Frequent coexistence of anti-topoisomerase I and anti-U1RNP autoantibodies in African American patients associated with ...
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Title: Frequent coexistence of anti-topoisomerase I and anti-U1RNP autoantibodies in African American patients associated with mild skin involvement: a retrospective clinical study
Physical Description: Journal Article
Creator: Satoh, Minoru
Krzyszczak, Malgorzata E.
Li, Yi
Ceribelli, Angela
Ross, Steven J.
Chan, Edward K. L.
Segal, Mark S.
Bubb, Michael R.
Sobel, Eric S.
Reeves, Westley H.
Publisher: BioMed Central
Place of Publication: London
Publication Date: May 10, 2011
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Abstract: INTRODUCTION: The presence of anti-topoisomerase I (topo I) antibodies is a classic scleroderma (SSc) marker presumably associated with a unique clinical subset. Here the clinical association of anti-topo I was reevaluated in unselected patients seen in a rheumatology clinic setting. METHODS: Sera from the initial visit in a cohort of unselected rheumatology clinic patients (n = 1,966, including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) were screened by radioimmunoprecipitation. Anti-topo I-positive sera were also tested with immunofluorescence and RNA immunoprecipitation. RESULTS: Twenty-five (15 Caucasian, eight African American, two Latin) anti-topo I positive patients were identified, and all except one met the ACR SSc criteria. Coexistence of other SSc autoantibodies was not observed, except for anti-U1RNP in six cases. When anti-topo I alone versus anti-topo I + U1RNP groups were compared, African American (21% vs. 67%), overlap with SLE (0 vs. 50%; P = 0.009) or PM/DM (0 vs. 33%; P = 0.05) or elevated creatine phosphokinase (CPK) (P = 0.07) were more common in the latter group. In comparison of anti-topo I-positive Caucasians versus African Americans, the latter more frequently had anti-U1RNP (13% vs. 50%), mild/no skin changes (14% vs. 63%; P = 0.03) and overlap with SLE (0 vs. 38%; P = 0.03) and PM/DM (0 vs. 25%; P = 0.05). CONCLUSIONS: Anti-topo I detected by immunoprecipitation in unselected rheumatology patients is highly specific for SSc. Anti-topo I coexisting with anti-U1RNP in African American patients is associated with a subset of SLE overlapping with SSc and PM/DM but without apparent sclerodermatous changes.
Acquisition: Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Minoru Satoh.
Publication Status: Published
Funding: Publication of this article was funded in part by the University of Florida Open-Access publishing Fund.
