Vol. 24, No. 1 & 2, December, 2010

Original Articles•IncreasedserumIFN-γinwomenwithahistoryofrepeatedimplantationfailuresafterinvitrofertilizationandembryotransferWei-Ting Hung, Yi-Ming Chen, Ming-Jer Chen, Der-Yuan Chen, Joung-Liang Lan, Hsin-Hua Chen

•DistinctMHCclassIandclassIIallelesinTaiwanesepatientswithankylosingspondylitisBao-Bao Hsu, Ming-Chi Lu, Kuo-Liang Yang, Kuang-Yung Huang, Chien-Hsueh Tung, Su-Qin Liu , Ning-Sheng Lai

•Pott'sdisease.Aretrospectivestudyof35patientsChun-Kai Chiu, Yu-Jih Su, Han-Ming Lai, Chung-Jen Chen, Tien-Tsai Cheng

•Isantiphospholipidantibodyrelatedtooutcomeoflupusnephritis?–A2-yearanalysisWen-Chan Chiu, Shun-Chen Huang, Chung-Jen Chen, Chung-Yuan Hsu, Tsong-Shing Yang , Ching-Lan Chou, Fu-Mei Su, Yu-Jih Su, Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen, Han-Ming Lai, Tien-Tsai Cheng

•PrognosticfactorsofsurvivalinpatientswithdermatomyositisandpolymyositisHsiao-Chun Chang, Yeong-Jian Jan Wu, Shue-Fen Luo, Huei-Huang Ho, Lieh-Bang Liou, Ji-Yih Chen, Wen-Pin Tsai, Chang-Fu Kuo, Chung-Han Yang, I-Jung Chen, Kuang-Hui Yu

•MyelitisinpatientswithsystemiclupuserythematosusChung-Yuan Hsu, Wen-Chan Chiu, Tsong-Shing Yang, Ching-Lan Chou, Yu-Jih Su, Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen, Han-Ming Lai, Tien-Tsai Cheng, Chung-Jen Chen

•Outcomeoflupusnephritis–A5-yearanalysisTsong-Shing Yang, Shun-Chen Huang, Chung-Jen Chen, Chung-Yuan Hsu, Wen-Chan Chiu, Ching-Lan Chou, Fu-Mei Su, Yu-Jih Su, Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen, Han-Ming Lai, Tien-Tsai Cheng

•AssociationofhighsensitivityC-reactiveproteinwithhyperuricemiainTaiwanesepatientswithgoutMing-Han Chen, Wei-Sheng Chen, Hui-Ting Lee, Chang-Youh Tsai, Chung-Tei Chou

•Angiopoietin-1andendoglinarenotassociatedwithpulmonaryarterialhypertensioninpatientswithsystemiclupuserythematousLing-Jung Yen, Hsiu-Man Keng, Chin-Chang Cheng, Jiung-Jun Chu, Chieh-Mei Hsu, Xin-Tian Lin, Jui-Cheng Tseng, Jui-Chieh Hu, Ling-Ying Lu

•Metabolicsyndromeinpatientswithrheumatoidarthritis:associationoflifestylewithanthropometricmeasurementsMing-Fu Chen, Yi-Ming Chen, Der-Yuan Chen, Joung-Liang Lan

•RupturedBaker’scystinpatientswithrheumaticdiseases:analysisof235Baker'scystsin198patientsSong-Feng Yeh, Deh-Ming Chang, Jenn-Haung Lai, Chen-Hung Chen, Tsung-Yun Hou, San-Yuan Kuo, Chi-Sheng Chiou, Chi-Ching Chang

•Clinicalandserologicalfeaturesofpatientswithanti-Jo-1antibodiesTing-Hui Chang, Song-Chou Hsieh, Chia-Li Yu

Formosan Journal of Rheumatology(formerly Journal of Rheumatology, R.O.C.)

Contents

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78

Case Reports•SonographicfindingsofWeberChristiandiseaseinvolvingthebreasts:acasereport

Kuang-Yung Huang, Yi-Ming Chen, Der-Yuan Chen, Hsin-Hua Chen

•Refractorychylothoraxinapatientwithsystemiclupuserythematosus:casereportBao-Bao Hsu, Chien-Hsueh Tung, Ming-Chi Lu, Kuang-Yung Huang, Ning-Sheng Lai

•Multicentricreticulohistiocytosismimickingrheumatoidarthritisina35-year-oldwoman–casereportChyou-Shen Lee, Mei-Eng Tu, Tien-Ling Chen

Clinical Image

•“Hide-bound”bowelsigninapatientwithprogressivesystemicsclerosisandchronicintestinalpseudo-obstructionPei-Chen Hsu

Cover Image: Chyou-Shen Lee

Multicentricreticulohistiocytosis.Skinsigns:shinypink1-2mmpapulesarrangedingroupsontheauricleofears(A)andnailfoldmargin(B).Histopathology:diffuseanddenseinfiltratecomprisinglargemultinucleatedmacrophages(C),andhistoimmunostainspositiveforCD68(D).

Contents

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92

97

第 24 卷 第 1 & 2 期 民國 99年 1 2 月

原 著

• 反覆性經體外受精及胚胎植入後著床失敗之女性血清中之干擾素-γ較高 1洪維廷 陳一銘 陳明哲 陳得源 藍忠亮 陳信華

• 台灣僵直性脊椎炎病人第一型和第二型主要組織抗原對偶基因相關性之探討 8許寶寶 呂明錡 楊國樑 黃光永 童建學 劉素勤 賴寧生

• 結核性脊椎炎回溯性的分析 14 邱俊凱 蘇昱日 賴漢明 陳忠仁 鄭添財

• 抗磷脂抗體是否為紅斑性狼瘡腎炎的預後因子 22邱文燦 黃純真 陳忠仁 許鐘元 楊聰信 周靜蘭 蘇富美 蘇昱日 尤珊富 邱俊凱陳英州 賴漢明 鄭添財

• 多發性肌炎與皮肌炎病患之存活及預後因子分析 29張筱桾 吳詹永嬌 羅淑芬 何輝煌 劉烈邦 陳基益 蔡文彬 郭昶甫 楊宗翰 陳逸戎 余光輝

• 全身性紅斑性狼瘡病人之脊髓炎 36許鐘元 邱文燦 楊聰信 周靜蘭 蘇昱日 尤珊富 邱俊凱 陳英州 賴漢明 鄭添財 陳忠仁

• 紅斑性狼瘡腎炎的預後-五年分析報告 44楊聰信 黃純真 陳忠仁 許鐘元 邱文燦 周靜蘭 蘇富美 蘇昱日 尤珊富 邱俊凱陳英州 賴漢明 鄭添財

• 探討台灣痛風病人的高尿酸血症與高敏感性C-反應蛋白的關係 50陳明翰 陳瑋昇 李惠婷 蔡長佑 周昌德

• Angiopoietin-1, Endoglin與紅斑性狼瘡肺高壓的相關性研究 56顏伶容 耿秀曼 鄭錦昌 曲敬正 林新田 許介眉 曾瑞成 胡瑞潔 呂聆音

• 類風濕性關節炎病人的代謝症候群與生活習慣及體位測量相關性之研究 64陳銘夫 陳一銘 陳得源 藍忠亮

• 貝克氏囊腫破裂於風濕性疾病患者：分析198位病人發現235個貝克氏囊腫 72葉松峰 張德明 賴振宏 陳政宏 侯宗昀 郭三元 邱啟勝 張棋楨

• Jo-1抗體陽性病人之臨床特徵及血清學表現 78張婷惠 謝松洲 余家利

病例報告

• 韋伯-克里斯欽疾病侵犯乳房之超音波發現：病例報告 84黃光永 陳一銘 陳得源 陳信華

• 紅斑性狼瘡併發頑固性乳糜胸－一病例報告 88許寶寶 童建學 呂明錡 黃光永 賴寧生

• 類似類風濕性關節炎之多中心性網狀組織細胞增多症-病例報告 92李修身 涂玫音 陳天令

臨床影像

• 硬皮症病人併發假性腸阻塞 97徐北辰

中華民國風濕病雜誌

目　錄

Original Article

�

Formosan Journal of Rheumatology 20�0;24:�-7

Increased serum IFN-γ in women with a history of repeated implantation failures after in vitro fertilization and embryo transfer Wei-Ting Hung1, Yi-Ming Chen1,2, Ming-Jer Chen2,3, Der-Yuan Chen1,2,4, Joung-Liang Lan1,2,4,

Hsin-Hua Chen1,2

1Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.2School of Medicine, National Yang-Ming University, Taipei, Taiwan3Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan4Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan

Objective: Tocompareserumcytokines,includinginterferon-γ(IFN-γ),tumornecrosisfactor-α(TNF-α),interleukin-4(IL-4)andIL-10,betweennon-pregnantwomenwithrepeatedimplantationfailures(RIFs)afterinvitrofertilizationandembryotransfer(IVF-ET)cyclesandthosewithnormalfertilityduringlatefollicularphase.Methods:SerumlevelsofIFN-γ,TNF-α,IL-4andIL-10in24womenwithRIFand40womenwithnormalfertilityweremeasuredusingLuminex-basedcytokineassays.Results: AsignificantlyhigherserumlevelofIFN-γwasobservedinwomenwithRIF(median=38.50pg/mL,interquartile[IQ]range2.44-86.73pg/mL)thanincontrols(median=2.44pg/mL,IQrange2.44-47.01pg/mL,p<0.05).AsignificantlyhigherIFN-γ/IL-4ratiowasobservedinwomenwithRIF(median=7.7,IQrange1.0-21.1)thanincontrols(median=2.9,IQrange1.0-8.4,p<0.05).Conclusion:AsignificantlyhigherserumIFN-γandIFN-γ/IL-4ratioinwomenwithRIFafterIVF-ETcyclesmightsuggestskewedTh1immunestatuswaspossiblyassociatedwiththepathogenesisofimplantationfailures.

Key words:Serumcytokines,repeatedimplantationfailure,invitrofertilization

Introduction

Human invitro fertilization (IVF)andembryotransfer(ET)areaccompaniedbyalowimplantationrateevenafteraverysuccessfulIVF,andthereareacertainnumberofidiopathicsterilitieswhicharedueto

repeatedimplantationfailures.Thisfailuremaybeduetoeitheradefectinimplantation,asnohumanchorionicgonadotrophin(hCG)productioniseverdetected,andtherecanbeoccultpregnancylossoccurringafteratransientdetectionofhCGproductionfollowinganimmediatedropinhormonelevelswhichisevidenceofearlypregnancyloss.Earlypregnancylossesarelikelytodifferfromaconstitutiveabortion,andevenrecurrentimmediatepostimplantationfailuresarelikelytodifferfromrecurrentspontaneousabortion.

Theactionsofcytokineareassociatedwithmostprocesses in thebody, including immune functionand implantation[1].Amongtheirmajor regulatoryfunctions,cytokinesparticipate indifferentiationofnaiveT-helpercellsintoT-helpertype(Th)-1cells,or

CorrespondingAuthor:Hsin-HuaChen,M.D.DivisionofAllergy,ImmunologyandRheumatology,DepartmentofInternalMedicine,TaichungVeteransGeneralHospital.No160,Sec3,Taichung-KangRoad,TaichungCity,40705,Taiwan.Tel:+886-4-23592525ext3354,Fax:+886-4-23503285E-mail:shc5555@hotmail.comReceived: March 31, 2009Revised: June 20, 2009Accepted: July 17, 2010

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Cytokines in recurrent implantation failure

Th-2cells.ThecytokineproductsofTh-1andTh-2cellstendtobemutuallyinhibitory.Inhumans,Th-1cellssynthesizemainlyinterleukin-2(IL-2),tumornecrosisfactor-α(TNF-α)and interferon-γ (IFN-γ),whereasTh-2cellsproduceIL-4,IL-5,IL-6andIL-10[2].Th-1cytokinesareconsideredtobedetrimentaltopregnancy,viadirect embryotoxic activity, orviadamage toplacentaltrophoblasts,orpossiblybyactivatingcellsthataredeleterious to theconceptus,whereasTh-2cytokinesmaydirectlyorindirectlycontributetothesuccessofpregnancybydownregulatingpotentialTh-1reactivity[3,4].MurineandhumanstudieshavesuggestedashifttowardTh2insuccessfulpregnancies,althoughhumanstudieshavebeenlessconclusive[5-15].Localproductionofcytokinesbyuterineandplacentalcellsareconsideredtoinfluenceembryoimplantation,decidualization,andplacentation[16,17].EvaluationofdifferentcytokineconcentrationsinmaternalserumprovedthatIFN-γpositivepatientshadadoubleriskofapoor IVFpregnancyandasignificantly lowerimplantation rateoutcomecomparedsubjectswithnegativeIFN-γ.[18].AnotherstudyshowedpatientswithrecurrentmiscarriagehadhigherlevelofIL-2andIFN-γthancontrolgroup.TheproductionofIL-10byphytohemagglutininstimulatedmononuclearcellsofhealthcontrolwashigher thanrecurrentmiscarriagewomen[19].Comparedwithnon-pregnantwomen,recurrentmiscarriage patients hadhigherTNF-αproducingCD3+/CD4+T-cellcountsandlowerIL-10producingCD3+/CD8+T-cellcounts [20].Anotherstudy also found that bothwomenwith recurrentmiscarriageandwomenwithrecurrent implantationfailure(RIF)afterIVFhadsignificantlyhigherratiosofTNF-α/IL-4andTNF-α/IL-10-producingThelperlymphocytesinperipheralbloodbeforepregnancyorIVFtreatmentcomparedwithmultiparouswomen[21].However,whetherthereisanydifferenceinserumTh1andTh2cytokinesandtheirratiosbetweennon-pregnantwomenwithRIFafter IVFand thosewithnormalfertilityisstillnotknown.Thepurposeofthisstudywastocompareserumcytokines,includingIFN-γ,TNF-α,IL-4andIL-10,betweennon-pregnantwomenwithrepeatedimplantationfailuresafterIVF-ETcyclesandthosewithnormalfertilityduringlatefollicularphasebyusingLuminex-basedcytokineassays.

Patients and Methods

PatientsThe studydesignwasaprospectivecontrolled

study.ThisstudyprotocolwasapprovedbytheEthicsCommitteeforClinicalResearchatTaichungVeteransGeneralHospital,andinformedconsentwasobtainedfromeachparticipant.StudygroupswerewomenwithahistoryofRIFafterIVF-ETcycleswhovisitedtheoutpatientdepartmentofgynecologyatTaichungVeteransGeneralHospitalandwereinvestigatedbyagynecologist(M-JChen).Theirhistorywasreviewedandexaminationswereperformedwhich includedphysical examinations, ultrasonography, hysterosalpingography (HSG)andblood testsof follicle-stimulatinghormone(FSH),luteinizinghormone(LH),freethyroxine(freeT4),thyroidstimulatinghormone(TSH),prolactin,antinuclearantibodies,anticardiolipinantibodies,lupusanticoagulant,antithyroglobulinandantimicrosomalantibodies.Controlswerevolunteers.Allcontrolswereinterviewedbyarheumatologist(H-HChen),duringwhichtimepersonalandfamilyhistorieswereascertained.Participantsinthestudygroupandthecontrolgroupwereenrolledconsecutivelyiftheymettheinclusioncriteria.Peripheralbloodwasobtainedbetweenday8andday13duringthemenstrualcycle.

Forthestudygroup(RIFgroup),theinclusioncriteriawere:(1)primaryinfertility;(2)agedbetween25-45yearsold,withoutactivediseaseincludingautoimmunediseaseandnotonanymedication;(3)withoutahistoryofultrasounddetectableembryosinuterus;(4)womenwithahistoryoftwoormoreimplantationfailures(hCGnegativeorchemicalpregnancy)undergoingIVF-ETcycles,withoneormoremorphologicallygoodqualityembryotransferredpereachIVFcycle,excludingdonoroocytecycles;(5)noapparentcauseforIVFfailurecouldbedocumented; (6)at least twomonthsafterlastfailedIVF-ETcycle;(7)nomalefactorinfertility;(8)uterineanatomicalabnormalities;(9) tubalfactorinfertility;(10)endometriosis;(11)noabnormalthyroidfunctionorprolactinlevel;(12)regularmenstruation;(13)nohistoryofanypositive test forantinuclearantibody,antithyroglobulin,antimicrosomalantibodies,lupusanticoagulantoranticardiolipinantibodies;(14)noactiveinfectionorahistoryofmalignancy.

Forthecontrolgroup,theinclusioncriteriawere:(1)notpregnant; (2)agedbetween25-45yearsold;(3)normalfertilehealthywomenwithahistoryofoneormorenormaldeliveries;(4)nohistoryofinfertility,complicatedpregnanciesorspontaneousabortions;(5)atleasttwomonthsafterlastdelivery;(6)regularmenstruation;(7)nohistoryofendometriosis,abnormalthyroidfunction,abnormalprolactinlevel;(8)nohistoryofimmunedisorder;(9)noactiveinfectionorhistoryofmalignancy.

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Hung et al

Cytokine MeasurementsFourcytokines, IFN-γ,TNF-α, IL-4and IL-10

weremeasuredusingtheProcarta4-plexcytokinekit(Panomics/Affymetrix,CA,USA).Medianfluorescenceintensity,calculatedfromduplicatesforeachsample,wascollectedusingtheLuminex-100systemversion2.3(Luminex).TheLuminex-100instrument,incorporatingafive-parameterlogisticcurve-fittingmethod,wasusedtocalculatesamplecytokineconcentrations.Mostoftheserumshowedasignificantsignal-to-noiseratioattheminimumstandardconcentration(2.44pg/mL)specifiedbythemanufacturer’sinstructions.Weconsidered2.44pg/mLtobethelowerlimitofdetection(LOD).

Statistical methodsWhenthecytokineorhormonewasundetectable,we

usedLODtostandforitsvalue.Resultsarepresentedas themedian(interquartile range)unlessspecifiedotherwise.TheMann-WhitneyU testwasused tocomparevariablesbetweengroups.However,ifcytokinemeasurements in less than50%of samplesweredetectable,wedidn’tcomparethelevelofcytokinesbetweengroups.Thedifferences in thedetectableratesofcytokinesbetweenthestudygroupandcontrolgroupwereexaminedusing thechi-squaredmethodandFisher'sexact tests.ThecorrelationcoefficientwasobtainedbythenonparametricSpearman'srankcorrelation test.Aprobabilityof less than0.05wasconsideredsignificant.StatisticalcalculationswereperformedusingtheStatisticalPackagefortheSocialSciences(SPSS),WindowsVersion13.0(SPSSInc.,Chicago,IL,USA).

