussystemicsclerosis(historicallyknownasCRESTsyndrome)anddiffuse
cutaneoussystemicsclerosis(Jimenez2012Gabrielli2009).Limitedcutaneoussystemic
sclerosistypicallyaffectstheskinonlimitedareasofthebody,suchasthefingers,hands,
orthefaceandislesslikelytoinvolveinternalorgansearlyindiseaseprogression.
Diffusecutaneoussystemicsclerosis,whichmaystartsuddenlyandspreadovermuchof
thebody,isassociatedwithapoorerprognosis(Hughes2012).Thereareabout19new
casesofsystemicsclerosispermillionpeopleperyear(Jimenez2012).
Conventionalmanagementstrategiesforsclerodermaarelimitedtointerventionsthatcontrol
specificsymptomsnodrughasbeendevelopedthatsuccessfullytreatstheunderlying
cause(s)ofscleroderma(Hinchcliff2008).Ontheotherhand,naturalstrategiesmayoffera
meansofdirectlytargetingfibrosis,adestructiveprocessthatinvolvestheformationoftough
connectivetissuethroughinflammatorypathwaysandisacentraldrivingforcebehind
sclerodermaprogression.Naturalconstituentslikeepigallocatechingallate(EGCG)fromgreen
tea,Nacetylcysteine,andvitaminEmayhelppreservetissueintegrityinsclerodermasufferers
(Chang2013Rosato2009bFiori2009deSouza2009).Moreover,maintainingadequate
bloodlevelsofvitaminDmaybeanimportantconsiderationforindividualsaffectedby
scleroderma,sincestudiesshowitcandirectlymodulatesignalingpathwaysthatcontributeto
fibrosis(Slominski2013Arnson2011).
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Inthisprotocolyouwilllearnaboutthedifferenttypesofsclerodermaandhowtheyare
diagnosedandtreated.Futureresearchdirectionswillbeexplored,andavarietyof
scientificallystudiednaturalinterventionswillbereviewed.Someimportantdietaryandlifestyle
considerationswillbepresentedaswell.

DevelopmentandProgressionofScleroderma
Sclerodermaisprimarilytheconsequenceof3majorfactors:bloodvesseldamage,an
autoimmuneresponse,andfibrosis.Inmanyways,thesefactorscreateaviciouscycle,thus
thediseaseistypicallyprogressivethisisespeciallysoforsystemicsclerosis(Gabrielli2008
Gomer2008).

BloodVesselDamage
Smallbloodvesselsareespeciallypronetothedamageanddysfunctioncausedby
scleroderma.Vasculardysfunctionismostlytheresultofinflammationandfibrosis,which
causebloodvesselstobecomestiffanddisrupttheirabilitytoexpandandcontract(Varga
2008).Amajorhallmarkofvasculardamagethatoccursinsclerodermaisendothelial
dysfunction.Theendotheliumisthedelicateinnermostliningofbloodvessels(Varga2008
Deanfield2005Patel2001Gabrielli2009).Inseverecasesofsystemicsclerosis,dramatic
vasculardysfunctioncanbelifethreatening(Hummers2008).
Inaddition,sclerodermaisassociatedwithincreaseddepositionofcalciuminbloodvessels.In
onestudy,systemicsclerosispatientswerefoundtohavean11foldincreasedriskof
moderatetoseverecalcificationinthearteriesthatsupplytheheart(Mok2011).Moreover,
autopsyinvestigationsofsystemicsclerosispatientshavefoundextensivecalcificationofsmall
bloodvesselsthatsupplythebrain(Heron1998).

InflammationandAutoimmuneResponse
Inflammatoryandautoimmunereactionsalsocontributetothetissuedamageanddysfunction
seeninscleroderma.Bloodvesselalterationsleadtoaninflammatoryresponsewithinthe
endothelium.Inturn,damagedendothelialcellsreleaseinflammatorysignalingmoleculesthat
recruitimmunecells,inparticularCD4+helperTcells,tothebloodvesselwalls.Thepresence
ofexcessiveinflammatorymediatorsservestoreinforcethecontinueddeteriorationofblood
vesselintegrityandsubsequentgenerationofmoreinflammationandfibrosis.Autoimmunity
alsocontributestoinflammatorydamageofthebloodvessels,thoughitisnotknownwith
certaintyifanautoimmuneresponseisthekeyinitiatingfactorinscleroderma(Varga2008
Castro2010Gabrielli2009).