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RESEARCHARTICLEOpenAccess Frequentcoexistenceofanti-topoisomeraseIand anti-U1RNPautoantibodiesinAfricanAmerican patientsassociatedwithmildskininvolvement:a retrospectiveclinicalstudy MinoruSatoh 1,2* ,MalgorzataEKrzyszczak 1 ,YiLi 1 ,AngelaCeribelli 3 ,StevenJRoss 1,3 ,EdwardKLChan 3 MarkSSegal 4 ,MichaelRBubb 1 ,EricSSobel 1,2 andWestleyHReeves 1,2 Abstract Introduction: Thepresenceofanti-topoisomeraseI(topoI)antibodiesisaclassicscleroderma(SSc)marker presumablyassociatedwithauniqueclinicalsubset.Heretheclinicalassociationofanti-topoIwasreevaluatedin unselectedpatientsseeninarheumatologyclinicsetting. Methods: Serafromtheinitialvisitinacohortofunselectedrheumatologyclinicpatients( n =1,966,including434 systemiclupuserythematosus(SLE),119SSc,85polymyositis/dermatomyositis(PM/DM))werescreenedby radioimmunoprecipitation.Anti-topoI-positiveserawerealsotestedwithimmunofluorescenceandRNA immunoprecipitation. Results: Twenty-five(15Caucasian,eightAfricanAmerican,twoLatin)anti-topoIpositivepatientswereidentified, andallexceptonemettheACRSSccriteria.CoexistenceofotherSScautoantibodieswasnotobserved,exceptfor anti-U1RNPinsixcases.Whenanti-topoIaloneversusanti-topoI+U1RNPgroupswerecompared,African American(21%vs.67%),overlapwithSLE(0vs.50%; P =0.009)orPM/DM(0vs.33%; P =0.05)orelevated creatinephosphokinase(CPK)( P =0.07)weremorecommoninthelattergroup.Incomparisonofanti-topoIpositiveCaucasiansversusAfricanAmericans,thelattermorefrequentlyhadanti-U1RNP(13%vs.50%),mild/no skinchanges(14%vs.63%; P =0.03)andoverlapwithSLE(0vs.38%; P =0.03)andPM/DM(0vs.25%; P =0.05). Conclusions: Anti-topoIdetectedbyimmunoprecipitationinunselectedrheumatologypatientsishighlyspecific forSSc.Anti-topoIcoexistingwithanti-U1RNPinAfricanAmericanpatientsisassociatedwithasubsetofSLE overlappingwithSScandPM/DMbutwithoutapparentsclerodermatouschanges. Introduction AutoantibodiestotopoisomeraseI(topoI,alsoknown asScl-70)isanestablishedserologicmarkerofscleroderma(systemicsclerosis,SSc)andassociatedwithdiffusesclerodermaandsevereinterstitiallungdisease (ILD)[1-3].ItishighlyspecificforSScwhentestedwith standarddoubleimmunodiffusion[4,5];however,several studiesusingenzyme-linkedimmunosorbentassay (ELISA)reportedhighprevalenceofanti-topoIin systemiclupuserythematosus(SLE)[6-9],causingconfusionandcontroversies[10,11].SSccouldstartfrom theRaynaud ’ sphenomenon(RP),precedingtheonsetof SScformanyyears,ILD,arthritis,andothers[12]. Becauseautoantibodiesareusuallyproducedbeforetypicalclinicalmanifestations,itwouldnotbeasurpriseto findanti-topoIinundifferentiatedconnectivetissuedisease(UCTD),undiagnosedpatients[5],orevenincertainpatientswithSLEwhoaregoingtodevelopSSc later[13].Theclinicalassociationofanti-topoIwasreevaluatedbasedonradioimmunoprecipitationscreening ofserafromacohortofunselectedpopulationina rheumatologyclinicthatincludesundiagnosedpatients *Correspondence:minoru.satoh@medicine.ufl.edu 1 DivisionofRheumatologyandClinicalImmunology,Departmentof Medicine,UniversityofFlorida,1600SWArcherRd,Gainesville,FL,32610 USA Fulllistofauthorinformationisavailableattheendofthearticle Satoh etal ArthritisResearch&Therapy 2011, 13 :R73 http://arthritis-research.com/content/13/3/R73 2011Satohetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.