Results

Demographic data and clinical characteristics for women with RIF and controls

Twenty-fourwomenwereenrolledintheRIFgroupand40womenwereenrolledinthecontrolgroup.Thedemographicdata,numberofpreviousfailedIVF-ETcyclesanddayofthemenstrualcycleonwhichbloodwasobtainedaresummarizedinTable1.Therewerenosignificantdifferencesinageanddayofmenstrualcyclebetweengroups.

Measurements of serum cytokinesThedataofserumIFN-γ,TNF-α,IL-4andIL-10

aresummarizedinTable1.Ofthefourcytokines,onlyIFN-γhadadetectablerateover50%.ThedetectablerateofINF-γinwomenwithRIFwashigherbutthe

differencewasnotsignificant.

Comparisons of serum cytokines between women with RIF and controls

AsshowninTable2,thedetectableratesofserumTNF-α, IL-4andIL-10werefar less than50%, thedifferencesof thesecytokine levelsbetweengroupscouldnotbeestimated.AsshowninFig.1,thelevelofserumIFN-γinwomenwithRIFwassignificantlyhigherthanincontrols(median=38.50pg/mL,interquartile(IQ)range2.44-86.73pg/mLVS.median=2.44pg/mL,IQrange2.44-47.01pg/mL,p<0.05).

Comparisons of Th1/Th2 cytokine ratios (IFN-γ/IL-4 and IFN-γ/IL-10) between women with RIF and controls

AsshowninTable3,theIFN-γ/IL-4ratioinwomenwithRIFwas significantlyhigher than incontrols(median=7.7,IQrange1.0-21.1VS.median=2.9,IQ range1.0-8.4,p<0.05).However, therewasnosignificantdifferenceintheratioofIFN-γ/IL-10betweenwomenwithRIFandcontrols(median=11.2,IQrange1.0-25.7VS.median=2.9,IQrange1.0-19.3,p=0.072).

The association between the number of IVF and serum levels of cytokine

Wealso analyzed the associationbetween thenumberofIVFinrecurrentmiscarriagewomenandtheserumlevelsofdifferentcytokine.AsshowninFig.2,thewasnoassociationbetweenthenumberIVFreceivedinrecurrentmiscarriagewomenandserumlevelsofcytokine,includingINF-γ,TNF-α,IL-4andIL-10.

Discussion

Toourknowledge,thisstudyisthefirsttoinvestigateserumIFN-γ,TNF-α,IL-4andIL-10byusingLuminex-

Table 1. Demographic data, clinical characteristics in women with normal fertility and those with repeated implantation failures (RIF) after in vitro fertilization and embryo transfer (IVF-ET) cyclesa

Control(n = 40)

RIF(n = 24)

Total(n = 64)

Age (years) �5.0 (��.0-40.8)

��.0 (�4.0-�9.8)

�6.0 (�2.0-40.0)

No of IVF-ET cycles 0 2.5 (2.0-8.0)

-

Day of the menstrual cycle

�0.5 (9.0-�2.0)

9.5 (8.0-��.8)

�0.0 (8.0-�2.0)

aValues are median (interquartile range).

4

Cytokines in recurrent implantation failure

basedcytokineassays innon-pregnantwomenwithRIFafter IVF-ETcyclesandnormalfertilewomen.UnderstandingcytokinespriortopregnancymayhelptoelucidatewhetheranimmunedisorderispresentinwomenwithunexplainedRIFafterIVF-ETandthusattempttotreatthembeforeIVFcycles.WeobservedahigherserumIFN-γlevelandahigherserumIFN-γ/IL-4ratioinwomenwithRIFafterIVF-ETwithoutahistoryofspontaneousabortioncomparedwithcontrols.Differentfromourmethod,Kwak-Kimetal.usedflowcytometrytomeasuretheproportionofTh1andTh2cytokineproducing lymphocytesand their ratios inwomenwithrecurrentmiscarriageandwomenwithmultiple implantationfailuresafterIVFcycles[21].TheyfoundthatTNF-αproducingCD3+/CD8–cells,

andTh1/Th2ratiosofTNF-α/IL-4andTNF-α/IL-10ratioinCD3+/CD8–cellsweresignificantlyhigherinwomenwithmultipleIVFfailureswithoutahistoryofspontaneousabortioncomparedwithcontrols.TheyconcludedthattheprevalenceofdominantTh1immuneresponsesinperipheralbloodlymphocytesmayreflectthesystemiccontributionofTh1cytokinestorecurrentspontaneousabortionormultipleimplantationfailuresinIVFcycles.OurdatamightfurthersupportthenatureofskewedserumTh1cytokinesecretionalthoughthelowdetectableserumTNF-α.Fasoulioticsetal.measuredserialmaternalserumIL-2solublereceptor-α(IL-2sRα),TNF-αandIFN-γafterIVFusingcommerciallyavailableenzyme-linkedimmunosorbentassay(ELISA)kitsandfoundthatelevatedmaternalserumlevelsofIL-2sRa

Table 2. Laboratory findings in women with normal fertility and those with repeated implantation failures (RIF) after in vitro fertilization and embryo transfer (IVF-ET) cyclesa

Control (n = 40) RIF (n = 24) Total (n = 64)IFN-γ detected (%) 20 (50.0%) 17 (70.8%) 37 (57.8%)IFN-γ level (pg/mL) 2.44 (2.44-47.0�) �8.50 (2.44-86.7�)c ��.56 (2.44-58.�5)TNF-α detected (%) 1 (2.5%) 4 (16.7%) 5 (7.8%)TNF-α level (pg/mL)b �.09 (2.44-28.42) 7.7� (2.44-50.40) 4.8� (2.44-50.40)IL-4 detected (%) 5 (12.5%) 5 (20.8%) 10 (15.6%)IL-4 level (pg/mL)b 4.4� (2.44-�8.25) ��.55 (2.44-7�.00) 7.�0 (2.44-7�.00)IL-10 detected (%) 1 (2.5%) 4 (16.7%) 5 (7.8%)IL-10 level (pg/mL)b 2.45 (2.44-2.95) 4.74 (2.44-29.24) �.�� (2.44-29.24)

aValues are median (interquartile range) unless designated otherwise.bValues are mean (range).cp<0.05 compared with control

Figure 1. The levels of serum cytokine in recurrent miscarriage patients (RM) and health controls (HC).

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Hung et al

andIFN-γasearlyas11daysafterembryotransferwereassociatedwithpoorIVFpregnancyoutcomes[18].ThestrengthsofLuminex-basedcytokineassaysusedinourstudyarelowsamplevolumerequirements,lowassaycostperanalyte,andapotentialformanyanalytespersample.Notably,cytokinesignalingoperatesinapleiotropic(eachcytokineactsonmultiplemoleculartargets)andredundant(severalcytokinesrespectivelyelicitthesamecellularresponse)fashion.Thus,bloodlevelsofmultiplecytokinescollectivelymayreflectsubtlestatesof immunedysfunctionand/or immunerelateddisease.However,whenwemeasuredcytokinelevelsinasymptomaticsubjects,itispossiblethatmanysampleswillhaveundetectablecytokinelevels,justlikethedatainourstudy.Inourstudy,exceptforIFN-γ,mostserumsamplesdidnothavedetectableforaTNF-α,IL-4andIL-10forasignificantsignal-to-noiseratioattheminimumstandardconcentration(2.44pg/mL)specifiedbythemanufacturer’sinstructions.

Thisstudyhasseverallimitations.First,smallsamplemaylimititsapplication.Second,cross-sectionalstudydesigndidnotprovideachancetoevaluatewhetherdifferenttimingofserumcollectiondidinfluenceserum

cytokinelevel.Inconclusion,our results furtherstrengthen the

currentlyexistingnotionthatsuggeststhatunexplainedimplantationfailuremightbeassociatedwithanincreaseinTh-1cytokines.However,thisstudydoesnotaddressadirectcauseandeffectrelationshipbetweenmaternalTh-1 type reactivityand implantation failure.Thebiologicalsignificanceof the increasedpre-existingserumIFN-γlevelandIFN-γ/IL-4ratioinwomenwithRIFafterIVF-ETremainstobeevaluatedwithlargerprospectivestudies.

Acknowledgements

ThisworkwasfoundedbyagrantformTaichungVeteransGeneralHospital(TCVGH-973801A).

WethanktheBiostatisticsTaskForceofTaichungVeteransGeneralHospital,Taichung,Taiwan,ROC,forassistancewithstatisticalanalysis.

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5.LimKJ,OdukoyaOA,AjjanRA,LiTC,WeetmanAP,CookeID.TheroleofT-helpercytokinesinhumanreproduction.FertilSteril2000;73:136-42.

6.WegmannTG.Foetalprotectionagainst abortion: is itimmunosuppressionorimmunostimulation?AnnImmunol(Paris)1984;135D:309-12.

7.FiorentinoDF,BondMW,MosmannTR.Two typesofmouseThelpercell. IV.Th2clonessecreteafactor thatinhibitscytokineproductionbyTh1clones. JExpMed1989;170:2081-95.

8.WegmannTG,LinH,GuilbertL,MosmannTR.Bidirectionalcytokineinteractionsinthematernal-fetalrelationship: issuccessfulpregnancyaTH2phenomenon?ImmunolToday1993;14:353-6.

9.Yui J,Garcia-LloretM,WegmannTG,Guilbert LJ.

Figure 2. The association between IVF-ET cycle numbers and serum cytokine levels in recurrent mischarge patients. rho = Spearman’s rank correlation coefficients; p = significant levels.

Table 3. Cytokine ratio in women with normal fertility and those with repeated implantation failures (RIF) after in vitro fertilization and embryo transfer (IVF-ET) cyclesa

Control(n = 40)

RIF(n = 24)

Total(n = 64)

IFN-γ/IL-4 (ratio)

2.9 (�.0-8.4)

7.7 (�.0-2�.�)b

4.7 (�.0-�0.4)

IFN-γ/IL-10 (ratio)

2.9 (�.0-�9.�)

��.2 (�.0-25.7)

4.7 (�.0-2�.�)

aValues are median (interquartile range).bp<0.05 compared with control

6

Cytokines in recurrent implantation failure

Cytotoxicityoftumournecrosisfactor-alphaandgamma-interferonagainstprimaryhumanplacental trophoblasts.Placenta1994;15:819-35.

10.LinH,MosmannTR,GuilbertL,TuntipopipatS,WegmannTG.SynthesisofThelper2-typecytokinesatthematernal–fetalinterface.JImmunol1993;151:4562-73.

11.RaghupathyR,MakhseedM,AziziehF,OmuA,GuptaM,FarhatR.Cytokineproductionbymaternal lymphocytesduringnormalhumanpregnancyandinunexplainedrecurrentspontaneousabortion.HumReprod2000;15:713-8.

12.PiccinniMP,BeloniL,LiviC,MaggiE,ScarselliG,RomagnaniS.Defective productionof both leukemiainhibitoryfactorandtype2T-helpercytokinesbydecidualT cells in unexplained recurrent abortions.NatMed1998;4:1020-4.

13.Hill JA,ChoiBC.Maternal immunological aspectsofpregnancy success and failure. JReprodFertil Suppl2000;55:91-7.

14.WilczynskiJR.Th1/Th2cytokinesbalance–yinandyangofreproductiveimmunology.EurJObstetGynecolReprodBiol2005;122:136-43.

15.ChaouatG,Ledee-BatailleN,DubanchetS,ZourbasS,SandraO,MartalJ.TH1/TH2paradigminpregnancy:paradigmlost?Cytokinesinpregnancy/earlyabortion:reexaminingtheTH1/TH2paradigm.IntArchAllergyImmunol2004;134:93-119.

16.DimitriadisE,WhiteCA, JonesRL,SalamonsenLA.Cytokines,chemokinesandgrowthfactorsinendometrium

relatedtoimplantation.HumnReprodUpdate2005;11:613-30.17.SaitoS.Cytokinenetworkatthefeto-maternalinterface.J

ReprodImmunol2000;47:87-103.18.FasouliotisSJ,SpandorferSD,WitkinSS,Schattman,Liu

HC,RobertsJE,RosenwaksZ: .Maternalserumlevelsofinterferon-cand interleukin-2soluble receptor-apredicttheoutcomeofearlyIVFpregnancies.HumReprod2004;19:1356-7.

19.HosseinH,MahrooM,AbbasA,etal.Cytokineproductionbyperipheralbloodmononuclearcellsinrecurrentmiscarriage.Cytokine2004;28:83-6.

20.NgSC,GILMANGilman-SACHSSachsA,THAKERThakerP,.ExpressionofIntracellularintracellularTh1andTh2CytokinescytokinesinWomenwomenwithRecurrentrecurrentSpontaneous spontaneousAbortionabortion,ImplantationimplantationFailuresfailuresafterIVF/ETorNormalnormalPregnancypregnancy.AmericanJournalofReproductiveImmunology2002;48:77-86.

21.Kwak-KimJY,ChungBangHS,NgSC,etal.IncreasedThelper1cytokineresponsesbycirculatingTcellsarepresentinwomenwithrecurrentpregnancylossesandininfertilewithmultipleimplantationfailuresafterIVF.HumanReproduction2003;18:767-73.

22.WongHL,PfeifferRM,FearsTR,VermeulenR,JiS,RabkinCS.Reproducibilityandcorrelationsofmultiplexcytokinelevelsinasymptomaticpersons.CancerEpidemiolBiomarkersPrev.2008;17:3450-6.

7

Hung et al

反覆性經體外受精及胚胎植入後著床失敗之女性血清中之干

擾素-γ較高

洪維廷� 陳一銘�,2 陳明哲2,� 陳得源�,2,4 藍忠亮�,2,4 陳信華�,2

�台中榮民總醫院 過敏免疫風濕科

2國立陽明大學

�台中榮民總醫院 婦產部

4國立中興大學 醫學科技研究所

目的：本研究的目的是探討在反覆性經體外受精及胚胎植入後著床失敗女性與正常生育女性血清細

胞激素濃度，包括干擾素-γ，腫瘤壞死因子-α，介白質-4及介白質-10。方法：24位反覆性體外受精

著床失敗女性及40位正常生育女性，以Luminex-basedcytokineassays測定血清干擾素-γ，腫瘤壞死

因子-α，介白質-4及IL-10濃度。結果：24位反覆性體外受精著床失敗女性干擾素-γ血清濃度比40位

正常生育女性高 (中位數38.50pg/mL，四分位距2.44-86.73pg/mLvs.中位數2.44pg/mL，四分位距

2.44-47.01pg/mL，p<0.05)。反覆性體外受精著床失敗女性干擾素-γ/介白質-4比值比正常生育女性

高 (中位數7.7，四分位距1.0-21.1vs.中位數2.9，四分位距1.0-8.4，p<0.05)。結論：反覆性經體外

受精及胚胎植入後著床失敗女性之血清干擾素-γ濃度及干擾素-γ/介白質-4比值比正常生育女性高，

顯示胚胎著床失敗的病理機轉可能與偏向Th1免疫狀態相關。

關鍵詞：細胞激素、反覆著床失敗、體外受精

Original Article

8

Introduction

The close relationship between ankylosingspondylitis(AS)andHLA-B27antigenisuniversallyrecognized [1,2],but thenatureof thisassociationremainsasubjectofdebate.AlthoughB27allelecarriedahighriskofAS,mostB27-positive individualsdonothavespondylitis.GenesotherthanB27hadbeenaddressedindiseasepathogenesisofASincludingthe

Distinct MHC class I and class II alleles in Taiwanese patients with ankylosing spondylitis Bao-Bao Hsu1, Ming-Chi Lu1, Kuo-Liang Yang2, Kuang-Yung Huang1, Chien-Hsueh Tung1,

Su-Qin Liu1, Ning-Sheng Lai1,3

1Department of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Buddhist Hospital, Chiayi, Taiwan2Buddhist Tzu Chi Stem Cells Center, Hualien, Taiwan3School of Medicine, Tzu Chi University, Hualien, Taiwan

Correspondingauthor:LaiNing-Sheng,M.D.,Ph.D.SectionofAllergy,ImmunologyandRheumatology,DepartmentofMedicine,DalinTzuChiBuddhistHospital.No2,Ming-ShenRoad,DalinTown,CityofChiaYi,Taiwan.Tel:+886-5-2648000ext5010,Fax:+886-5-2648555E-mail:nslai@airpa.org.twReceived: December 15, 2009Revised: March 25, 2010Accepted: April 14, 2010

Objective:OurpurposewastoinvestigatewhetherMHCclassIandclassIIantigens,otherthanB27,wereassociatedwithTaiwanesepatientswithankylosingspondylitis(AS).Methods:HLAclassIandclassIIantigenswereanalyzedinB27positiveASpatients(n=130)andB27positivehealthycontrols(n=260)usingtheSSP-DNAtypingmethod.Thechi-squaretestorFisher'sexacttestwasusedtoanalyzeOddsratio.Results:AllelefrequenciesofCw12(93.85%),Cw7(20.0%)andCw8(9.23%)werefoundtobesignificantlyincreasedinASpatientsascomparedtoB27positivecontrols(OR89.09,p<0.0001;OR6.25,p<0.0001;OR13.12,p<0.0001,respectively),inwhichCw3(80.0%)wassignificantlyincreased(OR0.12,p<0.0001).AllelefrequenciesofB75(6.15%),B60(20.0%)andB61(4.62%)werehigherinpatients(OR8.46,p=0.003;OR2.07,p=0.0128;OR6.24,p=0.0186,respectively),soashigherfrequenciesofB13(22.31%)andB58(36.15%)incontrols(OR0.03,p<0.0001,andOR0.44,p=0.0011).A11/B27/Cw3wasthemostcommonallelesincontrols(70.0%)(OR0.11,p<0.0001),incontrasttoA11/B27/Cw12inASpatients(78.5%)(OR21.28,p<0.0001).Furthermore,A33/B58/Cw3wascommonlyfoundbothinpatientsandcontrolsgroups(20.0%and21.54%,respectively)(OR0.91,p=0.83).TheassociationexplainedthehighallelefrequenciesofA11/A33,B27/B58,Cw3/Cw3,DR12/DR13,DR17inB27(+)controls(15.38%)(p<0.0001)andA11/A33,B27/B58,Cw3/Cw12,DR12/DR13,DR17inASpatients(15.4%)(p<0.0001).ThepowerofassociationbetweenASandHLA-DR15andDQ2werefoundtobelow,althoughsignificant(p=0.0411andp=0.0467,respectively).Conclusions:AllelesofA11/B27/Cw12wascloselyassociatedwithHLA-B27-positiveASpatients,soasA11/B27/Cw3inB27-positivecontrols.OurfindingsarecompatiblewiththehypothesisthatallelesofMHCotherthanB27mayconferfurtherrisktosusceptibilityofAS.