Fibrosis
Fibrosisdescribesthehardeningorstiffeningoftissuesthatarenormallysoftandmalleable.It
occursasaresultofoveractivationofspecializedcellscalledfibroblasts,whichproduce
collagenandthe"glue"(calledextracellularmatrix)thatholdstissuestogether.Connective
tissueismadeofcollagenandotherproteins,sowhenexcessivecollagenisproducedvia
overactivationoffibroblasts,connectivetissuecanaccumulateabnormally,thuscontributingto
tissuefibrosis.DNAdamageandproinflammatoryoxidativestress,whichisincreasedin
patientswithscleroderma,isproposedtobeamajordrivingforcebehindfibroblast
overactivation(Gabrielli2012Avouac2010).
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Fibrosisisresponsibleforthemostobvioussymptomofsclerodermahardeningoftheskin.
However,fibrosisoforgansandbloodvesselscanoccuraswellandthiscontributestosomeof
thesystemiccomplicationsassociatedwithscleroderma.

TheRoleofOxidativeStressandInflammationinScleroderma
Accumulationoffreeradicalsisthoughttoplayasignificantroleinthedevelopmentand
progressionofscleroderma,especiallyintissuefibrosis.Ithasbeensuggestedthat
perturbedbalancebetweenendogenousfreeradicalformationandantioxidantdefense
mechanismsmaybepresentinscleroderma,leadingtoexcessivegenerationofreactive
oxygenspecies(Gabrielli2012).Indeed,increasedoxidativeDNAdamagehasbeen
observedinsclerodermapatientscomparedtohealthycontrols(Avouac2010).
Thereareafewtheoriesabouthowfreeradicalscontributetotissuefibrosisin
scleroderma.First,freeradicalsmaydirectlyactivatespecializedcellscalledfibroblasts,
whichproducecollagenandtheextracellularmatrix.Anothertheorysuggeststhat,rather
thandirectlyactivatingfibroblasts,freeradicalsmaymakeitmuchmoredifficultfor
excessconnectivetissuetobebrokendownandclearedbythebody,leadingto
accumulationoffibroustissueindirectly.Mostlikely,bothofthesemechanisms,and
probablyothersyettobediscovered,areinvolvedintherelationshipbetweenoxidative
stressandtissuefibrosisinscleroderma(Gabrielli2012).
Despiteuncertaintiessurroundingtheexactcontributionofreactiveoxygenspeciesto
scleroderma,scientistsproposethattherapywithantioxidantsmayeffectivelymitigate
someofthefibroticchangesinducedbyoxidativestress.Forexample,evidencefrom
animalandhumanstudiessuggeststheantioxidantphytochemicalepigallocatechin
gallate(EGCG)foundingreenteamayguardagainstfibroticchanges(Dooley2010,
2012).
Inflammationalsoplaysaroleinmediatingthedevelopmentofscleroderma.Particularly,
thebloodvesseldamagecharacteristicofsclerodermaislargelydrivenbyinflammatory
reactions.Inflammationmayalsocontributetotissuefibrosis(Barnes2011).
Theinflammatorymediatorinterleukin6(IL6)hasattractedsignificantinterestfromthe
researchcommunityasapotentialtherapeutictargetinsclerodermatreatment.
Interestingly,fibroblastsisolatedfromskinlesionsofindividualswithsystemicsclerosis
expresshigherlevelsofIL6thanfibroblastsfromhealthyindividuals(Feghali1992).
ClinicaltrialsareunderwayinvestigatingtheefficacyofIL6modulationinscleroderma
treatment(Barnes2011).
Additionalevidenceinsupportofanimportantroleforinflammationinscleroderma
comesfromfindingsthatcomponentsoftheimmunesystemcalledTcellshavebeen
foundatsitesoffibrosisinanactivatedstate.Thismeansthattheseimmunecellsare
recruitedtothesiteoffibrosisandareactivelypromotinginflammatoryreactions,
includingthegenerationofIL6(O'Reilly2012).Moreover,thedegreeofskinthickening
atsitesofcutaneousfibrosisinsclerodermacorrelateswiththenumberofTcellsthat
haveinfiltratedthetissue,suggestinganintimaterelationshipbetweenfibroticchanges

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andthepresenceofinflammatoryimmunecells(Fleischmajer1977).Treatment
modalitiestargetingTcellshaveshownsomepromiseandarecontinuallybeing
evaluated(O'Reilly2012).

CausesandRiskFactors
Theexactcauseofsclerodermaisunknown.However,severalfactorsarethoughttoinfluence
risk,includingenvironmentalexposuresandgeneticsusceptibility(ie,familyhistory)(Castro
2010Agarwal2010a,bDieude2011).Forexample,exposuretochemicalslikepolyvinyl
chloride(usedintheplasticsindustry),industrialsolvents(suchaspaintthinners),andsilica
maytriggerorexacerbatescleroderma(Barnes2012Varga2008Mora2009NIAMS2010).
Also,over30genesandgeneregionsareknowntoinfluencesclerodermasusceptibilitymost
ofthesegenesarerelatedtotheimmunesystem(Mayes2012).