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andpatientswithawidevarietyofdiagnosesinaddition toestablishedsystemicautoimmunerheumaticdiseases, suchasSSc,SLE,polymyositis/dermatomyositis(PM/ DM),andrheumatoidarthritis(RA).MaterialsandmethodsPatientsAll1,966subjectsenrolledintheUniversityofFlorida CenterforAutoimmuneDiseases(UFCAD)registry from2000to2010werestudied.Diagnosesofthe patientsinclude434SLE,85PM/DM,119SSc,35RA, and40Sjgrensyndrome(SS).Clinicalfindingsof patientsateachvisitwereevaluatedandrecordedby therheumatologistsattheCenter,followingthestandardrheumatologyclinicevaluationformsofthe UFCAD.DiagnosesofpatientswerebytheAmerican CollegeofRheumatology(ACR)classificationcriteriafor SLE[14,15],SSc[16],andRA[17],therevisedEuropean criteriabytheAmerican-EuropeanConsensusGroupfor SS[18],andtheBohan ’ scriteriaforPM/DM[19]. Mixedconnectivetissuedisease(MCTD)[20]isnot classifiedseparately,andSSc patientsdiscussedinthis reportincludepatientswhoalsofulfillcriteriaofother diagnoses(overlapsyndrome).ILDwasdefinedbychest radiographand/orhigh-resolutioncomputedtomography(HRCT).TheprotocolwasapprovedbytheInstitutionalReviewBoard(IRB).Thisstudymeetsandisin compliancewithallethicalstandardsinmedicine,and informedconsentwasobtainedfromallpatientsaccordingtotheDeclarationofHelsinki.AutoantibodyanalysisAutoantibodiesinserafromtheinitialvisitofeach patientwerescreenedbyimmunoprecipitation(IP) using[35S]-methionine-labeledK562cellextract[21]. RNAcomponentsofautoantigenswereanalyzedwith silverstaining(SilverStainPlus;Bio-Rad,Hercules,CA). ACAwereexaminedbyimmunofluorescenceantinuclearantibodies(ANAs)usingHEp-2slidesfromINOVA Diagnostics(SanDiego,CA)anda1:80-dilutedserum.StatisticalanalysisPrevalenceofautoantibodies andclinicalmanifestation wascomparedbyFisherExacttestusingPrism5.0for Macintosh(GraphPadSoftware,Inc.,SanDiego,CA).A valueof P <0.05wasconsideredsignificant.ResultsDetectionofanti-topoisomeraseIandprevalenceofantitopoIinSScandSLEAnti-topoIantibodiesweredetectedin25(1.3%)of 1,966subjectsenrolledtoUniversityofFloridaCenter forAutoimmuneDiseases.Prevalenceofanti-topoIin theSSccohortwas21%(25of119);18%(15of85)in Caucasians,31%(eightof25)inAfricanAmericans,and 25%(twoofeight)inHispanics.AnSScpatientof mixedethnicbackgrounddidnothaveanti-topoI. Noneoftheanti-topoI-positiveserahadotherSSc-specificautoantibodies[3],includinganti-RNApolymerase (RNAP)I/III,PM-Scl,orKubyIP;ACAbyimmunofluorescence;oranti-U3RNP/fibrillarinoranti-Th/Toby RNAanalysisfromIP.However,sixof25anti-topoIpositiveserahadcoexistinganti-U1RNPantibodies,two withanti-Sm.Analysisofprotein(Figure1a,b)and RNAcomponents(Figure1c)byIPareshown. Anti-topoI+U1RNPwascommoninAfricanAmerican(four(16%)of25)butrareinCaucasianSSc(two (2%)of85; P =0.02bytheFisherExacttest).Inpatients whofulfilledtheACRSLEc riteria,anti-topoIwas foundinthree(2%)of153inAfricanAmerican,all threecaseswithanti-U1RNP(twowithanti-Sm)andas SLE-SScoverlapsyndrome.Noneof208Caucasianor 44LatinSLEhadanti-topoIbyIP.Thus,eveninunselectedpatientsatourrheumatologyclinic,anti-topoIby