Key words:MHC,alleles,ankylosingspondylitis

Formosan Journal of Rheumatology 20�0;24:8-��

9

Hsu et al

majorhistocompatibilitycomplex(MHC),complementcomponentsC2,C4,factorBalleles[3,4],HLA-B27subtypes,genes involved inantigenprocessingandtransport(TAP),andclassIcloselyrelatedgenessuchasthoseencodingMICAandTNF-α.Whetherornotthesegenesdirectlydeterminespathogenicityremainscontentious[5].DistinctMHCclassIandIIantigensinAShadbeenpreviouslyreportedinseveralpopulations[6,7]. In thisbriefstudy,class Iandclass IIMHCantigensweredeterminedinB27-positiveTaiwaneseASpatientsandcontrols.TheseenableustorecognizetheimportanceofmajorhistocompatibilitycomplexgenesinthedevelopmentofAS,independentofB27antigen.

Subjects and methods

Patient and controlsHLA-B27antigenwasthemostimportantmolecule

indiseaseprocessofAS.ToevaluatetheroleofMHCclassIandclassIIantigensindiseasepathogenesisofAS, independentofB27,onlyHLA-B27(+)patients(n=130)andcontrols(n=260)wereincludedinthestudy.AllpatientsfulfilledtheNewYorkcriteriafordefiniteAS[8].HLA-B27(+)normalcontrolswerefromTzuChiTaiwanMarrowDonorregistry(TCTMDR)[9].DonorsregistryatTCTMDRwerebonemarrowdonorvolunteersfromahealthypopulation.Patientswithinflammatorylowbackpain,restrictionofspinalmotionandfamilyhistoryofspondyloarthropathywereexcludedfromcontrolsbytelephoneinquiry.ThestudywasapprovedandregulatedbylocalIRBofDalinTzuChiGeneralHospital(A09601002).

DNA tissue typing of HLA-A, B, C, DR and DQ

HLAtissueantigensweredeterminedbytheSSP-DNAtypingtechnique(DynalALLSetandCombiSet™SSPKits;Dynal,Carlsbad,CA).Briefly,DNAwasobtainedfromnon-heparinizedperipheralbloodcellsusingtheQIAampDNAextractionkit(Qiagen,Valencia,CA).BecausehighpurityDNAwasimportant,anopticaldensity260:280ratiowasrequiredtobewithintherangeof1.6to1.8.Thepolymerasechainreaction(PCR)wascarriedoutinPCRcapscontaininggenomicDNA(at50ng/μL),AmpIITaqDNApolymerase(at5IU/μL)withspecificprimersandreactionagents.VolumesrequireddependedonthenumbersofPCRreactions(Dynal).PCRreactionswereperformedinaPerkin-ElmerGeneAmpPCRsystem9700withthefollowingprotocol:initialdenaturationat96°Cfor120seconds,

followedby10cyclesof96°Cfor15seconds,65°Cfor60seconds,20cyclesof96°Cfor10seconds,61°Cfor50secondsand72℃for30seconds,endingwith4°C.Reactionproductswereanalyzedona2%agarosegel.

Statistical analysisStatisticalanalysiswasperformedwithSASsoftware

(Version9.1.3,SASInstituteInc.,Cary,NC,U.S.A.).Thechi-squaretestorFisher'sexacttestwasusedtoanalyzecategoricalproportionsandoddsratio.Pvalue<0.05wasconsideredstatisticallysignificant.

Results

Atotalof130B27-positiveASpatientsand260B27(+)control (fromTCTMDR)wereenrolled forevaluationofbothclassI(Table1)andclassIIMHCallelesfrequencies(Table2).Thedistributionofsexandagebetweengroupswereappropriate(datanotshown).AllelefrequencyofA26,ararealleleinTaiwanese,wassignificantlyhigherinpatientgroup(7.7%vs.1.5%,OR=5.33with95%CI=1.49-23.66,p=0.0035).AllelefrequenciesofB13(0.77%vs.22.31%,OR=0.03with95%CI=0.00-0.16),B58(20.00%vs.36.15%,OR=0.44with95%CI=0.27-0.73)were lower inpatientsgroup.Onthecontrary,theallelefrequenciesofHLA-B75,HLA-B60andB61werehigherinpatientsgroup(6.15%vs.0.77%,OR=8.46with95%CI=1.64-82.47inB75;20.00%vs.10.77%,OR=2.07with95%CI=1.16-3.71inB60;and4.62%vs.0.77%,OR=6.24with95%CI=1.09-63.78inB61).Thedifferencesoftheseallelesallreachstatisticalsignificance.AllelefrequencyofCw12wassignificantlyhigherintheASgroupthancontrols(93.85%vs.14.62%,OR=89.09with95%CI=40.28-197.05).TheallelesfrequenciesofCw7,Cw8,although less remarkable,werealsosignificantlyhigherinpatientgroup(20%vs.3.84%,OR=6.25with95%CI=2.91-13.42inCw7;and9.23%vs.0.77%.OR=13.12with95%CI=2.83-121.73inCw8).Incontrast,allelefrequencyofCw3wassignificantlylower inpatients(32.31%vs.80%,OR=0.12with95%CI=0.07-0.19).AllelesfrequenciesofHLA-DR15andDQ2werefoundtosignificantlyhigherinpatientsgroup,but less remarkably (p=0.041andp=0.047,respectively).

ConsideringtheequaleffectsofsisterchromosomesofHLAantigens indiseasepathogenesis, themostcommonallele frequencieswere further analyzed(Table3).TheallelefrequencyofA11/B27/Cw12inASpatientswas78.46%andwasonly14.6%incontrols.In

�0

MHC alleles in AS

contrast,allelefrequencyofA11/B27/Cw3was70.0%incontrols,butonly20%inASpatients.A33/B58/Cw3wascommonlypresentedinbothpatientsandcontrols(20.0%and21.54%,respectively).A11/A33orA11,B27/B58,Cw3/Cw3,DR12/DR13orDR17andA11/A2

orA24,B27/B13,Cw3/Cw3,DR12/DR15orDR16werethemostcommontwoallelesinB27(+)controls,whileA11/A33,B27/B58,Cw3/Cw12,DR12/DR13orDR17andA11/A11,B27/B60,Cw7/Cw12,DR12/DR4orDR8werecommonlypresentedinASpatients.

Table 2. HLA class II alleles frequencies in HLA-B27 positive AS patients and controlsAllele AS (n = ��0) Control (n = 260) OR 95% CI p valueDR4 40(�0.77) 64 (24.62) �.�6 0.85-2.�7 0.�95�DR7 4 (�.08) �0 (�.85) 0.79 0.�8-2.82 0.78�7DR8 22 (�6.92) �4 (��.08) �.�5 0.76-2.4� 0.�072DR9 24 (�8.46) 50 (�9.2�) 0.95 0.55-�.6� 0.855�DR��(5) 20 (�5.�8) �4 (��.08) �.2� 0.66-2.20 0.�869DR�2(5) 58 (44.62) �04 (40.00) �.2� 0.79-�.85 0.�8��DR��(6) 6 (4.62) 26 (�0.00) 0.44 0.�7-�.09 0.0678DR�4(6) 22 (�6.92) �6 (��.85) �.27 0.7�-2.26 0.4208DR�5 (2) �2 (9.2�) 44 (�6.92) 0.5 0.25-0.98 0.04��*DR�6(2) 6 (4.62) 24 (9.2�) 0.48 0.�9-�.�9 2.6DR�7(�) �6 (�2.�2) 48 (�8.46) 0.62 0.�4-�.�4 0.�2�9DQ2 �8 (��.85) 58 (22.��) 0.56 0.��-�.00 0.0467*DQ4 28 (2�.54) 40 (�5.�8) �.5� 0.88-2.58 0.����DQ5 �6 (27.70) 70 (26.92) �.04 0.65-�.67 0.872�DQ6 �4 (26.�5) 90 (�4.62) 0.67 0.42-�.07 0.0907DQ7 82 (6�.08) ��8 (5�.08) �.5� 0.98-2.�� 0.0605DQ8 �2 (9.2�) 26 (�0.00) 0.92 0.45-�.88 0.8092DQ9 24 (�8.46) 40 (�5.�8) �.25 0.7�-2.�7 0.4�9�

*statistically significant

Table 1. HLA class I allels frequencies in HLA-B27 positive AS patients and controlsAllele AS (n = ��0) Control (n = 260) OR 95% CI p valueA2 42 (�2.��) 96 (�6.92) 0.82 0.52-�.27 0.�689A�� ��0 (84.62) 2�8 (8�.85) �.06 0.59-�.89 0.8447A24 20 (�5.�8) 52 (20.00) 0.7� 0.4�-�.28 0.268�A26 �0 (7.69) 4 (�.54) 5.�� �.49-2�.66 0.00�5*A�� �4 (26.�5) 82 (��.54) 0.77 0.48-�.2� 0.2728B�� � (0.77) 58 (22.��) 0.0� 0.00-0.�6 <0.000�*B46 �4 (�0.77) 20 (7.69) �.45 0.7�-2.97 0.�099B5� �4 (�0.77) �4 (5.�8) 2.�2 0.98-4.59 0.0522B54(22) 2 (�.54) 6 (2.��) 0.66 0.06-�.77 0.724B55(22) 2 (�.54) �0 (�.85) 0.�9 0.04-�.88 0.�5�2B58(�7) 26 (20.00) 94 (�6.�5) 0.44 0.27-0.7� 0.00��*B60(40) 26 (20.00) 28 (�0.77) 2.07 �.�6-�.7� 0.0�28*B6�(40) 6 (4.62) 2 (0.77) 6.24 �.09-6�.78 0.0�86*B62(�5) 6 (4.62) 6 (2.��) 2.05 0.5�-7.82 0.2256B75 8 (6.�5) 2 (0.77) 8.46 �.64-82.47 0.00�*Cw� �8 (��.85) 24 (9.2�) �.58 0.82-�.0� 0.�657Cw2 4 (�.08) 22 (8.46) 0.�4 0.08-�.04 0.0522Cw4 8 (6.�5) 6 (2.��) 2.78 0.94-8.�8 0.054�Cw7 26 (20.00) �0 (�.85) 6.25 2.9�-��.42 <0.000�*Cw8 �2 (9.2�) 2 (0.77) ��.�2 2.8�-�2�.7� <0.000�*Cw�2 �22 (9�.85) �8 (�4.62) 89.09 40.28-�97.05 <0.000�*Cw� 42 (�2.��) 208 (80.00) 0.�2 0.07-0.�9 <0.000�*

*statistically significant

��

Hsu et al

Discussion

Morethan90%ofASpatientsarepositivefortheHLA-B27gene,butASonlydevelopsinfewerthan2%ofB27positiveindividuals.ThismightindicatethatB27,aspresentlydefined,isnotsufficientforthedevelopmentofAS,althoughitclearlyimpartsahighrelativerisk.Severalhypotheseshavebeenproposedtoexplaintheseobservations.Non-HLA-genefactors,includinggenesencodingTAP,MICA,TNF,errorsintheB27foldingand/orassembly,environmentalinfluencesandMHCclassIandIIantigensotherthanB27[6,7]hadallbeenreported.TheHLA-A9alleleissignificantlyincreasedinBasqueASpatients[10].ThepresenceofHLA-B40inHLA-B27positiveindividualswasshowntoincreaserisk of diseasemore than three-fold [11].HLA-DRB1*08influencedthedevelopmentofacuteanterioruveilitisinJapaneseASpatients[12],butnotinMexicanMestizoheritage[13].ArecentstudyinvolvingBritishCaucasianASpatientsreported thatHLA-DRgeneshaveaweakeffectonsusceptibilitytoAS[14].LinkagedisequilibriumanalyseshavedescribedsignificantincreasesinCw1,Cw2,DR1,andB27antigensinSpain[15],andA2,Cw2,B27,DR2,andDQ1haplotypesinanItalianpatientgroup[16].IncurrentstudyofallelefrequenciesinTaiwaneseASpatientsusingB27-positivehealthyvolunteersascontrols,wefoundahighallelefrequencyofCw12inourpatients(93.85%).A11/B27/Cw12allelewasfoundin78.46%ofpatients,while14.6%incontrols(Table3).AllelefrequencyofCw3wassignificantlyhigherincontrols(80.0%).A11/B27/Cw3wasfoundin70%controls,whileonly20.0%in

patients.AlleleofA33/B58/Cw3,onthecontrary,wascommonlypresentedinbothpatientsandcontrols(20.0%and21.54%,respectively).Thiscouldpartiallyexplainthedistinctalleles inpatientandcontrolgroups, i.e.A11/A33,B27/B58,Cw3/Cw3,DR12/DR13orDR17incontrolandA11/A33,B27/B58,Cw3/Cw12,DR12/DR13orDR17inpatients.Linkagedisequilibriumandhaplotypesanalysiswerenotperformedinthissmallcohortstudy.DatafromTCTMDR[7],however,havewelldemonstratedthatA33/B58,A11/B27,A11/B60,B58/DR17,B58/DR13,B13/DR15,B60/DR4,B60/DR8,B60/DR11,A33/B58/DR17,A33/B58/DR13,A11/B60/DR4,andA11/B60/DR8weretherathercommonhaplotypesinTaiwaneseindividuals.ItmightthereforebededucedthatallelesofA11/B27/Cw12/DR12inASpatients,A11/B27/Cw3/DR12incontrolandA33/B58/Cw3/DR13orDR17inbothgroupsmightberelatedtodistincthaplotypes(Table3).

Our studyalsoconfirmedprevious reports thatHLA-DRandDQantigensconferredminoreffectstosusceptibilityofankylosingspondylitis[14].OurdataalsoconfirmedthereportsbyRubinetal.[11]thatB60andB61antigensconferredfurtherrisktodevelopmentofASinadditiontoHLA-B27antigens(OR=2.07and6.24,respectively). IthadbeenreportedthattheB60allelewassignificantlyincreasedinB27-negativeTaiwaneseASpatients[17].

Inconclusion,wehavehereinshownthatthealleleofCw12ratherthanCw3wascloselyassociatedwithankylosingspondylitisinTaiwan.ThishypothesiswassupportedbyourobservationthathaplotypesofA11/B27/Cw12weresignificantlyassociatedwithAS,butrarelypresentedinHLA-B27positivehealthycontrols.

Table 3. The most common alleles in HLA-B27 positive Taiwanese AS patients and controlsAlleles Control

n = 260AS patients

n = ��0 OR 95%CI p value

A11/B27/Cw12 �8 (�4.6) �02 (78.5) 2�.28 �2.�8-�6.58 <0.000�A11/B27/Cw3 �82 (70.0) 26 (20.0) 0.�� 0.07-0.�8 <0.000�A33/B58/Cw3 56 (2�.5) 26 (20.0) 0.9� 0.54-�.5� 0.8�A11/A33 or A11,B27/B58, Cw3/Cw3,DR12/DR13 or DR17*

50 (�9.2) 0 (0.0) <0.000�

A11/A2 or A24,B27/B13, Cw3/Cw3,DR12/DR15 or DR16**

�4 (��.�) 0 (0.0*) <0.000�

A11/A33,B27/B58, Cw3/Cw12,DR12/DR13 or DR17

0 (0.0) 20 (�5.4) <0.000�

A11/A11,B27/B60, Cw7/Cw12,DR12/DR4 or 11 or 8

0 (0.0) �0 (7.7) <0.000�

*include allele of A11/A33, B27/B58, Cw3/Cw3, DR12/DR13 or DR17, n = 40 (15.38%) and A11/A11, B27/B58, Cw3/Cw3, DR12/DR13 or DR17, n = 10 (3.84%)

**include allele of A11/A2, B27/B13, Cw3/Cw3, DR12/DR15 or DR16, n = 14 (5.38%) and A11/A24, B27/B13, Cw3/Cw3, DR12/DR15 or DR16, n = 20 (7.69%)

�2

MHC alleles in AS

Thissuggests thepossibility thatothergeneswithintheHLAregioncouldplaysomerole inconferringsusceptibilitytoAS.

References1.BrewertonDA,CeffreyM,HartFD,JamasDCO,NichollsA,SturrockRD.AnkylosingspondylitisandHL-A27.Lancet1973;1:904-7.

2. SchlossteinL,TerasakiPI,BluestoneR,PearsonCM.HighassociationofanHLAantigen,W27,withankylosingspondylitis.NEnglJMed1973;288:704-6.

3.LachmannPJ,HobartMJ.ComplementgeneticsinrelationtoHLA.BrMedBull1978;34:247-52.

4.ArnasonA,ThorsteinssonJ,SigurbergssonK.Ankylosingspondylitis,HLA-B27andBf.Lancet1978;l:339-40.

5.WoodrowJC,EastmondCJ.HLAB27andthegeneticsofankylosingspondylitis.AnnRheumDis1978;37:504-9.

6.BrownMA,PileKD,KennedyLG,CalinA,DarkeC,BellJetal.HLAclassIassociationofankylosingspondylitisinthewhitepopulationintheUnitedKingdom.AnnRheumDis1996;55:268-70.

7.LocheadJA,ChalmersIM,MarshallWH,LarsenB,SkanesVM,PayneRHetal.HLA-B27haplotypesinfamilystudiesofankylosingspondylitis.ArthritisRheum1983;26:1011-16.

8.BennettPH,BurchTA.Theepidemiologicaldiagnosisofankylosingspondylitis.ProceedingsoftheThirdInternationalSymposiumonPopulationStudiesoftheRheumaticDiseases.NewYork,1966.PHBennett,PHNWood,eds.Amsterdam:ExcerptaMedicaFoundation,1968,pp305-13.

9.ShawCK,ChangTK,ChenSN,WuS.HLApolymorphismandprobabilityofHLA-matchedunrelatedmarrowdonorsforChineseinTaiwan.TissueAntigens1997;50:610-9.