SignsandSymptoms
Themanifestationsofsclerodermaarevariableanddependentupontheextentofsystemic
involvement.Forexample,localizedsclerodermamayaffectonlythefingersandcause
moderatehardeningoftheskin,whereasseveresystemicsclerosiscancompromiseinternal
organssuchasthelungsandkidneysandbelifethreatening.Someofthemoreprominent
featuresofsclerodermainclude:

SkinChanges
Skinmanifestationsofsclerodermaincludepuffyandswollenfingers,hands,andtoes,along
withthickeningandhardeningoftheskin,whichcanalsoaffectthefaceandtrunk.Theareas
oftheskinaffectedoftenappearshinyandhairlossoccursinaffectedregionsaswellskin
mayalsoappearabnormallylightordark.Tighteningoftheskinonthefacecangiveamask
likeappearance.Sometimes,patientsdevelopulcersontheirfingertipsortoes,whichcanlead
toscarring.Inaddition,smallbloodvesselsjustbeneaththetoplayeroftheskinmaybecome
dilatedandmorevisuallypronounced,calledtelangiectasias(Gaby2006Chatterjee2010
A.D.A.M.2013).

Raynaud'sPhenomenon
Raynaud'sphenomenonispresentinupto95%ofpatientswithscleroderma(Hinchcliff2008
Simonini2000NIAMS2010).Raynaudsphenomenonisacomplexvasculardisorderinwhich
bloodvessels,particularlythoseinthefingersandtoes,orrarelythetongue,nose,ears,lips,or
nipples,overreacttocoldtemperatureoremotionalstress(MayoClinic2011Herrick2012
Martnez2011).Thebloodvesselsconstrict(ie,vasoconstriction),reducingbloodflowtothe
affectedextremity.Thisresultsinnumbnesswhilebloodflowisreducedandtinglingand/or
painasbloodflowreturnstotheaffectedarea(Herrick2012Martnez2011).Theseattacks
maylastfromminutestohours,andtheintensityofdiscomfortmayvaryfrommildtosevere
(Malenfant2011NCBI2011Martnez2011).Inseverecases,prolongedoxygendeprivation
canleadtotissuedeathintheaffectedextremities(Herrick2012).Moreinformationisavailable
intheRaynaudsPhenomenon(/protocols/heart_circulatory/raynauds_phenomenon_01.htm)
protocol.

InternalOrganInvolvement
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Systemicsclerosiscanaffectmultipleinternalorgans.However,thediseasedoesnotprogress
inexactlythesamewayinallpatients.Somesignificantmanifestationsinclude(BalbirGurman
2012):
Symptomsduetolunginvolvementincludedrycoughandshortnessofbreath
(A.D.A.M.2013).Coughisusuallycorrelatedwiththedegreeoffibrosisinthelungs
(Theodore2012).Lungfunctiontestsareabnormalinasmanyas80%ofscleroderma
patients(Jimenez2012).
Heartandcardiovascularcomplicationsarecausedbyscarringandweakeningofthe
heartmuscle,andincludemyocarditisandarrhythmia(NIAMS2012).Inaddition,patients
withsystemicsclerosishavesignificantlyincreasedriskofatherosclerosis,heartattack,
stroke,andperipheralvasculardiseasecomparedtohealthyindividuals(Man2013Au
2011).Thus,individualswithsystemicsclerosisarealsoencouragedtoreviewLife
ExtensionsAtherosclerosisandCardiovascularDisease
(/protocols/heart_circulatory/coronary_artery_disease_atherosclerosis_01.htm)protocol.
Aseriouscomplication,whenthekidneysareaffected,issclerodermarenalcrisis.This
mayleadtoabruptonsethighbloodpressureandprogressivekidneyfailure(NIAMS
2012).
Digestiveproblemsincludedifficultyswallowing,esophagealreflux,bloating,diarrhea,
constipation,andfecalincontinence(A.D.A.M.2013).