IPishighlyspecificforSScandSScoverlapsyndrome.Clinicalmanifestationsofpatientswithanti-topoIversus anti-topoI+U1RNPClinicalmanifestationsof19patientswithanti-topoI versussixpatientswithanti-topoI+U1RNPwerecompared(Table1).AllpatientsfulfilledtheACRSScclassificationcriteriaexceptfora48-year-oldCaucasian womanwithRP,ILD,andpolyarthritis.Nosclerodermatouschangeswerenoted,andshemaybeconsideredsystemicsclerosissinescleroderma.Theanti-topoIgroup was68%Caucasian,whereas67%ofanti-topoI+ U1RNPgroupwasAfricanAmerican( P =0.059).Twoof theanti-topoI+U1RNPpatientswerealsopositivefor anti-Sm( P =0.05;Figure1).Proximalsclerodermawas common(79%)inanti-topoIgroup.Incontrast,three (50%)ofsixanti-topoI+U1RNPpatientshadnosclerodermatousskinchanges( P =0.03).OverlapwithSLEor PM/DMandelevationofcreatinephosphokinase(CPK) werecommoninanti-topoI+U1RNPgroup( P =0.009 forSLE, P =0.07forCPK, P =0.05forPM/DM;Table1). Clinicalfeaturesofsixcas esofanti-topoIwithantiU1RNParesummarized(Table2).InfourAfrican Americanpatients,case2haddiffusecutaneousscleroderma(dcSSc)buttheotherthreedidnothavesclerodermatousskinchanges;theyfulfilledACRclassification criteriaforSScbasedonpittingscarsandILD.Overlap ofSScwithSLEorPM/DMwasseeninthreeAfrican Americancases.Racialdifferenceinanti-topoI-positivescleroderma patientsClinicalfeaturesofCaucasianversusAfricanAmerican patientswithanti-topoIwerecompared(Table3).InSatoh etal ArthritisResearch&Therapy 2011, 13 :R73 http://arthritis-research.com/content/13/3/R73 Page2of6

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serology,four(50%)ofeightofAfricanAmericanswith anti-topoIhadcoexistinganti-U1RNP,twowithantiSm,butthiswasonlyintwo(13%)of15Caucasians. Proximalsclerodermawas notedin87%ofCaucasians butonlyin38%ofAfricanAmericans( P =0.03).Three ofeightAfricanAmericananti -topoI-positivepatients didnothavesclerodermatouschanges,andtwohad sclerodactylyonly( P =0.03,noskinchangesandsclerodactylyonlycombined).OverlapwithSLEandelevated CPK( P =0.03versusCaucasians)andoverlapwithPM/ DM( p =0.05)werealsocommoninAfricanAmericans. Lackofskinchanges,andoverlapwithSLEandPM/ DMarecommoninAfricanAmericanpatientswith anti-topoI+U1RNPbutnotanti-topoIantibodies alone.Theseclinicalfeatureswerenotpresentintwo casesofanti-topoI+U1RNPinCaucasians,suggesting thatthisclinicalsubsetmayberelativelyuniquetoAfricanAmericans. Figure1 Coexistenceofanti-snRNPsantibodiesinanti-topoI-positivesera (a) 12.5%SDS-PAGE. (b) 8%SDS-PAGE.Sixserawithanti-topoI and-snRNPs(twoanti-Sm+U1RNP;fouranti-U1RNP)wereidentifiedbyimmunoprecipitationof[35S]-methionine-labeledK562cellextract. PositionsofTopoI,componentsofsnRNPs(U5RNP-200kDas;U1-70kDa;U1-A,B ’ /B,U1-C,D1/D2/D3,E,F,andG),andmolecularweightare indicated.U1,Sm,TopoI,prototypeseraforeachspecificity;TopoI+Sm,anti-topoIwithanti-SmandU1RNP-positiveSScsera;TopoI+U1RNP, anti-topoIandU1RNP-positiveSScsera;NHS,normalhumanserum. (c) AnalysisofRNAcomponentsinanti-topoI-positivepatientswith coexistinganti-snRNPs.RNAcomponentsimmunoprecipitatedbyhumanautoimmuneserawereanalyzedwithurea-PAGEandsilverstaining.Six