10.DeJuanMD,RetaA,CancioJ,BelzuneguiJ,CuadradoE.HLA-A*9,aprobablesecondarysusceptibilitymarker toankylosingspondylitisinBasquepatients.TissueAntigens1999;53:161-6.

11.RubinLA,AmosCI,WadeJA,MartinJR,BaleSI,LittleAHetal.Investigatingthegeneticbasisforankylosingspondylitis.LinkagestudieswiththemajorHistocompatibilitycomplexregion.ArthritisRheum1994;37:1212-20.

12.MonowarulIslamSM,NumagaJ.FujinoY,MasudaK,OhdaH,HirataRetal.HLA-DR8andacuteanterioruveilitisinankylosingspondylitis.ArthritisRheum1995;38:547-50.

13.PloskiR,FlatoB,VinjeO,MaksymowychW,ForreO,ThorsbyE.AssociationtoHLA-DRB1*08,HLA-DPB1*0301andhomozygosityforanHLA-linkedproteasomegene injuvenileankylosingspondylitis.HumImmunol1995;44:88-96.

14.BrownMA,KennedyLG,DarkeC,GibsonK, PileKD,ShatfordJLetal.TheeffectofHLA-DRgenesonsusceptibility toandseverityofankylosingspondylitis.ArthritisRheum1998;41:460-5.

15.SanmartiR,ErcillaMG,BrancosMA,CidMC,ColladoA,Rotes-QuerolJ.HLA-classIIantigens(DR,DQloci)andperipheralarthritisinankylosingspondylitis.AnnRheumDis1987;46:497-500.

16.LaNasaG,MathieuA,MulargiaM,CarcassiC,VaccaA,LeddaAetal.AssociationoftheHLA-A2,Cw2,B27,S31,DR2haplotypewithankylosingspondylitis.Apossibleroleofnon-B27factorsinthedisease.DisMarkers1993;11:191-203.

17.WeiJC,TsaiWC,LinHS,TsaiCY,ChouCT.HLA-B60andB61arestronglyassociatedwithankylosingspondylitisinHLA-B27negativeTaiwanChinesepatients.Rheumatology2004;43:839-42.

��

Hsu et al

台灣僵直性脊椎炎病人第一型和第二型主要組織抗原對偶基

因相關性之探討

許寶寶� 呂明錡

� 楊國樑

2 黃光永

� 童建學

� 劉素勤

� 賴寧生

�,�

�佛教大林慈濟綜合醫院 內科部 過敏免疫風濕科

2佛教花蓮慈濟醫學中心 骨髓幹細胞中心

�花蓮慈濟大學醫學院

目的：我們嘗試去探討僵直性脊椎炎（Ankylosing spondylitis,AS）病人致病基因除了HLA-B27

人類白血球抗原之外，其它人類第一型和第二型主要組織抗原是否與疾病病理機轉有關。材料和

方法：我們使用序列特異引子聚合酶連鎖反應的DNA序列鑑定法（PCR-SSPDNAtyping）分析兩

群病人的HLAclass I andclass II組織抗原。第一群是130位患有僵直性脊椎炎且HLA-B27皆陽性

的病人，第二群是260位HLA-B27陽性的健康人。我們使用卡方檢定法或費氏精確檢定法來分析

其勝算比。結果：患有HLA-B27陽性僵直性脊椎炎這群病人其對偶基因Cw12（93.85%）、Cw7

（20.0%）、Cw8（9.23%）出現頻率明顯增加，相對的在HLA-B27陽性健康人卻是Cw3（80.0%）

頻率有意義的增加。對偶基因B75（6.15%）、B60（20.0%）、B61（4.62%）在HLA-B27陽性僵

直性脊椎炎病人出現較高的頻率，相對於HLA-B27陽性健康人其B13（22.31%）、B58（36.15%）

卻有較高的頻率發生。這兩族群人所擁有的對偶基因差異性皆有統計學上的意義。A11/B27/Cw3

（70.0%）最常出現在HLA-B27陽性健康人；相對的，A11/B27/Cw12（78.5%）是最常出現在

HLA-B27陽性僵直性脊椎炎病人。A33/B58/Cw3常出現在HLA-B27陽性僵直性脊椎炎病人與

HLA-B27陽性健康人，各佔20.0%和21.54%。這些關係解釋了為何對偶基因（A11/A33,B27/B58,

Cw3/Cw12,DR12/DR13,DR17）在HLA-B27陽性僵直性脊椎炎病人身上有較高的頻率（15.4%），

而HLA-B27陽性健康人身上其對偶基因（A11/A33,B27/B58,Cw3/Cw3,DR12/DR13,DR17）有較高

的發生頻率（15.38%）。HLA-DR15以及DQ2與脊椎炎也有弱相關。 結論：A11/B27/Cw12對偶基

因跟HLA-B27陽性的僵直性脊椎炎病人有密切的關係，而A11/B27/Cw3卻是跟HLA-B27陽性的健康

人有密切關係。這同時說明除了HLA-B27外，其他MHC對偶基因可能與僵直性脊椎炎的風險性有

密切關係。

關鍵詞：主要組織相容性複合體、對偶基因、僵直性脊椎炎

Original Article

�4

Introduction

Pott'sdisease,isapresentationofextrapulmonarytuberculosis (TB) that affects the spine, akindoftuberculousinfectionoftheintervertebraljoints[1].TBofthebonesandjointsmayaccountfor10to35%ofcasesofextrapulmonaryTBand,overall,foralmost2%ofallcasesofTB[2-5].SpinalTBisthemostcommon

formofskeletalTB,accountingforone-halfofthecasesofarticuloskeletalTB[6,7].

WorldHealthOrganizationin2009estimated8.9-9.9millionincidentcasesofTB,9.6-13.3millionprevalentcasesofTB,1.1-1.7milliondeathsfromTBamongHIV-negativepeopleandanadditional0.45-0.62millionTBdeathsamongHIV-positivepeoplein2008[8].TBisstillprevalentinunder-developedcountries,mostinAsiaandAfrica,anditisstillaseverepublichealthproblemglobally. InTaiwan,basedonTaiwanTuberculosisControlReport2009ofCentersforDiseaseControl(CDC),Taiwan,theincidenceofnewcasesofTBwas14,265people,correspondingtoanincidencerateof62.0/100,000persons,andthedeathsfromTBwas762people,adeathrateof3.3/100,000in2008.

Although spinal involvementoccurs inonly aminorityofsubjectswithTB,spinalTBisconfusedwithotherspinal infectionin theearlystagedespitetheadvancesmadeindiagnosticprocedures,surgical

Pott's disease – a retrospective study of 35 patients Chun-Kai Chiu, Yu-Jih Su, Han-Ming Lai, Chung-Jen Chen, Tien-Tsai ChengDivision of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan

Correspondingauthor:Tien-TsaiCheng,M.D.DivisionofAllergy,Immunology,andRheumatology,DepartmentofInternalMedicine,ChangGungMemorialHospital-KaohsiungMedicalCenter.No123,Ta-PeiRoad,Niao-SungHsiang,KaohsiungHsien833,Taiwan.Tel:+886-7-7317123ext8800,Fax:+886-7-7322402E-mail:tiantsai@ms2.hinet.netReceived: January 8, 20101st revision: April 15, 20102nd revision: July 01, 2010Accepted: July 08, 2010

Objective:TheaimofourstudywastoillustratetheexperienceofPott'sdiseaseatamedicalcenterinsouthernTaiwan.Methods:Weundertookaretrospectivestudyof35adultcasesofPott'sdiseasepresentingovera10-yearperiodtoChangGungMemorialHospital-Kaohsiungmedicalcenter.Results:Ofthesubjectsrecruited,24(68.6%)aremale.Themeanagewas65.2±9.3years.Eightsubjects(22.9%)hadaprevioushistoryofpulmonaryand/orextra-pulmonarytuberculosis.Backache(n=33,94.3%)andneurologicalmanifestations(n=25,71.4%)werethe2leadinginitialpresentations.Thoracicspinewasthesitemostfrequentlyinvolved(n=14,40%).Thediagnosiswasmadebysurgicalinterventionin24(68.6%)subjectsandcomputertomography-guidedbiopsyintherest.AllsubjectsreceivedchemotherapytreatmentforTBand24ofthesubjects(68.6%)requiredsurgicalinterventionfordiagnosisorrefractoryneurologicalinvolvement.Ofallofthesubjectswhocompleteda1-yearfollow-upperiod,nomortalitywasfound.Conclusion:InourseriesofPott'sdisease,maleisthedominantgender,thoracicspineisthemajorsiteinvolved,backacheistheleadinginitialmanifestation,andneurologicalinvolvementisthemostimportantcauseofsurgicalintervention.Additionalsurgerywassignificantlyrelatedtoafavorableoutcome.

Key words:Pott'sdisease,tuberculosis

Formosan Journal of Rheumatology 20�0;24:�4-2�

�5

Chiu et al

techniques, andeffectivemedications.Adelay inestablishingthediagnosisandtreatmentcanleadtotheprogressionofneurologicaldeficitsandspinaldeformitythatwilldiminishthelikelihoodofrecovery.

Herein,weillustrate theexperienceofspinalTBinthisinstitutionbyreviewingthechartsofsubjectswhohadpathologyand/ormicrobiologyprovenTBinvolvementinspines.

Subjects and methods

Study populationThestudyincludedallconsecutiveadultsubjects

(aged>18years)diagnosedwithspinalTBbetweenMay1995andMay2004inChangGungMemorialHospital-Kaohsiung(CGMHK)medicalcenter.ThishospitalisatertiarycarereferralcenterlocatedinKaohsiungCountyin southernTaiwan, servingapopulationofabout2,000,000.

Inclusion criteria and definitionsWesearchedthedatabaseofcomputersystemin

CGMHKwiththefollowingdiagnosiscodes,01500,01501, 01502, 01503, 01504, 01505, 01506, ofInternationalClassificationofDiseases,NinthEdition,ClinicalModification(ICD-9-CM).Atotalof124chartswithabovediagnosiscodesduring theperiodwereretrieved.Toexcludethepresumptivediagnosisofthecharts,weonlyreviewedthechartsofthosesubjectsfulfilled thedefinitediagnosiscriteriaofspinalTB.Thecriteriaincludedthat thesubjectshadsymptomsand signs suggestive of spinalTB and revealedmicrobiologicand/orhistopathologicalevidencesofspinalTB.Thehistopathologicalevidencewasdefinedaseitherpresenceofgranulomatousinflammationorbacilliwithpositiveacid-faststain (AFS) in tissue.ThemicrobiologicevidencewasdefinedaspositivetissuecultureforTB.Atotalof35subjectsfulfilledthecriteria.WeexcludedthesubjectswithconcurrentbonemetastasisorprimarytumorsandspinalTB.

Data collectionThemedicalrecordswerereviewedfordemographic

data, comorbidity diseases, presenting signs andsymptoms,presenting levelof spinal involvementincludinganatomicextension, inflammatorymarkersincludingwhite cell count (WCC), erythrocytesedimentationrate(ESR),andC-reactiveprotein(CRP)atdiagnosis,microbiologicalandhistologicalresults,and therapeuticmanagement includingdurationof

chemotherapyandeventualsurgicalintervention.ThedefinitionofpositivefindingsinimagingcompatiblewithvertebralosteomyelitiswereconsideredtobeoneormoreofthosepreviouslyreportedbyModic[9].

Outcome and follow-upAllofthesubjectsweremonitoredbythephysician

ofoutpatientclinicsforatleastoneyear.Theoutcomewassurveyedbyaspectsofbackpain, radiographicevidences of spinal deformity and neurologicaldeficits.Intermsofoutcomeafteroneyear,wedefined"improved" as subjectshad lessbackpain and/oramelioratedneurologicdeficitwithnoradiographicalevidenceofprogressionofspinallesionordeformity,"unchanged" if therewerenonoticeablechanges ineitherpreexistingsymptomsorradiographicalsignsand"worse"asaggravatedsymptomsoranyevidenceofprogressionofspinaldeformity.

Statistical analysisThis is a descriptive study.Data analysiswas

performedaccordingtothestudyobjectives.Patients'characteristicswere reportedas simpledescriptivestatistics(i.e.,means±SD).AllstatisticalanalysiswasperformedwithSPSSsoftware(version17;SPSS,Inc.,Chicago,IL).Pvalueswerecalculatedusingtheχ2orFisherexact testforcategoricalvariablesandbytheStudentttestforcontinuousvariables.

Results

Patient demographics and baseline laboratory findings

AsillustratedinTable1,atotalof35subjectsmetdiagnosticcriteriaforPott'sdiseaseoverthe10-yearstudyperiod.Themeanagewas65.2±9.3years.Ofthesubjects,27 (77.1%)wereolder than60years,24(68.6%)weremale,and7(20%)hadcomorbiditydiseases,includingdiabetesmellitusin3,hypertensionin2,livercirrhosisin1,andlymphomain1.PasthistoryofpulmonaryTBin7,concurrentTBmeningitisin1,Other20subjectshadnomedicaldiseasesorhistoryofpulmonaryTB.Ninesubjects(25.7%)hadactivepulmonaryTBbasedonthepositiveresultofsputumcultureorsmearforTB.

Thebaseline levels of inflammatorymarkers,includingESR,CRP,andWCC, revealedelevated68.6%,57.1%,and22.9%ofthosesubjectssurveyed,respectively.Hemogramdisclosed77.1%ofsubjectstestedwereanemic(hemoglobin<12g/dL),andthe

�6

Pott's disease

differentialcountofWCCrevealedmeanabsolutelymphocyte(1049.9±489.0cells/mL)andgranulocyte(7165.7±3279.4cells/mL),respectively.

Diagnostic pathwaysAcomputertomography(CT)-guidedpercutaneous

needlebiopsyofspinewasperformedin11(31.4%)subjects. Inparticular,6of them(54.6%) revealedgranulomatousinflammationsuggestiveofspinalTBinhistologicalexamination,TissueAFSbacilliwaspositivein1(9.1%),andTBcultureofspinebiopsysampleswaspositive in5 (45.5%).The restof thesubjectsreceivedsurgicalinterventionsandthehistologyand/ormicrobiologysurveysdisclosed the findingsaforementioned.

Clinical presentations and imaging findingsAtadmission,33(95.3%)subjectshadbackand/or

neckpain,25(71.4%)showedneurologicaldeficitsi.e.legweakness,legnumbnessetc,anorexia(31.4%),bodyweightloss(11.4%),urineorstoolincontinence(8.6%),andgibbus (2.9%).Feverwas found in14(40%).Twenty-five(71.4%)hadneurologicalsignssecondary to the infection, inwhich radiculopathy(51.4%)andparaplegia(37.1%)werethemostfrequentmanifestations,asshowninTable2.

Intheaspectofimagestudiesofallofthesubjects,spinalplainradiographrevealedfindingscompatiblewiththespinalinfectionin22subjects(62.9%).Theinitial tentativeplain radiographicdiagnosiswasinfectiousspondylitis in25(71.4%),metastasis in3cases (8.6%),andunknowncause inother7cases.SpinalCTscanningwasperformedin10andmagneticresonanceimaging(MRI)in31,sixofwhomreceivedbothevaluations.EitherMRIorCTdemonstratedevidencescompatiblewithspinalinfection.NolesionssuggestiveofpulmonaryTBwerefoundinplainchestradiographof23(65.7%).Intermsofsitesinvolved,thethoraciclevelwasin14(40%),thethoracic+lumbarlevel in7(20%), the lumbar level in9(25.7%), thelumbar+sacrallevelin4(11.4%)andboththecervicalandthoracicspinesin1(2.9%),asshowninTable3.Gallium67scintigraphywasperformedfor5subjectsandalldisclosedincreaseduptakelesionsatthespineinvolved.

Treatment and outcomeAll35subjectswere treatedat least sixmonths

ofchemotherapyforspinalTB.Surgicalinterventionwasperformed fordiagnosis, severeneurologicaldeficits,spinaldeformity,intractablepain,andabscessenlargementunresponsivetomedications.Twenty-foursubjects(68.6%)requiredsurgical interventionwithanti-TBmedicationsand11(31.4%)receivedanti-TBmedicationsalone.Inourseries,weanalyzedfactorshavinganinfluenceontreatmentforspinalTBinpatientswithadditionalsurgeryversusanti-TBchemotherapyalone.Additionalsurgerywassignificantlyrelatedtoa

Table 1. Patient demographics and baseline laboratory data

Characteristic n (%)Number of subjects �5Mean age (years) 65.2 ± 9. � Sex (male/female) 24/11TB history, n (%)

Past history of pulmonary TB 7 (20)Concurrent TB meningitis � (2.9)

Major comorbidity diseases, n (%) 7 (20)Diabetes mellitus � (8.6)Hypertension 2 (5.7)Liver cirrhosis � (2.9)Lymphoma � (2.9)

Baseline laboratory dataHigh WBC (>10800 cells/mL) 8 (22.9)High ESR (>20-40 mm/hr) 2 (5.7)Very High ESR (>40 mm/hr) 22 (62.9)High CRP (>5 mg/L) 20 (57.�)Anemia (<12 g/dL) 27 (77.�)Hypoalbuminemia (<3 gm/dL) 8 (22.9)

Table 2. Clinical features of �5 patients with Pott's disease

Complaints n (%)Back/Neck pain �� (94.�)Fever �4 (40)Anorexia �� (��.4)Weight loss 4 (��.4)Gibbus � (2.9)Neurological signs 25 (7�.4)

Radiculopathy �8 (5�.4)Paraplegia �� (�7.�)Incontinence � (8.6)

Subjects may have more than one clinical features.

Table 3. Distribution of lesionsLocalization n (%)Thoracic spine �4 (40)Thoracic + Lumbar spine 7 (20)Lumbar spine 9 (25.7)Lumbar + Sacral spine 4 (��.4)Cervical and thoracic spine � (2.9)

�7

Chiu et al

favorableoutcome,whereasage,gender,pastTBhistory,andsiteoflesionexceptlumbarspineinvolvedwerenotsignificantlydifferentbetweenthebothgroups,asshowninTable4.Ofthe35subjectswhocompleteda1-yearfollow-upperiodincludingtheperiodofchemotherapy,intheaspectofoutcome,24(68.6%)wereimproved,10(28.6%)unchanged,and1(2.9%)worse.