DiagnosisandConventionalTreatment
Physiciansmaysuspectsclerodermabasedonpresentationofthecharacteristicsignsand
symptomsmentionedpreviously.Althoughthereisnospecifictestforscleroderma,a
diagnosticworkupmayincludeadetailedmedicalhistory,laboratoryfindings,andskinbiopsy
(NIAMS2010Nashel2012Khoo2011).
Doctorsmaytestforautoantibodiesagainsttopoisomerase(Scl70),centromereassociated
proteins,andnuclearantigens(ANA)thiscanaidindiagnosisbutmustbesupportedbyother
evidence(Grassegger2008).Rheumatoidfactor,anotherautoantibody,maybepresentin
somepatientsaswell.Abnormalitiesonroutinelabtestsmayhelpidentifyinvolvementof
specificorgans(Ferri2013).ElevatedlevelsoftheinflammatorymarkerCreactiveprotein
(CRP)havebeenassociatedwithworseoutcomesinsomepatientsandmayhelpinfluence
treatmentdecisions(Muangchan2012).Diagnosingsclerodermacanbedifficultduetothe
significantvariabilityindiseasepresentation.
Sclerodermahasnoknowncure.Thereareavarietyofmedicationsthatcanhelppalliate
symptomsandreducecomplicationsofscleroderma,butmedicationsthatmodifythecourseof
thediseasearelacking(KowalBielecka2009Opitz2011Baumhakel2010Gayraud2007).
TreatmentsforOrganSpecificComplicationsofScleroderma(Hinchcliff2008)
Complication

Treatment
Drugsthatcanimprovebloodflow:
Adrenergicblockers

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Raynaud'sphenomenon

Skinfibrosis

Gastroesophagealreflux
disease(GERD)

Intestinaldysmotility
and/orbacterial
overgrowth

AngiotensinIIreceptorblockers
Longactingcalciumchannelblockers
(dihydropyridines)
Pentoxifylline(Trental)
Digitalsympathectomy(surgerythatinterruptsthesmall
nervestothearteriesfeedingthefinger)
Immunomodulatorydrugs(Dpenicillamine[Cuprimine],
mycophenolatemofetil[Cellcept],cyclophosphamide
[Cytoxan])
Antacids
Drugsthatreducestomachacid:
HistamineH2blockers
Protonpumpinhibitors
Antibiotics
Correctionofnutritionaldeficiencies
Promotilityagents

Pulmonary(lung)fibrosis cyclophosphamide(Cytoxananimmunesuppressingdrug)
oralveolitis

Pulmonaryarterial
hypertension

Diuretics
Supplementaloxygen
Drugsthatminimizebloodvesselclots(Warfarin
[Coumadin])
Drugsthatimprovebloodflowincluding:
Endothelin1receptorinhibitors(bosentan[Tracleer])
Phosphodiesterase5inhibitors(sildenafil[Revatio])
Prostacyclinanalogues(epoprostenol[Flolan],
treprostinil[Remodulin],iloprost[Ventavis])

Sclerodermarenalcrisis

Dialysis
Bloodpressureloweringdrugs(eg,shortactingangiotensin
convertingenzymeinhibitors)

Sideeffectsofconventionaltreatmentvarywithmedication,andmayincludefluidbuildupinthe
feet,constipationandgastrointestinaldisturbances,fatigue,flushing,allergicsymptoms,
gingivitis(inflammationofthegums),anderectiledysfunction.Steroidssuchasprednisoneare
frequentlyusedfortheirantiinflammatoryaction.However,steroidshavesignificantside
effects,includinglossofbonedensityandweightgain.

FutureResearchDirections

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Despiteintensivestudyforseveralyears,manyquestionsaboutsclerodermaremain
unanswered.Thisisreflectedbythefactthatthemortalityrateforsclerodermapatientshasnot
changedsignificantlyoverthepast40years(Elhai2012).However,asscientistscontinueto
piecetogetherthebiologicframeworkofscleroderma,thereishopethattherapeuticsthat
targetpathwaysleadingtotissuefibrosiscanbedevelopedresultinginimprovedpatient
outcomes(Leask2012).
Muchofsclerodermaresearchnowfocusesondevelopingwaystoreducetheproliferation
and/oractivationoffibroblasts(Jungel2011).Avenuesbeingpursuedincludeepigeneticsand
variousmethodsofmodifyinggrowthandsignalingpathwaysthatleadtofibroblastactivation
(Gordon2010).Unfortunately,someofthesestrategieshaveprovedineffectiveoronlyableto
providemarginalbenefitsinclinicaltrials(Prey2012).
Onestrategythathasshownsomepromiseissuppressionoftheimmunesystemwithdrugs
thatdestroyBcellsorinhibittheirproduction.Examplesofdrugsinthiscategoryinclude
rituximab(Rituxan)andmycophenolatemofetil(CellCept).Inpreliminarytrials,these
interventionshaveshownsomebenefit(Le2011Mendoza2012Daoussis2012).However,
largerclinicaltrialsareneededtomorethoroughlyassesstheviabilityofthisapproach.
Otherongoingresearcheffortsareevaluatingimmunosuppressionfollowedbytransplantation
ofautologousperipheralbloodstemcells,andhighdosecyclophosphamide(NCT00114530
NCT00501995).