anti-topoI-positivepatientshadcoexistinganti-UsnRNPs(twoanti-Sm(U1,2,4to6,and5;lanes1and2)andfouranti-U1RNP(lanes3to6)) wereidentified.Total,totalRNAs;U1,Sm,prototypehumanserumforeachspecificity;TopoI+Sm,anti-topoIwithanti-SmandU1RNP-positive SScsera;TopoI+U1RNP,anti-topoIandU1RNP-positiveSScsera;NHS,normalhumanserum;positionsof7S,5.8S,and5SrRNA,tRNAs,andU1, 2,4,5,and6snRNAsareshown. Satoh etal ArthritisResearch&Therapy 2011, 13 :R73 http://arthritis-research.com/content/13/3/R73 Page3of6

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DiscussionAnti-topoIisahighlyspecificdiseasemarkerofSSc whentestedbyimmunodiffusion[4,5]orIPasinthe presentstudy.ItcanbeoccasionallyfoundinundiagnosedpatientssuchasUCTD[22]orRP[5],atleast partially,becauseautoanti bodiesareusuallyproduced beforeclinicalmanifestation[23].Inonestudy,antitopoIweretestedbyELISAin2,181unselectedindividualstofindnonewaspositive[24].Allthesedatasupportthehighspecificityofanti-topoIforSSc. Reportsonhighprevalenceofanti-topoIinSLEby ELISAanditsassociationwithSLEactivityandnephritis [8,9]challengedthegeneralobservationonSScspecificityofanti-topoIandtriggeredmuchconfusionand manycontroversies[5,10,11].Whenwetested46SLE sera(fromLouisiana,notincludedinthepresentstudy) byacommercialanti-topoIELISA,41%werepositive; however,onlytwoof19wereIPpositive[10].Inthe studythathad32(25%)of128prevalenceofanti-topoI inSLE[8],onlyfourof32ELISApositivesweredouble immunodiffusionpositive,anddatasupportingthespecificityofELISAwerelimited.Somealsoreported13% to29%prevalenceofanti-topoIinSLE[6,7,9,25] whereasothersreportedlowprevalencebyELISA[5,11]. Thus,theprevalenceofanti-topoIinSLEappearsto dependonthesourceofantigensorELISAkits.In somestudies[8-10],anti-topoIELISApositivesinSLE aredetectingantibodiesthataredifferentfromthose detectedbyimmunodiffusi onandIP.Falsepositives causedbyanti-dsDNA/chromatinantibodiesinSLEsera Table1Clinicalmanifestationsofanti-topoIinAfrican AmericanversusCaucasianpatientsSpecificityTopoI ( n =19) TopoI+U1RNP ( n =6) P Age(yr,meanSD)55.1012.946.68.6 Male26%17% Caucasian68%33% AfricanAmerican21%67%0.059 Latin11%0 Anti-Sm033%0.05 Proximalscleroderma79%50% Nosclerodermatouschanges5%50%0.03 Sclerodactylyonly16%0 Pittingscars74%83% ILD74%83% Sclerodermakidney16%0 OverlapwithSLE050%0.009 ElevatedCPK11%50%0.07 OverlapwithPM/DM033%0.05CPK,creatinephosphokinase;ILD,interstitiallungdisease. P valuesarewith theFisherExacttest. Table2Clinicalcharacteristicofsixcaseswithanti-topoIcoexistingwithanti-snRNPsautoantibodiesCase123456 Anti-snRNPsSm,U1RNPSm,U1RNPU1RNPU1RNPU1RNPU1RNP RaceAfrAmAfrAmAfrAmAfrAmCaucasianCaucasian TypeofskininvolvementNoscldcSScNosclNoscldcSScdcSSc PittingscarsYYYYY ILDYYYYY RaynaudphenomenonYYYYYY PulmonaryhypertensionY Esophagealdysmotility Y FlexioncontractureYY Acro-osteolysisY P SLEoverlap/numberofACRcriteriaY 6 Y 5 N 2 Y 5 N 2 N 2 PM/DMoverlapElevatedCPKDMPMAfrAm,AfricanAmerican;dcSSc,diffusecutaneousscleroderma;F,female;ILD,interstitiallungdisease;M,male;Y,present;N,notpresent;NoSc l,no