Discussion

AsTaiwanisanendemicareaofpulmonaryandextra-pulmonaryTB,casesofsuspiciousspinalTBwerenotinfrequentlyseeninthisarea.DespiteseveralreportsonspineTBhadbeenpublishedintheliteratures[10,11],thediagnosiscriteriawereobscureandambiguousinamajority. Inaddition, it isusuallydifficult forearlierdifferentialdiagnosisbetweenspinalTBandpyogenicspondylitis,becauseitsclinicalmanifestations,laboratorydataandimagingfindingsintheinitialstageareindistinguishabletopyogenicspondylitis.ThebestwayistothinkofthediagnosisofspinalTB.Someclueswhichcomefromthehistory,shouldincludepatientsliveinanendemicareaorcountry,afamilyhistoryofTB,andahistoryofpriorknownorpossibleTBorcontact.ThemostcommoncauseofdelayinthediagnosisofspinalTBisfailuretoconsiderthediagnosis.

Themeanageofourcohortwasolderthanotherseries[12,13]and20%ofthesubjectshadcomorbiditydiseases. It implied thatwhen immunitybecomesattenuatedbecauseofagingordisease, thelatentTBmaybereactivated[14]andmayprecipitatethespinalTB.

The usual haematological and biochemicalparametersareoflittlevalueinthedifferentialdiagnosisof infectivespondylitis.Despite70%ofthesubjectshadelevatedlevelofESRandanemiainourseries,theelevatedESRleveland/oranemiawasalsofoundin

mostsubjectsofpyogenicspondylitis.However,whenveryhighvalueofESRispresent,itstronglysuggestpyogenicspondylitis[15].

In pathogenesis of spinalTB, the bacillemiaassociatedwithprimaryTBinfectiontypicallyseedsorganismsthroughoutthebody;spinemaybeinfectedduring this stage.SpinalTBusually starts in theanteroinferioraspectofthecancellousvertebralbodywith inflammatorybonedestructionandcaseatingnecrosis.Oncetheprocessisestablished,activeinfectionspreadsdownbehindtheanteriorligamenttoinvolvetheadjacentvertebralbody.Localdestructionoftenproducescollapseofbonystructuresandherniationof thediskintothevertebralbodies.It ispotentiallyseriousandcancausepain,rootdeficitandkyphosis.Morecommonlyspinalcordcompressionmayleadtomyelopathyorparaplegia.Lossofneurologicalfunctionmaymanifestonlyafteryears,eveniftheTBhasbeencuredadequately[16,17].Thisistheresultofchroniccompressionofthespinalcordoralocalreactivation.

Ingeneral,TBiscurable.Themainstayoftreatmentischemotherapywithatleastisoniazid[INH],rifampicin[RIF],andpyrazinamide[PZA].TheAmericanThoracicSocietyrecommendssixmonthsofchemotherapyforspinalTBinadultsand12monthsinchildrenbecausereliabledataarelackingonshortertreatmentduration[18].TheBritishThoracicSociety recommendssixmonthsoftreatmentirrespectiveofage[19].Inrecentreviewoftheliterature,theauthorandcolleaguesfoundthatsixmonthsoftreatmentisprobablysufficientforeveryone [20]. In recentyears, fourdrug regimens(usuallyINH,RIF,PZA,andethambutol[EMB])areadvocatedand,forthemostpart,highlysuccessfulwhenadministeredaccordingtorecommendations[21].Someauthorsrecommendlongertreatmentregimens(9to12months)forpatientswithadvancedorextensivedisease,particularlyiftheresponsetotherapyisinconclusiveor

Table 4. Comparison in patients with chemotherapy alone and additional surgery in our seriesChemotherapy Chemotherapy and surgery p value

Age, mean ± SD (years) 65.8 ± 7.8 64.9 ± �0.� NSNo. males/females 7/5 17/6 NSPast TB history, n � 5 NSOutcome, improvement/non-improvement, n 5/7 19/4 0.0��Site of lesion, n

Thoracic 5 9 NSThoracic + Lumbar 4 � NSLumbar 0 9 0.0�2Lumbar + Sacral � � NSCervical and thoracic 0 � NS

NS: non-significance.

�8

Pott's disease

Table 5. Experiences of TB

spine of different series in Asia

Author(s)

Yearn

Country

LocationP

eak incidence of age (%

)R

atio of m

ale/female

Most

frequent lesion

Additional surgery

Outcom

e

Arthornthurasook et al.

[32]�98�

54S

outhern Thailand

� cervical,44 thoracic,66 lum

bar,� sacral

Sixth decade

(24.�)�.7

L4��

100% patients w

ere favorable in chemotherapy

alone, 95% patients w

ere favorable in chem

otherapy+surgery

Turgut, et al. [11]200�

694Japan

�� cervical,�74 thoracic,5� thoraco-lum

bar,7� lum

bar,� thoracic and lum

bar

�Thoracic

spine682

140 (34%) w

ere resolved, 169 (41%) im

proved, 59 (14%

) unchanged, 36 (9%) deteriorated and

10 (2%) deaths

Bhojra, et al. [33]

200266

India55 lum

bar,�� lum

bo-sacral

0.65L4-L5

��40 (61%

) were excellent, 14 (21%

) good, 1 (1.5%

) fair, and 11 (16.5%) poor

Dharm

alingam, et al.

[12]2004

��M

alaysia6 cervical,�0 thoracic,9 lum

bar,2 thoraco-lum

bar,4 skip

�0-�9 years old (27.�)

2.67Thoracic

spine20

(60.6%)

Zhang, et al. [13]�998

�09C

hina� cervical,2 cervico-thoracic,40 thoracic,�� thoraco-lum

bar,�� lum

bar,�� lum

bo-sacral,� sacral

2�-50 years old (77.2)

�.�8Thoracic

spine�09

�09 patients had failed initial focal debridement

for spinal TB

Park, et al. [37]

2007��7

Korean

6 cervical,� cervico-thoracic,4� thoracic,�� thoraco-lum

bar,59 lum

bar,�0 lum

bo-sacral

�.0�Lum

bar spine

84(62.2%

) 94 w

ere favorable and 22 unfavorable

Chiu, et al.

20�0�5

Taiwan

� cervico-thoracic,�4 thoracic,6 thoraco-lum

bar, 9 lum

bar,5 lum

bo-sacral

6�-70 years old (45.7)

2.�8Thoracic

spine24

(68.6%)

24 (68.6%) w

ere improved, 10 (28.6%

) unchanged, and 1 (2.9%

) worse

�9

Chiu et al

uncertain[22].Inpast,thereiscontroversyintheliteratureabout

thenecessityofadditional surgical intervention tospinalTB.Hodgsonadvocatedsurgicaltreatment[23],andKonstamandcolleaguesadvocatedconservativetreatment [24,25].Althoughrandomizedcontrolledtrials investigating indications are lacking,manyauthorsconsiderthefollowingindicationsforsurgicalintervention[26]:(1)advancedneurologicaldeficitscausedbycompressionof thespinalcord;(2)spinalinstabilitycausedbydestructionorcollapseof thevertebrae,destructionof twoormorevertebrae,orkyphosisofmorethan30degrees;(3)noresponsetochemotherapeutictreatment;(4)non-diagnosticbiopsy;and (5) largeparaspinal abscesses [27-29].Someauthorsevenadvocatesurgeryinmildcasesofspinaltuberculosis[30,11].Inourretrospectivestudy,patientswithadditionalsurgeryversusanti-TBchemotherapyaloneweresignificantlyrelatedtoafavorableoutcome(Table5).Potentialbenefitsofsurgeryarelesskyphosis,immediatereliefofcompressedneuraltissue,quickerreliefofpain,ahigherpercentageofbony fusion,quickerbony fusion, less relapse, earlier return topreviousactivities,and lessbone loss. Itmayalsopreventlateneurologicalproblemsduetokyphosisofthespineiffusionhasnotoccurred[31,30].

The report regardingwhich spinal segmentinvolvedpredominantlywascontroversial [32,33].Inourseries, the thoracicspinewas thechief levelinvolved.Whether it is due to the differences indefinitionof inclusioncriteria, the lagofdiagnosis,andevengeneticbackgroundofourseriesfromothersrequirefurtherinvestigation.Inaddition,neurologicaldeficitsweremorefrequentlyfoundinspinalTBthanpyogenicspondylitisinotherreport[34]andsurgicalintervention fordiagnosisor intractableneurologicdeficitwasneededfor themajorityof thosepatientsinourseries.It implicatedthatwepostulate that thedelayedandlaboriousdiagnosisofspinalTBwerealsothecontributingfactorsofneurologicdeficits.Whetheraggressiveandexpeditiousdiagnosticprocedure i.e.urgentCT-guidedneedleaspirationbiopsyorearliersurgicalbiopsyinsuspiciouscasescouldimprovetheprognosisneedsfurtherinvestigation.

25.7%patientswithconcomitantTBof the lunginourseries. Incontrast,Dharmalingametal.andArthornthurasooketal.reportedarateof66.6%and40.7%patientsintheirseries[12,32].

In the aspects of image study, only one thirdhadpulmonary lesiononplainchest radiography, itsuggested that spinalTBcouldnotbeexcluded in

subjectswithsuspiciousspinal infectionbutwithoutpulmonaryabnormality.Theplainspinalradiographdemonstratedsuspiciouslesionsin62.9%ofourcasesandcouldnothelpclinicianstomakedefinitediagnosisof spinalTB.However, the spinalCTand/orMRIdisclosedsuspiciouslesionsinallofthesuspiciouscasessurveyed.Westronglyrecommendthaturgentintensiveradiographicstudies,suchasspinalCTandMRI,bethechoiceinsuspiciouscasesofspinalTB[35].

Nevertheless,thedefinitediagnosisofspinalTBstillrequirespathologicalormicrobiologicalevidence.Theyieldofaspirationbiopsy,especiallypositiveinAFSbacilli,pathologicalfindingsandmycobacterialculturewasrelativelylowcomparedwithsurgicalbiopsy,inourseries.Therefore,anegativeinterpretationofaspirationbiopsyshouldbecautious,directsurgicalbiopsy ishighly recommendedamongcaseswith suspiciousspinalTB[36].

Thereare limitationsofourstudy.First, this isaretrospectivestudyandnotallofdataorexaminationrequiredcanbetraced.Second,asthetreatmentoptionisuptothedecisionbycaringphysician,ratherthanfollowingtheformulatedguideline,wecan’tanalyzewhichtherapeuticoptionismorepreferable.Third,theoutcomeofourseriesisfair;however,oneyearfollow-upperiodistooshort.Finally,whethermoreaggressivediagnostic or treatment strategy can improve theoutcomeneedsfurthersurvey.

Inconclusion,inthisretrospectivesurveyofPott'sdisease,wefoundthatmale is thedominantgender,thoracicspine is themajorsite involved,backacheis the leadinginitialmanifestation,andneurologicalinvolvementis themostimportantcauseforsurgicalintervention.Intensiveandaggressive treatment, i.e.additionalsurgicalinterventionmaysignificantlyrelatetoafavorableoutcomeforPott'sdisease.

References1. LifesoRM,Weaver P, andHarderEH.Tuberculous

spondylitisinadults.JBoneJointSurgAm1985;67:1405-13.2. NicholsonRA.Twentyyearsofboneandjointstuberculosis

inBradford.JBoneJointSurgBr1974;56:760-5.3. Wolfgang GL. Tuberculosis joint infection. Clin

Orthop1978;136:257-63.4. TayBK,DeckeyJ,andHuSS.Spinalinfections.JAmAcad

OrthopSurg2002;10:188-197.5. Boachie-AdjeiO,SquillanteR:Tuberculosisofthespine.

OrthopClinNorthAm1996;27:95-103.6. NicholsonRA.Twentyyearsofboneandjointtuberculosisin

Bradford.JBoneJointSurgBr1974;56:760-5.

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7. VohraR,KangHS,DograS,SaggarRR,andSharmaR.Tuberculous osteomyelitis. JBone Joint SurgBr1997;79:562-6.

8. Globaltuberculosiscontrol:ashortupdatetothe2009report.WorldHealthOrganizationMarch2009.

9. ModicMT,FeiglinDH,PiraimoDW,BoumphreyF,WeinsteinMA,DuchesneauPM,etal.Vertebralosteomyelitis:assessmentusingMR.Radiology1985;157:157-66.

10.SolagberuBA,AvorindeRO.TuberculosisofthespineinIlorin,Nigeria.EastAfrMedJ2001;78:197-9.

11. TurgutM.Spinal tuberculosis(Pott'sdisease): itsclinicalpresentation,surgicalmanagement,andoutcomes.Asurveystudyon694patients.NeurosurgRev2001;24:8-13.

12.DharmalingamM.Tuberculosisof the spine-theSabahexperience,epidemiology,treatmentandresults.Tuberculosis(Edinb)2004;84:24-8.

13.ZhangW,WuQ,andLinY.Analysisof reasons failedfocaldebridementin109patientswithspinaltuberculosis.ZhonghuaJieHeHeHuXiZaZhi1998;21:181-3.

14.KaufmannSH.Howcan immunologycontribute to thecontroloftuberculosis?NatRevImmunol2001;1:20-30.

15.Colmenero JD, Jiménez-MejíasME,Sánchez-LoraFJ,RegueraJM,Palomino-NicásJ,MartosF,GarcíadelasHerasJ,andPachónJ.Pyogenic,tuberculous,andbrucellarvertebralosteomyelitis:adescriptiveandcomparativestudyof219cases.AnnRheumDis1997;56:709-15.

16.RajeswariR,RanjaniR,SanthaT,SriramK,andPrabhakarR.Lateonsetparaplegia--asequelatoPott'sdisease.Areportonimaging,preventionandmanagement.IntJTuberculosisLungDis1997;1:468-73.

17.LukKD.Tuberculosisofthespineinthenewmillenium.EurSpineJ1999;8:338-45.

18.BassJB,JrFarerLS,HopewellPC,O'BrienR,JacobsRF,RubenF,etal.Treatmentoftuberculosisandtuberculosisinfectioninadultsandchildren.AmericanThoracicSociety/CentersforDiseaseControlandPrevention.AmJRespirCritCareMed1994;149:1359-74.

19.Chemotherapyandmanagementof tuberculosis in theUnitedKingdom:recommendations1998.JointTuberculosisCommittee of theBritishThoracic Society.Thorax1998;53:536-48.

20.VanLoenhout-RooyackersJH,VerbeekAL,andJuttePC.Chemotherapeutic treatmentforspinal tuberculosis. IntJTuberculosisLungDis2002;6:259-65.

21.AmericanThoracicSociety/CentersforDiseaseControland

Prevention/InfectiousDiseasesSocietyofAmerica:treatmentoftuberculosis.AmJRespirCritCareMed2003;167:603-62.

22.BlumbergHM,LeonardMK,andJrJasmerRM.Updateonthetreatmentoftuberculosisandlatenttuberculosisinfection.JAMA2005;293:2776-84.

23.HodgsonAR,StockFE.Anterior spine fusion for thetreatmentoftuberculosisofthespine.Theoperativefindingsandresultsoftreatmentinthefirstonehundredcases.JBoneJointSurg1960;42A:295-310.

24.KonstamPG,KonstamST.SpinaltuberculosisinSouthernNigeriawithspecial reference toambulant treatmentofthoracolumbardisease.JBoneJointSurg1958;40B:26-32.

25.KonstamPG,BlesovskyA.Theambulanttreatmentofspinaltuberculosis.BrJSurg1962;50:26-38.

26. JuttePC,VanLoenhout-RooyackersJH.Routinesurgeryinadditiontochemotherapyfor treatingspinal tuberculosis.CochraneDatabaseofSystematicReviews2006.

27.VidyasagarC,MurthyHK.Managementoftuberculosisofthespinewithneurologicalcomplications.AnnRCollSurgEngl1994;76:80-4.

28.WattsHG,LifesoRM.Tuberculosisofboneandjoints.JBoneJointSurg1996;78A:288-98.

29.MoonMS.Tuberculosisofthespine.Controversiesandanewchallenge.Spine1997;22:1791-7.

30.LeongJC.Tuberculosisof thespine. JBoneJointSurg1993;75-B(2):173-4.

31.HsuLC,ChengCL,LeongJC.Pott'sparaplegiaof lateonset.Thecauseofcompressionandtheresultsofanteriordecompression.JBoneJointSurg1988;70-B(4):534-8.

32.ArthornthurasookA.TuberculosisoftheSpineinSouthernThailand.JMedAssThailand1983;66:106-21.

33.Bhojraj SY. Lumbar and lumbosacral tuberculousspondylodiscitisinadults.JBoneJointSurg2002;4:84-B.

34.LuzzatiR.Diagnosis,managementandoutcomeofclinicallysuspectedspinalinfection.JInfect2009;58:259-65.

35.al-MulhimFA,IbrahimEM,el-HassanAY,MoharramHM.Magnetic resonance imagingof tuberculousspondylitis.Spine1995;20:2287-92.

36.DunnR,ZondaghI.Spinaltuberculosis:diagnosticbiopsyismandatory.SAfrMedJ2008;98:360-2.

37.ParkDW.Outcomeandmanagementofspinaltuberculosisaccordingtotheseverityofdisease:aretrospectivestudyof137adultpatientsatKoreanteachinghospitals.Spine2007;32:E120-E135.

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結核性脊椎炎回溯性的分析

邱俊凱 蘇昱日 賴漢明 陳忠仁 鄭添財

長庚醫療財團法人高雄長庚紀念醫院 風濕過敏免疫科

目的：本研究的目的是要來說明在南台灣的醫學中心的結核性脊椎炎的經驗。方法：我們經由病歷

回溯性的研究去分析在高雄長庚醫院醫學中心在過去10年期間的35名結核性脊椎炎的患者。結果：

其中有24名患者（68.6%）是男性。平均年齡是65.2±9.3歲。其中有8名患者（22.9%）去有肺結核

或肺外結核病的病史。患者最常出現的症狀是背痛（94.3%）。25名患者（71.4%）有神經學的症

狀表現。胸椎（40%）是最常被感染的部位。其中24名患者的結核性脊椎炎的診斷是經由手術的方

式來診斷，而其餘患者是經由針頭穿刺的切片方式來診斷。所有患者都接受抗結核菌的藥物治療，

其中有24名患者（68.6%）同時有接受手術的治療。結論：在我們的研究中，男性患者佔多數，胸

椎是最常被感染的部位，背痛是最常出現的症狀，而神經學的併發症是病患需要開刀治療的最重要

原因。藥物同時加上外科的治療的患者會比單獨只有接受藥物治療的患者預後會比較好。

關鍵詞：結核性脊椎炎、結核菌

Original Article

22

Introduction

From10%to40%ofsystemiclupuserythematosus(SLE) patients have revealed the presence ofantiphospholipid antibodies (aPLA) [1,2].ThepresenceofaPLAinSLEisassociatedwithseveremorbidity, especially thromboembolism,andevenlethalcomplications[3-5].Cerveraetal.demonstratedthatthromboseswerethemaincauseofdeathinSLEpatients,especiallyduring the last fiveyears [3,6].