DietaryandLifestyleManagementStrategies
Severaldietaryandlifestyleconsiderationsarerelevantforpeoplewithscleroderma.
SinceexposuretocoldmaytriggerepisodesofRaynaudsphenomenoninscleroderma
patients,takingstepstokeepwarmsuchaswearinggloveswhenventuringoutincold
temperaturesmaybehelpful(Maricq1996Herrick1998Ihler2003).Moreinformationis
availableintheRaynaudsPhenomenon
(/protocols/heart_circulatory/raynauds_phenomenon_01.htm)protocol.
Exerciseenhancesbloodcirculation,whichmaybebeneficialforsclerodermathatprimarily
affectshandsandfeet.Ithasalsobeenshowntoimprovemusclestrengthandfunctionaswell
asaerobiccapacityinpatientswithsystemicsclerosis(Pinto2011Semenova1973).Exercise
alsoimprovesendothelialfunctionandlowersbloodpressure,whichmayprovidesignificant
benefittopeoplewithscleroderma,sincebloodvesseldysfunctionisahallmarkofthedisease
(Tjonna2011Tinken2008Black2008).
Sclerodermapatientsalsooftenhavepoornutritionalstatus,withover28%ofthepatients
havingamediumorhighriskformalnutrition(Baron2009Krause2010).Reducedlevelsofthe
antioxidantsvitaminC,vitaminE,betacarotene,andseleniumhavebeenreportedamong
individualswithsclerodermaandRaynaud'sphenomenon(Simonini2000).Because
sclerodermaisassociatedwithincreasedoxidativestress,eatingplentyoffreshfruitand
vegetablesisimportant(Gabrielli2008SfrentCornateanu2008).

TargetedNaturalInterventions
EveningPrimroseOilandGammalinolenicacid(GLA)
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GLAisanomega6fattyacidavailablefromborageoil,eveningprimroseoilorblackcurrant
seedoil.Itservesasaprecursorforanantiinflammatorysignalingmoleculecalled
prostaglandinE1(Gaby2006).
Inarandomizedcontrolledtrial,patientswithRaynaudsphenomenon(withorwithout
scleroderma)weregiven6gofeveningprimroseoilperdayorplacebofor8weeks.After6
weeksoftreatment,theeveningprimroseoilgroupexperiencedsignificantlyfewerepisodesof
Raynaudsphenomenonthanthoseintheplacebogroup.Allofthesclerodermapatients
noticedimprovementtheauthorsnotedthiswassimilartotheirpreviousresultsusinga
prostaglandinE1infusion(Belch1985).Anotherstudygavesclerodermapatients1gevening
primroseoilthreetimesdaily.Afteroneyear,patientsexperiencedlesspainintheirhandsand
feet,healedulcers,andimprovedskintexture(Strong1985).

Sadenosylmethionine(SAMe)
Wellknownforitsuseinmoodmodulation,liverdisease,andosteoarthritis,SAMemayalsobe
ofbenefitinscleroderma(Bottiglieri2002).Onestudyfoundthatintravenousadministrationof
600mgSAMeperdayfortwomonths,followedbyoralingestionof400mg3timesdaily,
significantlyimprovedskinqualityinpatientswithsystemicsclerosis.Afterfourmonths,50%of
patientsinthestudyshowedasignificantimprovementinskintextureonepatienteven
experiencedimprovementinwalkingabilitiesduetoincreasedmalleabilityofskinonthefeet
andanklesand4subjectsdisplayedimprovedskinfoldthickness,anothermarkerofskin
texturequality.In3patientswhounderwentskinbiopsy,asignificantreductioninskinthickness
wasobserved(Oriente1985).

Nacetylcysteine(NAC)
TheantioxidantNacetylcysteine(NAC)hasshownpromiseinreducingtheseverityof
Raynaudsphenomenoninpeoplewithscleroderma.Severalstudieshaveshownthat,in
patientswithRaynaudsphenomenonasaresultofsystemicsclerosis,intravenousinfusionof
NACeffectivelyincreasesbloodflowtothefingersduetoitsbloodvesseldilatingeffectitalso
reducestheseverityandfrequencyoftheepisodesofRaynaudsphenomenon(Salsano2005
Sambo2001Rosato2009c).NAChasalsobeenshowntoreducelungrelatedcomplications
ofscleroderma(Failli2002).Anopenlabeltrialinwhich40patientswereadministered
intravenousNACfor5hoursfoundthatvascularfunctioninthekidneysimprovedfollowing
NACtreatmentinpatientswithsystemicsclerosiswhosediseasewasnotsevere(Rosato
2009b).Similarly,systemicsclerosispatientswithlimiteddiseaseseverityshowedimproved
markersofliverbloodflowfollowingthesameintravenousNACtreatment(Rosato2009a).