sclerodermatousskinchanges;P,possible. Table3ClinicalmanifestationsofAfricanAmerican versusCaucasianpatientswithanti-topoICaucasian ( n =15) AfricanAmerican ( n =8) P Age(yr,meanSD)56.511.545.913.2 Male20%38% Anti-U1RNP13%50%0.13 Anti-Sm025% Proximalscleroderma87%38%0.03 Noskinchanges7%38%0.03aSclerodactylyonly7%25% Pittingscar80%88% ILD73%75% Sclerodermakidney20%0 OverlapwithSLE038%0.03 ElevatedCPK7%50%0.03 OverlapwithPM/DM025%0.05aNoskinchangesandsclerodactylycombined.CPK,creatinephosphokinase; ILD,interstitiallungdisease. P valuesarewiththeFisherExacttest.Satoh etal ArthritisResearch&Therapy 2011, 13 :R73 http://arthritis-research.com/content/13/3/R73 Page4of6

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inELISAforautoantibodiestoDNA-bindingproteins, suchasKuandreplicationproteinA,arewelldocumented[10,26].Thus,themostlikelyexplanationappearsto bethatanti-topoIELISApositivesinSLEarefalsepositivescausedbyantibodiestoDNA/chromatin.Because topoIisanucleotidesequencenonspecificDNA-bindingprotein,onescenarioisthatserumDNAbindsto topoIcoatedonplate,andthisisfollowedbyantiDNA/chromatinantibodiesbindingtoDNA.Asecond scenarioisthatpreformeds erumanti-DNA/chromatin immunecomplexcanbindtotopoIviaitsDNAcomponent.Itisalsopossiblethatanti-topoIELISApositivesinSLEinsomestudiesreflectdetectionoflowaffinityantibodiesoranti bodiesotherthanIgGclass becauseofsecondaryantibodys pecificity.Alternatively, certainELISAantigensmaycontainimpuritiesasunrelatedantigens,orsomeSLEs erarecognizedenatured topoIepitopesnotpresentinnativemoleculesandthus appearunreactive(negative)inimmunodiffusionorIP. Anti-topoIantibodiesarepositivein1%to3%ofSLE patients,evenbyreliablemethodssuchasimmunodiffusion[8].ThismaybeexplainedbySLE-SScoverlapsyndrome,nottypicalpureSLE[10,27],asshowninthe presentstudy.Thus,anti-topoIbyimmunodiffusionor IPisspecificforSSc,andcautiousinterpretationis requiredforanti-topoIELISApositiveresultsinSLE. SScpatientscanbeclassifiedbasedonautoantibody specificitiesthatareassociatedwithuniqueclinicalsubsets[3].CoexistenceofSSc-relatedautoantibodiesis uncommon[3];however,acombinationofanti-topoI andanti-U1RNPappearstobeaninterestingandpossiblyclinicallyusefulexcep tion.Inadditiontocases reportedmainlyfromJapan[27-29],frequentassociation ofanti-topoIandanti-U1RNPinalargeJapaneseand Americancohortsalsowasobserved[1,2].Inonestudy, nine(12%)of78ofanti-topoI-positiveSSchadcoexistinganti-U1RNP,andanadditionalthreelaterdeveloped anti-U1RNP[1].Threepatientsinthiscohortalsohad anti-Smantibodies[27].AstudyfromFinlandreported 12%ofcoexistenceofanti-topoIandanti-U1RNP[30]. Detectionofanti-topoIinMCTDpatientsindicates coexistinganti-topoIandanti-U1RNP[31].Regarding theissueofraceandcoexistenceofthesetwospecificitiesinSSc,theprevalencewasreportedas2%inCaucasian,13%inAfricanAmerican,and16%inJapanesein anotherU.S.cohort[2].The50%prevalenceofantiU1RNPinanti-topoI-positiveAfricanAmericansinthe presentstudyishigherthanthatinotherstudiesto date.Furthermore,prevalenceofdiffusesclerodermain AfricanAmericanswaslowversusthatintheprevious