Is antiphospholipid antibody related to outcome of lupus nephritis? – A 2-year analysis Wen-Chan Chiu, 1Shun-Chen Huang, Chung-Jen Chen, Chung-Yuan Hsu, Tsong-Shing Yang ,

Ching-Lan Chou, Fu-Mei Su, Yu-Jih Su, Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen,

Han-Ming Lai, Tien-Tsai ChengDivision of Allergy, Immunology and Rheumatology, 1Department of Anatomic Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondingauthor:Tien-TsaiCheng,M.D.DivisionofRheumatology,AllergyandImmunology,ChangGungMemorialHospital-KaohsiungMedicalCenter,ChangGungUniversityCollegeofMedicine,Kaohsiung,Taiwan.No123,Ta-PeiRoad,Niao-SungHsiang,KaohsiungHsien,Taiwan833.Tel:+886-7-7317123ext8800,Fax:+886-7-7322402E-mail:tiantsai@ms2.hinet.netReceived: April 21, 2010Revised: June 14, 2010Accepted: September 30, 2010

Objective:Toinvestigatetheimpactofantiphospholipidantibodies(aPLA)onrenaloutcomeinlupusnephritis(LN).Materials and Methods:Aretrospectivechartreviewstudyofpatientswithbiopsy-provenLNwasconductedbetween1986and2007atChangGungMemorialHospitalinKaohsiung.AllofthepatientsfulfilledthesystemiclupuserythematosusclassificationcriteriaoftheAmericanCollegeofRheumatologyandhadhistopathologicalfindingscompatiblewithLN.OnlythosepatientswhoseaPLA,includinganti-cardiolipinantibody,anti-β2GPIantibody,VenerealDiseaseResearchLaboratorytest,andlupusanticoagulanthadbeencheckedwererecruited.Wereviewedthechartsandcollectedthedemographics,clinicalcharacteristics,serologicalparameters,andtreatmentcoursesofthepatientsrecruited.Therenaloutcomeendpointwaseitherend-stagerenaldiseaseordoublingofserumcreatininewithin24monthsResults:Atotalof66subjectswererecruited,including55femalesand11males.Themeanagewas30.5±11.1years.aPLAwaspresentin18patients(27.3%)(groupI),and48patients(72.7%)(groupII)hadnegativetestresults.Theseropositiveratiosofanti-dsDNAandanti-RNPingroupIweresignificantlyhigher(p=0.023and0.026)thaningroupII,respectively.Therewasnostatisticaldifferenceinotherparametersbetweenthegroups.ThesubjectsingroupIhadamorefavorable(p=0.038)renaloutcomeafter2yearsoffollow-up.Conclusions:Contradictorytopreviousstudies,thepresenceofaPLAinpatientswithLNisprobablyassociatedwithabetterrenaloutcome.

Key words: lupusnephritis,prognosis,InternationalSocietyofNephrologyandtheRenalPathologySociety(ISN/RPS)classification,antiphospholipidantibody

Formosan Journal of Rheumatology 20�0;24:22-28

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Chiu et al

Inalargeseries,Tektonidouetal.demonstratedthatantiphospholidsyndromenephropathyoccursamongpatientswithSLE,especiallyinthosewithaPLA[7].Ithasbeenreportedthatseveralfactors(age,gender,histopathologicfindings,etc.)wereassociatedwiththeprognosisof lupusnephritis (LN)[8].However, theaPLAinassociationwiththeprognosisoflupusnephritiswaspoorlyrecognized.MirandaJMetal.demonstratedthatglomerularthrombosisisanotherpoorprognosticfactorofrenaloutcomeinpatientswithLN[9].AndthepresenceofaPLAinSLEpatientsmayindicateahigherriskofdevelopingglomerular thrombosisandmayexaggeratetherenaloutcomeofLN[10-12].ApossibleexplanationisthattheaPLAmaycontributetotherenaloutcome,evenwithoutglomerular thrombosis.TheaimofthisstudywastoinvestigatetheimpactofthepresenceofaPLAonrenaloutcomeinLN.

Materials and Methods

WeperformedaretrospectivechartreviewstudyofpatientswithLNbetweenJanuary1986andSeptember2007atChangGungMemorialHospitalinKaohsiung.AlloftheLNpatientsfulfilledtheSLEclassificationcriteriaof theAmericanCollegeofRheumatology(ACR)andhadhistopathologicalfindingscompatiblewiththeInternationalSocietyofNephrologyandtheRenalPathologySociety(ISN/RPS)classificationofLN[13].OnlythosesubjectswhoseaPLA,includinganti-cardiolipinantibody(aCLA),anti-β2GPIantibody(aβGPI),VenerealDiseaseResearchLaboratory(VDRL)test,andlupusanticoagulant(LAC)hadbeencheckedwererecruited.Patientswhoreceiveddialysiswithinonemonthafterkidneybiopsy,orwhohadexpiredsoonerthaneither renaloutcomecouldbemeasured,wereexcluded.

WedefinedthepresenceofaPLAaspositivityforeitheroneofthetestsforaPLA.Positivitywasdefinedas±10phopsholipidunitsforaCLA(ELISAmethod,Varelisa,Phadia;normal<10GPL/MPLU/mL),≥10phospholipidunitsforaβGPI(ELISAmethod,Varelisa,Phadia; normal<10GPLU/mL),LACmeasuredutilizingasimplifieddilutedRussellvipervenomtest(dRVVT)(LifeTherapeutics,USA)orafalsepositiveVDRLtest. InpatientswithnormalaPTT, itwouldbeconsideredthatLACtesthadnotbeencheckedifdRVVThadnotbeencheckedforfurtherscreening.ThosewhorevealedpositiveaPLAwerecategorizedasgroupIandtheremainingpatientsasgroupII.

TheonsetofLNwasdefinedasthedateofkidney

biopsy.Wedefinedrenaloutcomeas thatproposedby theRenalSubcommitteeofRenal Insufficiencyof theACR[14].Inbrief, irreversiblerenalfunctiondeteriorationwasdefinedaspersistentSCr>2mg/dLformorethan6monthswithoutimprovementovertime,ortheneedofdialysistherapy.

Themedical recordsof subjects recruitedwerereviewedfordemographics,clinicalcharacteristics,treatment courses, comorbidity, and timing ofhistopathologicaldiagnosisofLN.Theendpointofrenaloutcomewaseitherpersistent2×SCrthatwasdefinedas2consecutivemeasurementsatleast6monthsapart(I)orend-stagerenaldisease(ESRD)(II)within24monthsafterkidneybiopsyhadbeenperformed.Thestudywasapprovedby theethicscommitteeof this institution[98-2053B].

Statistical AnalysisCategoricaldatabetweendifferentgroupswere

analyzedbychi-squareorFisher’s test,when theexpected cell countwas less than5.Weused theStudent'st-testorMann-WhitneyUtestforcontinuousvariablesof2 independentsamples.Survivalcurvesweredrawnusing theKaplan-Meier estimate andcomparedusingthelog-ranktest.Datawasexpressedasmean±standarddeviation,unlessspecified.Statisticalsignificancewasdefinedasap<0.05.Samplesizevariesfrom5to66becauseofmissingdata.AllanalyseswereperformedusingtheSPSSprogram,version15(SPSS,Chicago,IL)forWindowsXPProfessional.

Results

Atotalof66patientswereincludedinthisstudy.Thedemographicsandclinicalcharacteristicsof thepatientsareshowninTable1.Thepatientsincluded55womenand11men,withanageof30.5±11.1years(median,29years;range,12to57years).Fifty-threepatientshadnormalbaselineScrlevels(0.9±0.2mg/dL)andtherestofthepatientshadrenalinsufficiency(SCr,2.8±1.3mg/dL).Threeofthepatientswithrenalinsufficiencyhadanestimatedcreatinineclearancelessthan20mL/min.Forty-twopercentofpatientshadhypertension.Therenalhistopathologyrevealedthat,basedontheISN/RPSclassification(2003),9,2and49patientshadclassII,III,andIV,respectively.Therewere18(27%)and58patients(73%)ingroupIandgroupII,respectively.Ofthe18patientsingroupI,theaPLAprofileshowedaβGPIpositivityin6patients,IgGaCLApositivityin12patientsandIgMaCLApositivityin4

24

aPLA and lupus nephritis

patients.Althoughcollecteddatawasnotavailableforallincludedpatients,therewasnostatisticallysignificantdifferenceindemographics,clinicalcharacteristicsorlaboratorydatabetweenthegroups,exceptthepositivityratioofanti-dsDNA(p=0.023)andanti-RNP(p=0.026)(Table1).Duringthe2-yearfollow-upperiod(21.3±6.0months),10patients(15%)developedESRDand2(3%)2×SCr.ThepatientsingroupIhadlessrisk(p=0.038)ofdevelopingESRDor2×SCrthanthoseingroupII(Fig.1).

Discussion

SLE,anautoimmunedisorderwhichpredominantlyaffectsyoungwomen,isfrequentlycomplicatedbyrenalinvolvement.Approximatelyhalfofpatientsdevelop

renal involvementduringthecourseof theirdisease[6,15].Ithasbeendemonstratedthatseveralfactorsare

Table 1. Demographic, clinical and laboratory characteristics of the patientsa with lupus nephritisAllb aPLA positive aPLA negative p

n = 66 n = �8 n = 48Sex (male/female) 11/55 3/15 8/40 �.00Age (years) �0.5 ± ��.� ��.6 ± ��.7 29.4 ± 9.8 0.�69Body weight (kg) 56.5 ± �2.6 56.0 ± �0.7 56.7 ± ��.� 0.8�4SLE duration (years) 2.7 ± �.8 2.8 ± 4.� 2.6 ± �.7 0.85�Proteinuria (g/24h) �.6 (2.0;6.5) 2.5 (�.6;9.7) �.9 (2.�;6.5) 0.828Creatinine (mg/dL) 0.9 (0.7;�.26) 0.9 (0.75;�.�5) 0.9 (0.7;2.0) 0.652BUN (mg/dL) �9.5 (�4;�8.�) 22 (�5;�0.5) �8 (�4;�9) 0.958C3 (mg/dL) 46.5 (�2.7;8�.6) 44.7 (��.6;78.�) 50.� (�2.4;8�.9) 0.98�C4 (mg/dL) �0.2 (5.8;�7.4) 6.6 (4.2;��.�) �0.6 (5.8;�0.�) 0.22�Anti-dsDNA (+), n (%) 4� (82.7) �7 (�00) 26 (74.�) 0.02�Anti-RNP (+), n (%) 7 (26.9) 6 (50) � (7.�) 0.026Anti-Sm (+), n (%) 5 (�9.2) 4 (��.�) � (7.�) 0.�48Anti-Ro (+), n (%) �6 (5�.6) 7 (5�.8) 9 (50) �.00Anti-La (+), n (%) 5 (�6.�) � (7.7) 4 (22.2) 0.�68Hb (g/dL) �0.5 ± 2.6 �0.� ± 2.5 �0.5 ± 2.7 0.828Hct (%) ��.4 ± 7.0 �0.7 ± 6.6 ��.6 ± 7.2 0.652Platelet (1000/mm�) 2�� ± 89 228.4 ± 78.6 20�.7 ± 92.9 0.�26Albumin (g/dL) 2.2 (�.9;�.0) 2.� (�.8;�.0) 2.2 (�.9;2.9) 0.89TG (mg/dL) �98.5 (��5;266.�) �84.5 (�04;266) 205.5 (�20;29�) 0.725Chol (mg/dL) 2�2 (�8�;��0) 2�2 (�48;240) 268 (�87;���) 0.08�ISN/RPS class (2/3/4/5/6) 9/2/49/3/1 3/1/13/1/0 6/1/36/2/1 0.552Hypertension (+), n (%) 27 (4�) 9 (50) �8 (�7.5) 0.576Pulse steroid (+), n (%) �0 (�6.�) � (�7.6) 7 (�5.6) �.00Pulse Cyc (+), n (%) 24 (�8.7) 5 (29.4) �9 (42.2) 0.�98Oral Cyc (+), n (%) 7 (��.�) � (�7.6) 4 (8.9) 0.�8�Azathioprine (+), n (%) �6 (25.8) � (�7.6) �� (28.9) 0.52Cyclosporine (+), n (%) 6 (9.7) 2 (��.8) 4 (8.9) 0.662

aExcept where indicated otherwise, values are expressed as mean ± standard deviation or median (25th ; 75th percentile) as appropriatebNot all data are available and n (%) represent total data number available and its percentage of total 66 peopleAbbreviations: aPLA = antiphospholipid antibodies; ANA = antinuclear antibodies; anti-dsDNA = anti-double-stranded DNA antibody; anti-RNP = anti-ribonucleoprotein antibody; SLE = systemic lupus erythematosus; TG = triglyceride; Chol = total cholesterole; Hb = hemoglobulin; Hct = hemotocrit; WBC = white blood count; BUN = blood urea nitrogen; ISN/RPS class = International Society of Nephrology and the Renal Pathology Society classification, Cyc = cyclophosphamide

Figure 1. Outcome-free survival probability

25

Chiu et al

associatedwiththeprognosisofLN.Despitethefactthattheobservationsthatthepresenceofanti-dsDNAandaPLAinSLEpatientswasominousforLNremaintobeproved,weaimedtodelineatetheprognosticroleofaPLAinLNinthecurrentinvestigation.

TheaPLAareaspectrumofantibodies,andcanbedetectedasseveralserotypes,includingaCLA,aβGPI,VDRL,andLAC, inclinicalpractice.However, themanifestationofaPLA-associateddiseasesisrelatednotonlytothemethodsusedtomeasure,buttothelevelofthesingleantibody[16].Inaddition,theassociationbetween serotypes of aPLA and aPLA-relatedpresentationsisnotconcordant[17].

Moronietal.illustratedthataPLAplaysadevastatingroleinLN[18];however,Tsurutaetal.[19]couldnotdemonstratesimilarfindings.Therefore,whether thepresenceofaPLAinLNpatientsportendsaworserenaloutcomeiscontroversialatpresent.WhyfindingsontheassociationbetweenthepresenceofaPLAandtheprognosisofLNaresodiverseinpublishedreportsisobscureatpresent(Table2).However,wepostulatedthatnotonlydothedifferentserotypesplaydiverserolesinthepathogenesisofLN,asmentionedpreviously,butthat theheterogeneouspopulationsofLNpatients inthepreviousstudiesmayhavebeenvitalintheaPLA-associatedpresentations.InordertoincludeallserotypesofaPLAthatmightbeassociatedwiththeprognosisofLN,thosepatientswhohadbeentestedforthepresenceofaPLAbyeitheronemeasurementwererecruitedincurrentinvestigation.

TheseroprevalenceofaPLAinLNwasbetween26%and67%invariousstudies[11,18-21].Inthecurrentseries,theseroprevalenceofaPLAinLNpatientswas27%.Thediversityofseroprevalencemightbeattributed

tothedifferentpopulationsofLNpatientsandthewaythataPLAwasidentified.

Despitethefactthattheassociationofanti-dsDNAwithLNhasbeenreported,theimpactofanti-dsDNApositivityonlong-termrenalprognosisisstillunclear[8].Inthepresentstudy,asignificantlyhigherseropositiverate(p=0.023)wasfoundingroupIpatients.However,afterCoxregressionanalysis, thepresenceofanti-dsDNAhadnorenalprognosticeffectinourpopulationofLNpatients(datanotshown).

AlthoughithasbeendemonstratedthatLNpatientswithaPLAhadahigher riskof thromboticevents,especiallyafter long-termfollow-up[4,5,18,22],nothromboemboliceventwasdocumentedinallof thepatientsinthisstudyduringthefollow-upperiod.ThedifferentpopulationsofLNpatients,diverse lengthsoffollow-up,presenceofanti-phospholipidsyndromeinsubjectsenrolledandeventhedifferentserotypesofaPLAineachseriesmightexplainthediscrepancybetweentheresultsofthepresentstudyandthoseofotherinvestigations.

IthasbeenreportedthataPLAwasassociatedwithelevatedSCrlevels[7,10,12,18]andincreaseddailyurinaryprotein lossatpresentation [11].However,inthepresentstudy,notonlyweretheseassociationsnot observed, but nodifferences inother clinicalcharacteristicsbetweengroupswere identified. Inaddition, itwasalsodemonstrated that thepresenceof aPLAhad a negative impact on the long-termoutcomeofLN[18].However,contrarytothispreviousreport,thesurvivalanalysisinthepresentstudy(Fig.1)disclosedthat thepatients ingroupIhadabetterrenaloutcomethanthoseingroupII.Eventhoughnosimilarfindingshadbeenreported,Tsurutaetal.found

Table 2. Summary of antiphospholipid antibody and prognosis of lupus nephritis LN cases Country/race Follow-up Clinical thrombosis Renal outcomeFrampton et al. �99� 76 UK Cross-section NS NSPerdiguero et al. �995 2� Spain 55 ± 42 months NA worseBhandari et al. �998 5� UK 4� months

(range 4-�82 months)yes worse

Massengill et al. �997 �6 Caucasian/African

American

6 years (�990-�996)

NS NA

Naiker et al. 2000 40 26 Blacks/�4 Indians

Cross-section NA NS

Moroni et al. 2004 ��� Italy �7� ± �00 months yes worseNatejumnong et al. 2006 6� Thailand Cross-section NA NSTsuruta et al. 2009 49 Japan 76.4 ± 47.2 months yes NSCurrent series 66 Taiwan 2�.� ± 6.0 months NA better

NS = not significant; NA = data not available

26

aPLA and lupus nephritis

asignificantlowerprevalenceofclassVLNinaPLApositivepatients,butadditionalstudiesstillneedtobedonetoconfirmthisassociation[19].Therefore, theobservationthatseropositivityofaPLAinLNsuggestsapoorrenaloutcomeisinconsistent.