VitaminE
VitaminEhasbeenshowntobeusefulinthemanagementofanumberofautoimmune
diseasesinwhichtheskinisaffected,includingscleroderma(Ayres1978).Various
manifestationsofscleroderma,includingRaynaudsphenomenon,werereportedtorespond
welltovitaminEthevitaminEdosestoachievetheseeffectsrangedbetween200and1200
IUperday(Gaby2006).Moreover,insomecases,vitaminEwasalsoappliedtopically.For
example,onestudyshowedthattopicalapplicationofvitaminEgelhastenedhealingofdigital
ulcersinsystemicsclerosispatients(Fiori2009).
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Inaclinicaltrial,vitaminsCandEwerecombinedwithcyclophosphamideandcomparedto
cyclophosphamidealoneinpatientswithsystemicsclerosis.Thecombinationofthetwo
antioxidantnutrientsandcyclophosphamideledtolessprogressiveskinthickeningandatrend
towardimprovedlungfunctioncomparedtotreatmentwithonlycyclophosphamide(Ostojic
2011).A24weektrialfoundthatcoadministrationoftheantiinflammatoryandvasodilating
drugpentoxifyllinewithvitaminEreducedskinfibrosisinpatientswithsystemicsclerosis(de
Souza2009).

GreenTea
Severalstudieshaveshownthatgreentea,andoneofitsmainactiveconstituents,
epigallocatechingallate(EGCG),hasbeneficialeffectsontheendotheliumthedelicateinner
liningofbloodvessels,whichiscompromisedinscleroderma(Shenouda2007Widlansky
2007Alexopoulos2008).EvidencealsosuggeststhatEGCGcansuppresstissuefibrosisby
inhibitingasignalingpathwaythatpromotesexcessiveaccumulationofcollagen(Park2008).
ExperimentalstudiesarestronglysuggestiveofthetherapeuticpotentialofgreenteaEGCGin
treatingautoimmunediseases(Wu2011).Inaddition,alaboratorystudyfoundthatEGCG
decreasedcollagensecretionbyfibroblasts.Theauthorsconcludedthattheirresultssuggest
thattheantioxidant,EGCG,canreduceECM[extracellularmatrix]production,thefibrotic
markerCTGF[connectivetissuegrowthfactor]andinhibitcontractionofdermalfibroblastsfrom
SSc[systemicsclerosis]patients(Dooley2010).Numerousotherstudieshavenotedmultiple
antifibroticactionsofgreenteaconstituents(Xiao2013Chang2013Tsai2013Cai2013).
Whilethereisaneedforfuturehumanclinicaltrialstoconfirmthis,bearinginmindthewell
documentedcardiovasculareffectsofgreenteaandEGCGinhumans,patientswith
sclerodermaandotherautoimmunediseasesmaybenefitfromsupplementingwithgreentea
EGCG(Wu2011).

4Aminobenzoicacid(PABA)
SometimesreferredtoasamemberoftheBvitaminfamily,PABAisawatersolubleorganic
compoundthathasbeenstudiedasfarbackasthe1940sasaremedyforscleroderma
(Zarafonetis1948).CasereportsoftheeffectsofPABAinsclerodermapatientsaredispersed
throughoutthescientificliteratureoverthedecadesleadinguptothe1980s,atwhichpoint
morerigorousanalyseswerepublished(Meyers1977BMJ1968Gougerot1951).Evidence
fromretrospectivestudiesindicatePABAisassociatedwithseveralbenefitsforscleroderma
patients,includingimprovedsurvival,skinsoftening,andbettermaintenanceoflungfunction
overtime(Zarafonetis1988a,bZarafonetis1989).Unfortunately,in1994,adoubleblind,
placebocontrolledtrialfailedtoshowthatPABAwassuperiortoplacebofortreatingskin
manifestationsofscleroderma(Clegg1994).Despitetheresultsofthisstudy,casereportsof
benefitsinskinconditionsrelatedtosclerodermacontinuetobepublished(Gruson2005).
Althoughthemechanism(s)bywhichPABAmaymodifysclerodermaareunclear,onestudy
showedthatthecompoundwasabletoinhibitgrowthoffibroblastsderivedfromscleroderma
patients(Priestley1979).AdditionalstudiesareneededtoevaluatePABAasatreatmentfor
scleroderma.