study[2].Threeoffourcasesofanti-topoI+U1RNPpositiveAfricanAmericanpatientscanbeclassifiedas SScbyusingtheACRcriteriabasedonthepresenceof pittingscarsandILD[16];however,theylack sclerodermatousskinchanges.Thus,thissubsetof patientsmightnotbeincludedinthestudiesthat selectedSScpatientsbased ondiagnosisbyphysicians [2,32,33],sclerodactylyasaminimumrequirement[34], orbyusingotherSSccriteria[35].Theycanbeeasily classifiedas “ SLEwithILDandRP ” becausethisisthe commonpatternofpresenta tionamonganti-U1RNPpositiveSLEorMCTD.Thissubsetcouldalsobereal anti-topoI-positiveSLEwithoutfeaturesofSSc describedinsomeliterature[8].Itmaybeclinically importanttoidentifyanti-topoI,inadditiontoantiU1RNP,inthesepatients,becausetheformercouldbe associatedwithsevereILDandsclerodermarenalcrisis [2,3].ConclusionsAnti-topoIdetectedbyIPin unselectedrheumatology patientsishighlyspecificf orSSc.Anti-topoIandantiU1RNPfrequentlycoexistinAfricanAmericanpatients, andtheyareassociatedwithasubsetofoverlapsyndromeofSLE,SSc,andPM/DM,characterizedbyRP, pittingscars,andILDwithoutsclerodermatouschanges.Abbreviations ACR:AmericanCollegeofRheumatology;ANA:antinuclearantibodies;CPK: creatinephosphokinase;dcSSc:diffusecutaneousscleroderma;HRCT:highresolutioncomputedtomography;ILD:interstitiallungdisease;IP: immunoprecipitation;IRB:InstitutionalReviewBoard;MCTD:mixed connectivetissuedisease;PM/DM:polymyositis/dermatomyositis;RA: rheumatoidarthritis;RNAP:RNApolymerase;RP:Raynaud ’ sphenomenon; SLE:systemiclupuserythematosus;SS:Sjgrensyndrome;SSc:systemic sclerosis:scleroderma;TopoI:topoisomeraseI;UCTD:undifferentiated connectivetissuedisease;UFCAD:UniversityofFloridaCenterfor AutoimmuneDiseases. Acknowledgements WethankMarleneSarmiento,AnnieChan,andtheUFGCRCstafffor assistancewithclinicaldatacollection. ThisstudywassupportedbyNIHgrantR01-AR40391andM01R00082from theU.S.PublicHealthServiceandbygenerousgiftsfromLupusLink,Inc. (DaytonaBeach,FL)andMr.LewisM.SchotttotheUniversityofFlorida CenterforAutoimmuneDisease.Publicationofthisarticlewasfundedin partbytheUniversityofFloridaOpen-AccessPublishingFund. Authordetails1DivisionofRheumatologyandClinicalImmunology,Departmentof Medicine,UniversityofFlorida,1600SWArcherRd,Gainesville,FL,32610 USA.2DepartmentofPathology,Immunology,andLaboratoryMedicine, UniversityofFlorida,1600SWArcherRd,Gainesville,FL,32610USA.3DepartmentofOralBiology,CollegeofDentistry,UniversityofFlorida,1395 CenterDrive,Gainesville,FL32610USA.4DivisionofNephrology, Hypertension,andRenalTransplantation,DepartmentofMedicine,University ofFlorida,1600SWArcherRd,Gainesville,FL,32610USA. Authors ’ contributions MS,MEK,YL,SJR,andEKLCcarriedouttheimmunoassays,andMSdesigned thestudyandperformedthestatisticalanalysis.MSS,MRB,ESS,andWHR enrolledpatientsforthestudyandmaintainedthedatabase.MS,AC,and EKLCdraftedthemanuscript.Allauthorsreadandapprovedthefinal manuscript. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests.Satoh etal ArthritisResearch&Therapy 2011, 13 :R73 http://arthritis-research.com/content/13/3/R73 Page5of6

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