That aPLAwas associatedwith glomerularthrombosisinLNhasbeenreported[12,23].However,inthecurrentseries,wedidnotfocusonidentifyingglomerular thromboticmicroangiopathy,afeatureofacuteantiphospholipidsyndromenephropathy(APSN)[7,24,25].IthasalsobeenshownthatpersistentandmoderatetohightitersofaPLAweremorespecificforthrombosisinLNpatients[16].Inourstudy,weincludedpatientswithseropositiveaPLAirrespectiveoftiters.WhetherthepresenceofglomerularthrombosisinrenalpathologyorthetiterofaPLAisrelatedtotheprognosisofLNwasnotdeterminedinthecurrentsurvey.

Regarding theserotypesofaPLA,Naikeretal.demonstratedthataCLAwasnotrelevanttothrombosisinLN;however,Farrugiaetal.reportedthatLACwasmorespecific toAPSN[26,27]. Inaddition,astudyinvestigatingaPLAin lungadenocarcinomapatientsrevealedahighseropositiverateofIgMaβGPIinthesepatients,butalsoshowedadecrease in thrombosisrisk; the presence ofLACwas highly correlatedwiththrombosis inthesamepatientpopulation[28].Furthermore,notallpatientswithaPLAdevelopedthromboembolic eventsorAPSN [7,17].Besides,histologicalAPSNcouldbeduetothrombosisfactorsotherthanaPLA.Alloftheaboveevidencesuggeststhatfirst,aPLA-relatednephropathyisassociatedwiththromboticglomerularlesionsinsteadofseropositivityofaPLAperse;second,differentserotypesofaPLAmayinfluencetherenaloutcomeofLN.Duetothelimitationofthesamplesizeinthisstudy,wecouldnotdeterminewhetherserotypesofaPLAwererelatedtotheprognosisofLN.

Contrarytopreviousstudies,ourdatarevealedthatLNpatientswithseropositivityofaPLAhadabetteroutcomethantheseronegativepopulation.CoulditbepossiblethatcertainserotypesofaPLAhaveaprotectiveeffectforLNpatients?Tothebestofourknowledge,nodirectevidencesupportsthishypothesisatpresent;however,Nicoloetal.demonstrateda reductionofatherosclerosis in low-density lipoprotein receptor–deficientmicewiththepassiveadministrationofaPLA[29].Theypostulated that thepossiblepathogenesisinvolved thecross-reactivityofaPLAandoxidizedlow-densitylipoproteins(ox-LDL).Subsequentstudiessuggestedthatantibodiestoox-LDLmayprotectagainstatherosclerosis,possiblybecausetheycanscavengethe

ox-LDLparticles[30,31].Besides,resultsofastudyonatherosclerosis-pronemicemayalsosuggest thathumoralimmunizationwithox-LDLcouldreducetheseverityofdisease[32].Inanycase,thehypothesisthatsomeserotypeofaPLAhasapositiveimpactonLNstillneedstobeverified.

The limitationof this investigation is that it isaretrospectivechartreviewstudy,notallofthedatacouldberetrieved,andtheonsetofLNcouldnotbetraced.Therefore,notalloftheprognosticfactorspotentiallyassociatedwithrenaloutcomecouldbeanalyzed.Inaddition, themethodsused tomeasureaPLAlevelsweredifferentandthepopulationofLNpatientswasdiverseineachofthestudies,whichmayexplainthevastdifferencesbetweenourresultsandthoseofothersurveys.Informationofclinicalthrombosiswhichwasnotcollectedinthisstudyandthesmallcasenumberalsomakes the statistics less convincing.Finally,otherdrawbackstothestudyincludethatnotallaPLAserotypeswere tested in theLNpatients thatwererecruitedandthefollow-upperiodwasonly2years.Anyway,ourstudydemonstratedthatthepresenceofaPLAinLNpatientsprobablyconfersaprotectiveeffect,rather thanresultinginadevastatingrenaloutcome.However,thisobservationneedsfurtherstudy.

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30. ShawPX,HorkkoS,TsimikasS,ChangMK,PalinskiW,SilvermanGJ,etal.Human-derivedanti-oxidizedLDLautoantibodyblocksuptakeofoxidizedLDLbymacrophagesandlocalizestoatheroscleroticlesionsinvivo.ArteriosclerThrombVascBiol2001;21:1333-9.

31. VaaralaO,AlfthanG,JauhiainenM,Leirisalo-RepoM,AhoK,PalosuoT.Crossreactionbetweenantibodiestooxidisedlow-densitylipoproteinandtocardiolipininsystemiclupuserythematosus.Lancet1993;341:923-5.

32. FreigangS,HorkkoS,MillerE,WitztumJL,PalinskiW. ImmunizationofLDL receptor-deficientmicewithhomologousmalondialdehyde-modifiedandnativeLDLreducesprogressionof atherosclerosisbymechanismsotherthaninductionofhightitersofantibodiestooxidativeneoepitopes.ArteriosclerThrombVascBiol1998;18:1972-82.

28

aPLA and lupus nephritis

抗磷脂抗體是否為紅斑性狼瘡腎炎的預後因子

邱文燦 黃純真� 陳忠仁 許鐘元 楊聰信 周靜蘭 蘇富美 蘇昱日

尤珊富 邱俊凱 陳英州 賴漢明 鄭添財

長庚醫療財團法人高雄長庚紀念醫院 過敏免疫風濕科 �解剖病理科

目的：研究抗磷脂抗體對紅斑性狼瘡腎炎的腎功能預後的影響。方法：本研究回溯性調閱本院過

去經診斷為紅斑性狼瘡腎炎病人之病歷，他們都符合美國風濕病醫學會紅斑性狼瘡分類標準，並

於1986-2007期間在本院接受過腎臟切片，經確認為狼瘡性腎炎。但我們只收集有驗過至少一項

抗磷脂抗體試驗的病患之人口統計學，血清學資料及治療內容。主要觀察重點為24個月內達到

兩倍血中肌酸酐或末期腎病變/死亡的比率。結果：我們總共收錄66病患，其中包括55個女性及

11個男性。平均年齡30.53±11.09歲。18位病患抗磷脂抗體陽性（27.3%）（I），餘下48位病患

為陰性（72.7%）（II）。在2年的存活分析發現抗磷脂抗體陽性的病患（I）有較好的腎臟預後

（p<0.05）。結論：與之前的研究相反的是抗磷脂抗體陽性在我們狼瘡腎炎的病患可能有較好的腎

臟預後。

關鍵字：狼瘡腎炎、長期預後、ISN/RPSclassification、抗磷脂抗體

Original Article

29

Introduction

Polymyositis(PM)anddermatomyositis(DM)areinflammatoryconnectivetissuediseaseswithunknownetiologies,predominantly involvingthemusclesand

skin,butalsoproducingpulmonarymanifestationsandmaybeassociatedwithmalignancies[1-5].DMis amultisystem inflammatorydisorderprimarilyaffectingproximal skeletalmuscles and the skin,andischaracterizedbytypicalheliotroperashesandGottron'spapules.PreviousreportsfoundseveralfactorsassociatedwithahighmortalityrateforpatientswithPM/DM,suchas interstitial lungdisease(ILD),oldage,andcardiacinvolvement.[6-11,19,23].Notably,PM-orDM-associatedmalignanciesalsocontributetopoorprognosis.TheaimofthisstudywastodefinebothclinicalandbiochemicalfeaturesinpatientsdiedofPM/DM,andtoidentifypredictorsofPM/DMmortality.

Prognostic factors of survival in patients with dermatomyositis and polymyositis Hsiao-Chun Chang1, Yeong-Jian Jan Wu1,2, Shue-Fen Luo1,2, Huei-Huang Ho1,2,

Lieh-Bang Liou1,2, Ji-Yih Chen1,2, Wen-Pin Tsai1, Chang-Fu Kuo1, Chung-Han Yang1,

I-Jung Chen2, Kuang-Hui Yu1,2

1Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, and 2Chang Gung University, Tao-Yuan, Taiwan.

Correspondingauthor:Kuang-HuiYu,M.D.DivisionofAllergy,ImmunologyandRheumatology,ChangGungMemorialHospital.No5,Fu-ShinSt.,Kuei-Shan,Tao-Yuan,Taiwan.E-mail:gout@adm.cgmh.org.twReceived: Feburary 26, 2010Revised: June 24, 2010Accepted: June 30, 2010

Background:Todeterminetheincidence,characteristics,andprognosticfactorsofmortalityinpatientswithpolymyositis(PM)anddermatomyositis(DM).Materials and Methods:Medicalrecordsof151PM/DMpatientstreatedatChangGungMemorialHospitalbetween2000and2007wereretrospectivelyreviewed.Results:Twenty-five(16.6%)ofthe151PM/DMpatientshadassociatedcancer.Thirty-two(21.2%)ofthe151PM/DMpatientshadinterstitiallungdisease(ILD).Duringfollow-up,30(19.9%)patientsdied.Overallpatientcumulativesurvivalrateswere81.0,77.6,and74.6%at1,2,and5years,respectively.Inunivariateanalysis,oldageatPM/DMonset,cancer, ILD,DM,diabetesmellitus, lowcreatinephosphokinase(CPK)level,anduseofintravenousimmunoglobulinwereassociatedwithincreasedmortality(p=0.018,0.011,<0.001,0.002,0.001,0.009,and0.007,respectively).Multivariateanalysisexcludinganti-Jo-1antibodywasperformedafteradjustingforCPKlevel.OnlyILD(OR=12.93,95%CI=3.97-42.13,p<0.001)andcancer(OR=4.10,95%CI=1.21-13.91,p=0.023)wereassociatedwithmortality.Iftheanti-Jo-1antibodywasincludedinmultivariateanalysis(n=80),thenILD(OR=15.40,95%CI=2.68-88.02,p=0.002)andDM(OR=12.56,95%CI=1.21-130.62,p=0.034)wereassociatedwithincreasedmortality.Conclusion:ThisstudyunderlinesthehighmortalityratethatassociatedwithPM/DM.SurvivaltimewassignificantlyshorterforpatientswithILD,cancerorDMthanthosewithout.

Key words:Prognosis,survivalanalysis,polymyositis,dermatomyositis

Formosan Journal of Rheumatology 20�0;24:29-�5

�0

Survival outcomes for dermatomyositis and polymyositis

GiventheimpactofmalignancyandILDinPM/DMpatients,thisretrospectivestudyalsocharacterizedtheclinicalfeaturesofmalignancyandILDassociatedwithPM/DM.

Patients and Methods

Study populationThemedicalrecordsof151PM/DMpatientstreated

atChangGungMemorialHospital,Taoyuan,Taiwan,from2000to2007,werereviewed.ThedesignofthestudywasreviewedandapprovedbytheInstitutionalReviewBoardatthisinstitution.Ofthese151patients,83werediagnosedwithDM,and68werediagnosedwithPM.Allpatientsweretreatedasin-patients.Onehundredandfiftypatientsmet theBohanandPetercriteria(definite,n=73;probable,n=49;possible,n=28)[12],and1wasdiagnosedwithamyopathicdermatomyositis (ADM)basedon typicalDMrash(Gottronpapules),lackofmuscleweaknessandnormalcreatinephosphokinase (CPK) level [13].Allstudysubjectswerefurthercategorizedintothefollowingfivemaingroups:groupI,primaryidiopathicPM(IPM);groupII,primary idiopathicDM(IDM);groupIII,cancer-associatedmyositis;groupIV,juvenilePM/DM(definedasonsetatage17yearsoryounger[14]);and,groupV,overlappingsyndromes[12].

Clinicaldatawerecollectedfrommedicalrecords,including gender, age at onset, clinical featurespresented,laboratorytestresults,associatedconnectivetissuediseases,malignancies, ILD,andmortality.Mortalitywasdefinedaspatientdeath,as indicatedbyhospitalrecords.AllILDpatientswerecategorizedby the clinicaldiagnosisof idiopathicpulmonaryfibrosis (IPF), nonspecific interstitial pneumonia(NSIP),cryptogenicorganizingpneumonia(COP)andacute interstitialpneumonia (AIP)according to theinternationalconsensusdefiningtheclinicaldiagnosisandclassificationofILD[15].

Univariateanalysisusing logisticregressionwas

applied to identifypossiblepredictive factors formortality,suchasmeanageatdiseaseonset,gender,presentationsatonset,malignancies,ILD,medications,andbiochemicaldata.SignificantfactorsintheunivariateanalysiswereusedformultivariatelogisticregressiontoidentifyindependentriskfactorsformortalityofPM/DMpatients.

Statistical analysisNumericaldatawaspresentedasmeans±SD,while

categoricaldatawasexpressedaspercentages.Eitherthechi-squaretestorFisher’sexacttestwasusedforgroupcomparisonsinvolvingbinarydata,asappropriate.Fornumericaldata,aStudent’s t-testoranonparametricMann-WhitneyU-testwasusedtocomparetwogroups.All analytical resultswere considered significantatp<0.05.Additionally,multivariate analysiswasperformed using logistic regression to identifyindependentmortalityriskfactors.Theoddsratio(OR)waspresentedwitha95%confidenceinterval(95%CI).PatientsurvivalwasanalyzedbyKaplan-Meiercurveandthelog-ranktest.AllstatisticalcalculationswereperformedusingSPSS12.0software(SPSS,Chicago,IL,USA).

Results

Patient DemographicsOfthe151patientswithPM/DM,53(35.1%)were

maleand98(64.9%)werefemale;mean(±SD)agewasof48.4±18.0yearsatPM/DMonset.Themeanfollow-updurationwas2.3±2.2years.Table1showsthedemographicdataforallpatients.ThemostcommondiseasetypewasIPM(n=51,33.8%),followedbyIDM(n=45,29.8%),cancer-associatedPM/DM(n=25,16.6%),overlappingsyndromes(n=21,13.9%),andjuvenilePM/DM(n=9,6.0%).Twenty-one(13.9%)ofthe151patientshadco-presentationsofotherconnectivetissuediseases,includingsystemiclupuserythematosus,

Table 1. Demographic data of patients with polymyositis (PM) and dermatomyositis (DM) according to Bohan and Peter’s classification schemeClassification IPM IDM Cancer

associatedJuvenile DM/PM

Overlap syndrome

Total

Cases, n (%) 5� (��.8) 45 (29.8) 25 (�6.6) 9 (6.0) 2� (��.9) �5� (�00.0)Age at onset (yr) 49.0 ± �6.0 50.4 ± �5.8 57.7 ± ��.� 8.7 ± 4.8 48.8 ± ��.4 48.4 ± �8.0Female, n (%) �4 (67.7) 28 (62.2) �2 (48.0) 7 (77.8) �7 (8�.0) 98 (64.9)ILD, n (%) 8 (�5.7) �4 (��.�) 4 (�6.0) 0 6 (28.6) �2 (2�.2)Abbreviations: IPM = idiopathic polymyositis; IDM = idiopathic dermatomyositis; JDM/PM = juvenile dermatomyositis/polymyositis; ILD = interstitial lung disease

��

Chang et al

rheumatoidarthritisandprogressivesystemicsclerosis.Notably,14.7%(10/68)ofPMpatientsand14.9%(11/74)ofDMpatientshadoverlappingconnectivetissuediseases.Malignanttumorswereidentifiedin25(16.6%)of151patients.Amongthese25patientswithcancers,7(28%)hadPMand18(72%)hadDM.Inthisstudy,theprevalenceofILDwas21.2%(32of151).TheNSIPwasthemostcommontypeofILD(n=19),followedbyAIP(n=7),IPF(n=4),andCOP(n=2).AllpatientsdiagnosedwithAIPdisplayedground-glassopacitiesonhigh-resolutioncomputedtomography,andall7AIPpatientsdied.

Malignancies associated with PM/DMThe group with cancer-associated PM/DM

comprisedof25 (16.6%)patients.Nasopharyngealcancer(NPC)wasthemostcommontypeofmalignancy(9/25,36.0%).Othermalignancieswerebreastcancer(n=3,12.0%),lungcancer(n=3,12.0%),ovariancancer,stomachcancer,coloncancer,non-Hodgkinlymphoma,cervicalcancer,leukemia,uretercancer,prostatecancer,thyroidcancer,andcancerofunknownprimary(n=1

each,4.2%).

Univariate analysis of PM/DM patients with and without mortality

Table2comparesPM/DMpatientswithandwithoutmortalitybyunivariateanalysis.Basedonclinicaldata,thepatientswithmortalityhadanolderageofdiseaseonset thanthosewithout(55.3vs.46.7y;p=0.018).Furthermore, theprevalenceof cancer (33.3%vs.12.4%;p=0.011), ILD(56.7%vs.12.4%;p<0.001),DM(80.0%vs.48.8%;p=0.002),diabetesmellitus(36.7%vs.9.9%;p=0.001),anduseof intravenousimmunoglobulin (IVIG,23.1%vs.4.8%;p=0.007)werehigherinthemortalitygroupthaninthesurvivalgroup.However,themeanCPKlevelwaslowerinthemortalitygroupthaninthesurvivalgroup(1667.2vs.3578.2U/L;p=0.009).ThePM/DMpatientswithandwithoutmortalitydidnotdiffersignificantlyingender,arthritis/arthralgia,dysphagia,hypertension,hemoglobinlevel,whitebloodcellcount,plateletcount,aspartateaminotransferaselevel,alanineaminotransferaselevel,creatininelevel,andtiterofantinuclearantibodies(Table

Table 2. Univariate analysis of mortality associated with PM/DM patientsMortality (n = �0)

Survival (n = �2�)

p-value

Female, n (%) �6 (5�.�) 82 (67.8) 0.��8Onset age (yr) 55.� ± �7.2 46.7 ± �7.8 0.0�8*Cancer, n (%) �0 (��.�) �5 (�2.4) 0.0��*ILD, n (%) �7 (56.7) �5 (�2.4) < 0.00�*Dermatomyositis, n (%) 24 (80.0) 59 (48.8) 0.002*Arthritis/arthralgia, n (%) 7 (2�.�) �5 (28.9) 0.54�Dysphagia, n (%) �2 (40.0) 48 (�9.7) 0.974Diabetes mellitus, n (%) �� (�6.7) �2 (9.9) 0.00�*Hypertension, n (%) �0 (��.�) 25 (20.7) 0.�4�Maximal CPK (U/L) �667.2 ± �972.7 �578.2 ± 5276.5 0.009*Hemoglobin (mg/dL) ��.9 ± 2.� �2.5 ± �.9 0.094Platelet 240.8 ± ��2.� 26�.9 ± 90.4 0.4�4WBC 8928.0 ± 480�.6 827�.� ± 4���.2 0.452AST (n = ��6) �48.8 ± �78.2 �28.6 ± �40.6 0.268ALT (n = ��7) 95.� ± �00.2 �06.0 ± ���.9 0.5�4Cr (n = �42) �.00 ± 0.66 0.74 ± 0.88 0.6�5ANA positive (n = ��9) 20/26 (76.9) 77/113 (68.1) 0.�79Anti-Jo-� (n = 80) 4/18 (22.2) 5/62 (8.1) 0.�09Corticosteroid >0.5 mg/kg (%) 2� (76.7) 98 (8�.0) 0.595Methotrexate, n (%) 2 (7.7) 9 (7.2) �.000Azathioprine, n (%) 5 (9.2) 28 (22.4) 0.722Cyclophosphamide, n (%) 2 (7.7) 5 (4.0) 0.4�5IVIG, n (%) 6 (2�.�) 6 (4.8) 0.007*

Unless otherwise stated, categorical data are n (%) and continuous values are mean ± SD. Abbreviations: PM/DM = polymyositis/dermatomyositis; ILD = interstitial lung disease; SD = standard deviation; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatine phosphokinase; ANA = antinuclear antibody; IVIG = intravenous immunoglobulin. *p<0.05.