Melatonin
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Melatonin,alsoknownasthe"sleephormone,"isproducedandsecretedbythepinealgland
duringnighttime(PandiPerumal2006).Melatoninisinvolvedinsleepregulation,aswellasina
numberofothercyclicalbodilyactivities.
Melatoninhasseveralbeneficialeffectsontheendotheliumthataredirectlyrelevantfor
scleroderma:itscavengesfreeradicals,activatesantioxidantdefenseenzymes,reducesblood
pressure,andincreasesnitricoxidebioavailability(Scheer2004Rodella2013).Itsabilityto
protectagainstendothelialdamage,bloodvesselconstriction,plateletaggregation,andthe
accumulationofexcessiveamountsofwhitebloodcellsintissues(leukocyteinfiltration)might
explainthebeneficialeffectsofsupplementationthatweredescribedinpatientswith
scleroderma(Rodella2013).Inastudythatincluded5patients,supplementationofmelatonin
incombinationwithvitaminEandACTH,ahormonesecretedbytheanteriorpituitarygland
andimportantforthehealthoftheneuroimmunoendocrinesystem,achievedapartialresponse
inallpatientsafteronemonthoftreatment,anddiseaseprogressionwasstoppedinallfive
patientswhenthetreatmentwascontinuedfurther(Todisco2006).Alaboratorystudy
investigatedtheeffectofmelatoninonhumanskinfibroblasts(connectivetissuecells),and
reportedthatitcausedanover80%inhibitionofthegrowthandmultiplicationoffibroblasts
derivedfromtheskinofhealthyindividualsandsclerodermapatients(Carossino1996).

Gotukola(Centellaasiatica)
Gotukola(Centellaasiatica)isanherbfoundinmosttropicalandsubtropicalcountries,
includingIndia,SouthAfrica,Madagascar,andEasternEurope(Gohil2010).Gotukola
alleviatesmicrocirculatoryproblemsandmayhelpinflammatoryskinconditions,suchaslupus,
varicoseulcers,eczema,atopicdermatitis,andpsoriasis(Belcaro2011Gohil2010).In
additiontobeinganantiinflammatory,gotukolaisalsoanantioxidantthatcanhelpcontrol
oxidativestressassociatedwithinflammationand/orinfections(Belcaro2011Gohil2010).It
alsoaidswoundhealingandisusedforscarmanagement(Maquart1999Bonte1994
Widgerow2000Paocharoen2010Belcaro2011).
Gotukolahasbeenusedforlocalizedandsystemicsclerodermawithpositiveresults.After6
monthsofsupplementationinoralformwith30mg/day(10mg,threetimesaday),astudyon
12patientswithsystemicsclerosisshowedadecreaseofvasculardisorders,hardlesions,
hyperpigmentation,andimprovementinthepatientsgeneralcondition.Abeneficialresponse
wasalsoobtainedwithlocalapplicationofgotukolaointmentonfingerulcers,andthetherapy
waswelltolerated(Guseva1998).

Curcumin
Curcuminisamajorcomponentofthespiceturmeric.TurmerichasbeenusedinAyurvedic
medicinetotreatawiderangeofconditions,andpractitionersofalternativemedicineoften
recommendcurcuminasatreatmentforinflammatoryandautoimmunediseases(Aggarwal
2009,2011Jurenka2009).Moreover,curcuminhasbeenshowninthelasttwodecadesto
havepotentimmunomodulatory,neuroprotective,andanticancereffects(Jagetia2007Zhou
2011Sharma2005Cole2007Jurenka2009).Becausesclerodermaisadiseasethat
involvesexaggeratedcollagendepositionandexcessivegrowth(proliferation)offibroblasts,
curcuminmaybeabletoprovideatherapeuticbenefitthroughitsabilitytosuppressthe
proliferationoffibroblasts(Tourkina2004Punithavathi2003Smith2010).Laboratorystudies
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revealthatcurcuminsuppressestransforminggrowthfactorbeta(TGF),aprofibrotic
signalingmoleculeimplicatedinthedevelopmentofscleroderma(Song2011).Anotherstudy
foundthatcurcumincausedcelldeath(apoptosis)insclerodermalungfibroblastsbutnotin
normallungfibroblasts.Theauthorsconcludedtheseobservationssuggestthatcurcuminmay
havetherapeuticvalueintreatingscleroderma(Tourkina2004).

VitaminD
VitaminDisaprecursortothehormonecalcitriol,whichexertsavastarrayofactions
throughoutthebody.Calcitriolplaysanespeciallyprominentroleinmodulationoftheimmune
system(Panichi2003).Moreover,associationshavebeenmadebetweenlowbloodlevelsof
vitaminDandautoimmuneandinflammatorydisorders,includingscleroderma(AgmonLevin
2012Vacca2011).
Inonestudy,sclerodermapatientsweremorelikelytobedeficientinvitaminDcomparedto
healthycontrolsubjects.Inaddition,sclerodermapatientswithhighervitaminDlevelshadless
extensiveskininvolvementthanthosewithlowlevels.HighervitaminDconcentrationswere
associatedwithlessskinfibrosisaswell(Arnson2011).Thesefindingsareinlinewith
experimentalevidencethatsuggestscalcitriolandrelatedvitaminDmetabolitescanmodulate
growthfactorsignaling,therebyreducingthepropensityoffibroblaststopromotefibrosis
(Slominski2013).
Otherclinicaltrialsandcasereportshaveshownthatdirectadministrationofcalcitriolresultsin
symptomaticimprovementinsclerodermapatients.Inonesmalltrialconductedonthree
patientswithlocalizedscleroderma,calcitrioladministrationfor7monthsimprovedskin
tightnessandjointmobility(Hulshof1994).Anothertrialshowedoralcalcitrioltreatment
considerablyimprovedskinlesionsin5of7childrenwithscleroderma(Elst1999).Similarly,in
atrialconductedon11sclerodermapatients,calcitrioltreatmentforupto3yearswas
associatedwithsignificantimprovementscomparedtobaseline(Humbert1993).
ThesefindingsgivecredencetothenotionthatmaintenanceofadequatevitaminDblood
levelsshouldbeapriorityforsclerodermapatients.LifeExtensionsuggeststhatmostadults
targetanoptimal25hydroxyvitaminDlevelof5080ng/mL.

LifeExtensionSuggestions
NAcetylcysteine(/search/products.aspx?k=dptnacetyl)(NAC):600mgonetothree
timesdailywithorwithoutfood
VitaminE(/search/products.aspx?k=dptVitaminE):400IUwithatleast200mg
gammatocopheroldailywithfood
Greenteaextract(/search/products.aspx?k=dptGreenTea)(std.to98%polyphenols):
725mgdailywithorwithoutfood
Borageseedoil(/search/products.aspx?k=dptBorage):13002600mgdailywith
food(providing299598mgofGLA)
SAdenosylMethionine(/search/products.aspx?k=dptSAMe)(SAMe):400mgtwoto
threetimesdaily,preferablyonanemptystomach
Paraaminobenzoicacid(/search/products.aspx?k=dptPABA)(PABA):100500mg
dailywithfood
Melatonin(/search/products.aspx?k=dptMelatonin):0.35mg30to60minutes
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beforebed
GotuKola(/search/products.aspx?k=dptGotuKola):950mgtwotimesdaily,
preferablywithfood
Curcumin(/search/products.aspx?k=dptCurcumin)(ashighlyabsorbedBCM95):
400mgdailywithfood
VitaminD(/search/products.aspx?k=dptVitaminD3):50008000IUdailydepending
onbloodlevelsof25OHvitaminD
Inaddition,thefollowingbloodtestsmayprovidehelpfulinformation:
VitaminD,25Hydroxy(/search/products.aspx?k=dptVitaminDBT)
Inflammationpanel(/search/products.aspx?k=dptInflammationPanelBT)
DisclaimerandSafetyInformation
Thisinformation(andanyaccompanyingmaterial)isnotintendedtoreplacetheattentionor
adviceofaphysicianorotherqualifiedhealthcareprofessional.Anyonewhowishestoembark
onanydietary,drug,exercise,orotherlifestylechangeintendedtopreventortreataspecific
diseaseorconditionshouldfirstconsultwithandseekclearancefromaphysicianorother
qualifiedhealthcareprofessional.Pregnantwomeninparticularshouldseektheadviceofa
physicianbeforeusinganyprotocollistedonthiswebsite.Theprotocolsdescribedonthis
websiteareforadultsonly,unlessotherwisespecified.Productlabelsmaycontainimportant
safetyinformationandthemostrecentproductinformationprovidedbytheproduct
manufacturersshouldbecarefullyreviewedpriortousetoverifythedose,administration,and
contraindications.National,state,andlocallawsmayvaryregardingtheuseandapplicationof
manyofthetreatmentsdiscussed.Thereaderassumestheriskofanyinjuries.Theauthors
andpublishers,theiraffiliatesandassignsarenotliableforanyinjuryand/ordamageto
personsarisingfromthisprotocolandexpresslydisclaimresponsibilityforanyadverseeffects
resultingfromtheuseoftheinformationcontainedherein.
Theprotocolsraisemanyissuesthataresubjecttochangeasnewdataemerge.Noneofour
suggestedprotocolregimenscanguaranteehealthbenefits.Thepublisherhasnotperformed
independentverificationofthedatacontainedherein,andexpresslydisclaimresponsibilityfor
anyerrorinliterature.

Scleroderma
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