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Survival outcomes for dermatomyositis and polymyositis

2).ForotherPM/DMtherapyregimens,nosignificantdifferenceexistedbetweenmortalityandsurvivalgroupsforuseofsteroidsof>0.5mg/kg/dayprednisoloneequivalent(76.7%vs.81.0%;p=0.595),methotrexate(7.7%vs.7.2%;p=1.000), azathioprine (9.2%vs.22.4%;p=0.722),orcyclophosphamide(7.7%vs.4.0%;p=0.415).

Multivariate analysis of PM/DM patients with and without mortality

Severalfactorswereselectedforlogisticregressionanalysis,adjustedforCPKlevel,toidentifyindependentpredictorsformortalityofPM/DMpatients(Table3).Thesefactorsweremeanageatonset>45years,gender,cancer, ILD,DM,diabetesmellitus, IVIG,andanti-Jo-1antibody.First,anti-Jo-1antibodywasexcludedfrommultivariateanalysissinceonly80patientshadbeentested.Multivariateanalysisresults,adjustedforCPKlevel,revealedthatcancer(adjustedOR=4.10,95%CI=1.21-13.91,p=0.026)andILD(adjustedOR=12.93,95%CI=3.97-42.13,p=0.032)weretheonlytwoindependentriskfactorsassociatedwithmortality.Logisticregressionwasagainperformedafterincludingtheanti-Jo-1antibody(n=80).Notably,cancerstatusnolongerdifferedsignificantlybetweenthemortalityandsurvivalgroups(p=0.174).ILD(adjustedOR=15.40,95%CI=2.68-88.02,p=0.002)andDM(adjustedOR

=12.56,95%CI=1.21-130.62,p=0.034)werebothpredictorsofmortalityofPM/DMpatients(Table3).

Survival analysisOf the151PM/DMpatients, 30 (19.9%)died

duringfollow-up.ThepresenceofILDwasextremelydetrimental topatient survival.TheKaplan-Meiersurvivalcurvespresentedthesurvivalprobabilityforpatientswith(n=32)andwithout(n=119)ILD(Fig.1).Overallpatientcumulativesurvivalrateswere81.0%at1year,77.6%at2yearsand74.6%at5years.ThecumulativesurvivalratesofILDpatientsinthisstudywere51.2%,46.5%,and41.9%at1,2and5years,respectively.ThesurvivalratewassignificantlylowerforpatientswithILDthanthatforpatientswithoutILD(p<0.001)(Fig.1).ThemortalityratewashigherforILDpatients(53.3%,n=17)thanthatfornon-ILDpatients(10.7%,n=13,p<0.001).Thistendencystillexistedevenafterexcludingcancer-associatedPM/DMcases(50.0%vs.6.1%,p<0.001).

Discussion

DMandPMaresimilar inflammatoryconnectivetissuediseasesofunknownetiology,predominantlyinvolving themuscleswithandwithout skin.BothPMandDMareassociatedwithhighmorbidityandmortality.The5-yearsurvivalratesforthesepatientsrangedfrom52-95%inpreviousstudies,andcausesofdeathwererelatedtocardiacinvolvement,pulmonarycomplications,cancer,andinfection[1-11,16-25].ILDandmalignancyarefrequentassociatedconditionsand

Table 3. Multivariate analysis: adjusted odds ratio (OR) for risk of mortality in PM/DM patients after controlling for the creatine phosphokinase levelVariables Adjusted OR 95% CI p-valueAnti-Jo-� excluded (n = �5�)

Male vs. Female 2.62 0.84-8.20 0.098Age >45 years 0.84 0.27-2.6� 0.76�Cancer 4.�0 �.2�-��.9� 0.02�*ILD �2.9� �.97-42.�� < 0.00�*Dermatomyositis 2.97 0.9�-9.72 0.072Diabetes mellitus �.�2 0.9�-�0.48 0.066IVIG 2.69 0.6�-��.82 0.�90

Anti-Jo-� included (n = 80)Male vs. Female �.�2 0.20-6.20 0.900Age >45 years �.�6 0.2�-8.22 0.7�5Cancer 4.58 0.5�-40.9� 0.�74ILD �5.40 2.68-88.02 0.002*Dermatomyositis �2.56 �.2�-��0.62 0.0�4*Diabetes mellitus �.86 0.29-��.84 0.5��IVIG �.88 0.29-�2.0� 0.506Anti-Jo-� 4.97 0.49-50.68 0.�76

Abbreviations: ILD = interstitial lung disease; OR = odds ratio; CI = confidence interval; IVIG = intravenous immunoglobulin *p<0.05.

Figure 1. Survival curves for �5� polymyositis and dermatomyositis patients

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Chang et al

significantprognosticfactorsforPM/DMpatients.ILDoccurredin5-65%ofPMandDMpatients[11].Thisstudynotedthat32(21.2%)of151patientswithPM/DMhadILD,whichwasconsistentwithfindingsofpreviousinvestigations[6-11,17-25].Sincethefirst reportbyMillsandMathewsin1956[16],manyinvestigationsofPM/DM-related ILDhadelucidated its clinicalcharacteristicsandprognosis.Inthisstudy,theoverallcumulativesurvivalrateswere81.0%at1year,77.6%at2year,and74.6%at5years;theserateswereconsistentwiththoseinotherstudies[1-11,16-24].However,PM/DMpatientswithILDhada1-yearcumulativesurvivalrateofonly51.2%,indicatingthatPM/DMpatientswithILDhaveapoorerprognosisthanthosewithoutILD.

PredictorsofsurvivalofPM/DMpatientsarealwaysaconcerngiventheirassociationswithhighmorbidityandmortality.PreviousresearchershavedescribedmanymortalityvariablesforPM/DMpatients[6,9,11,17-25].Oldage(>45yearsofage)atPM/DMonset,cancer,ILD,andcardiac involvementwereassociatedwithmortality.However,multivariateanalysisinthisstudy,aftercontrollingforCPKlevel,revealedthatonlyILD,cancerorDMitselfremainedstatisticallysignificant.Moreover,thisstudyfoundthemortalityrateofpatientswithPM/DM-related ILD(53.3%)washigher thanthatreportedelsewhere(13.9-42.9%)[6,8,9,20,23].Apossibleexplanationwastheracialorenvironmentaldifferencesbetweenthestudypopulations.Infact,moststudieswithhighmortalityrateswereconductedinAsia[6].

Wengetal.reported23TaiwanesepatientsofPM/DMwith ILD.Patientsweresubdivided into rapidprogressiongroup(Hamman-Rich-likepattern),slowprogressiongroup,andasymptomaticgroup,accordingtotherapidityofprogressionofpulmonarysymptoms.Themortality rateof the rapidprogressiongroup(85.71%)washigherthanthatoftheslowprogressiongroup(25%)[26].Anearlierstudyperformedbyourgroupalsoobservedasimilartrend[6].

Furthermore,anassociationbetweenPM/DMandmalignancieshasbeenwidelyreported in literature[2-5,17-30].Therewere25(16.6%)patientsinthegroupwithcancer-associatedPM/DM.Inthisstudy,NPCwasthemostcommoncancerfollowedbybreastandlungcancers.Notably,NPCwasthemostcommoncancerassociatedwithPM/DMinsouth-easternAsianpatients[4,25,28].Conversely,themostfrequentcancertypesinwesterncountrieswerebreast,lung,andgastrointestinaltumors[2,28].MalignancyandILDareassociatedwithPM/DMandresponsibleforasignificantproportionofmorbidityandmortality;however,patientswith

malignancy-associatedPM/DMwerelesslikelytohaveILDthanPM/DMpatientswithoutmalignancy[2,6,28].

TherangeforPM/DMmortalitywas4-45%[28].Negativeprognostic factors forsurvivalofPM/DMpatientsidentifiedbypreviousstudiesincludedadvancedage,ILD,cancer,andpresenceofanti-Jo-1antibody.MultivariateanalysisinthisinvestigationshowedthatILD,cancer,orDMwereindependentpredictivefactorsformortalitywithPM/DMafteradjustingfortheCPKlevel.Comparedwithotherstudies,thisstudyrevealedasimilarpercentage(19.9%)ofoverallmortalityinPM/DMpatientsduringfollow-up.Moreover,themyositis-specificanti-Jo-1antibodiesdelineatedauniquegroupofPM/DMpatientswithremarkablysimilarclinicalfeatures,includingILD,arthritis,andpositiveantibodiesto tRNAsynthetases [29].However,only11.3%ofpatientswithmyositis inthisstudyhadtheanti-Jo-1antibody,thuslimitingthepredictiveabilityofthistest[3,6].

In conclusion, this case series revealed highincidencesof ILDandmalignancyamongPM/DMpatients;bothconditionswereassociatedwithreducedsurvival.TheILD-associatedPM/DMpatientshadacumulativemortalityrateof53.3%.ThepresenceofpoorprognosticfactorsshouldpromptclosemonitoringandaggressivetreatmentforPM/DMpatients.Closefollow-upofPM/DMpatientswith risk factors formortalityismandatory.

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3.FardetL,DupuyA,GainM,KettanehA,ChérinP,BachelezH,etal.Factorsassociatedwithunderlyingmalignancyinaretrospectivecohortof121patientswithdermatomyositis.Medicine2009;88:91-7.

4.HuangYL,ChenYJ,LinMW,WuCY,LiuPC,ChenTJ,etal.MalignanciesassociatedwithdermatomyositisandpolymyositisinTaiwan:anationwidepopulation-basedstudy.BrJDermatol2009;161:854-60.

5.MaozCR,LangevitzP,LivnehA,BlumsteinZ,SadehM,BankI,etal.Highincidenceofmalignanciesinpatientswithdermatomyositisandpolymyositis:an11-yearanalysis.SeminArthritisRheum1998;27:319-24.

6.ChenIJ,JanWuYJ,LinCW,FanKW,LuoSF,YuKH,etal.

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Interstitiallungdiseaseinpolymyositisanddermatomyositis.ClinRheumatol2009;28:639-46.

7.HirakataM,NagaiS.Interstitiallungdiseaseinpolymyositisanddermatomyositis.CurrOpinRheumatol2000;12:501-8.

8.DouglasWW,TazelaarHD,HartmanTE,HartmanRP,DeckerPA,SchroederDR,RyuJH.Polymyositis/dermatomyositis-associatedinterstitiallungdisease.AmJRespirCritCareMed2005;164:1182-5.

9.MarieI,HachullaE,ChérinP,etal.Interstitiallungdiseaseinpolymyositis anddermatomyositis.ArthritisRheum2002;47:614-22.

10. TazelaarHD,ViggianoRW,PickersgillJ,etal.Interstitiallungdiseaseinpolymyositisanddermatomyositis:clinicalfeaturesandprognosisascorrelatedwithhistologicfindings.AmRevRespirDis1990;141:727-33.

11. FathiM,LundbergIE.Interstitiallungdiseaseinpolymyositisanddermatomyositis.CurrOpinRheumatol2005;17:701-6.

12. BohanA,PeterJB.Polymyositisanddermatomyositis(firstoftwoparts).NEnglJMed1975;292:344-7.

13. EuwerRL,SontheimerRD.Amyopathicdermatomyositis:areview.JInvestDermatol1993;100:124S-127S.

14. AnsellBM.Juveniledermatomyositis.RheumDisClinNorthAm1991;17:931-42.

15. AmericanThoracicSociety/EuropeanRespiratorySocietyInternationalMultidisciplinaryConsensusClassificationoftheIdiopathicInterstitialPneumonias.ThisjointstatementoftheAmericanThoracicSociety(ATS),andtheEuropeanRespiratorySociety(ERS)wasadoptedbytheATSboardofdirectors,June2001andbytheERSExecutiveCommittee,June2001.AmJRespirCritCareMed2002;165:277-304.

16. Mills ES,MathewsWH. Interstitial pneumonitis indermatomyositis.JAmMedAssoc1956;160:1467-70.

17. MedsgerTAJr,RobinsonH,MasiAT.Factorsaffectingsurvivorship inpolymyositis.A life-table studyof124patients.ArthritisRheum1971;14:249-58.

18. BenbassatJ,GefelD,LarholtK,etal.Prognosticfactorsinpolymyositis/dermatomyositis.Acomputer-assistedanalysisofninety-twocases.ArthritisRheum1985;28:249-55.

19. MaugarsYM,Berthelot JM,AbbasAA, et al. Long-

termprognosisof69patientswithdermatomyositisorpolymyositis.ClinExpRheumatol1996;14:263-74.

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21. SultanSM,IoannouY,MossK,etal.Outcomeinpatientswith idiopathic inflammatorymyositis:morbidity andmortality.Rheumatology2002;41:22-6.

22. ItoM,Kaise S, Suzuki S, et al. Clinico-laboratorycharacteristicsofpatientswithdermatomyositisaccompaniedby rapidly progressive interstitial lung disease.ClinRheumatol1999;18:462-7.

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27. ChenYJ,WuCY,ShenJL.Predictingfactorsofmalignancyindermatomyositisandpolymyositis:acase-controlstudy.BrJDermatol2001;144:825-31.

28. AntiochosBB,BrownLA,LiZ,TostesonTD,WortmannRL,RigbyWF.Malignancyisassociatedwithdermatomyositisbutnotpolymyositis inNorthernNewEngland,USA.JRheumatol2009;36:2704-10.

29. RozelleA,TrieuS,ChungL.Malignancyinthesettingoftheanti-synthetasesyndrome.JClinRheumatol.2008;14:285-8.

30. BronnerIM,vanderMeulenMF,deVisserM,KalmijnS,vanVenrooijWJ,VoskuylAE,etal.Long-termoutcomeinpolymyositis anddermatomyositis.AnnRheumDis2006;65:1456-61.

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多發性肌炎與皮肌炎病患之存活及預後因子分析

張筱桾 吳詹永嬌 羅淑芬 何輝煌 劉烈邦 陳基益 蔡文彬 郭昶甫

楊宗翰 陳逸戎 余光輝

長庚紀念醫院暨長庚大學 風濕過敏免疫科

背景：探討多發性肌炎（polymyositis,PM）及皮肌炎（dermatomyositis,DM）病患死亡之發生率，

臨床特徵，及預後因子。材料及方法：本回溯性研究分析於2000年至2007年間，因PM/DM在長庚

醫院接受治療之151個PM/DM病患的病例資料。結果：151個PM/DM的病患中有25個（16.6%）罹

患相關惡性腫瘤；有32個（21.2%）病患發生間質性肺病（interstitial lungdisease, ILD）。在追蹤

期間共有 30位（19.9%）病患死亡。本研究的病患總體存活率：一年為81.0%，兩年為77.6%，五

年為74.6%。利用單變項迴歸分析，發現PM/DM的發病年齡較晚，惡性腫瘤，合併ILD，皮肌炎，

合併糖尿病，低肌酸磷化酶值（creatinephosphokinase,CPK），以及使用 IVIG皆和較高的死亡率

有關（p值分別為0.018，0.011，<0.001，0.002，0.001，0.009，及0.007）。在排除 anti-Jo-1抗體

並調整CPK值後進行多變項分析，得到結果僅ILD（OR=12.93,95%CI=3.97-42.13,p<0.001）與

惡性腫瘤（OR=4.10,95%CI=1.21-13.91,p=0.023）為死亡的相關因子。若將anti-Jo-1列入多變項

分析 （n=80），則得到ILD（OR=15.40,95%CI=2.68-88.02,p=0.002）以及皮肌炎診斷（OR=

12.56,95%CI=1.21-130.62,p=0.034）和較高的死亡率有關。結論：本研究顯示PM/DM病患有相當

高的死亡率。合併ILD、惡性腫瘤或皮肌炎的病患之存活時間明顯地較無上述因子的病患來得短。

關鍵詞：預後、存活分析、多發性肌炎、皮肌炎

Original Article

�6

Introduction Neurologicandpsychiatric symptomsoccur in10-80%ofpatientswithsystemiclupuserythematosus(SLE) [1-5].Myelitis,a rarebut severeneurologicpresentation,isestimatedtoaffect1-2%ofpatientswithSLE[6].Itisaninflammatorysyndromeofthespinalcord,withahighmorbidityrate.Itinitiallypresentswithweaknessinthelowerextremities,sensoryloss,andlossofrectalandurinarybladdersphinctercontrol[7].

Despite itshighmorbidityrate,onlyafewlarge-scaleretrospectivecohortstudieshavebeenconducted.

Myelitis in patients with systemic lupus erythematosus Chung-Yuan Hsu, Wen-Chan Chiu, Tsong-Shing Yang, Ching-Lan Chou, Yu-Jih Su,

Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen, Han-Ming Lai, Tien-Tsai Cheng,

Chung-Jen ChenDepartment of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondingauthor:Chung-JenChen,M.D.DepartmentofRheumatology,ChangGungMemorialHospital.123,TaPeiRoad,Niao-SungHsiang,KaohsiungHsien,Taiwan.Tel:+886-7-7317123ext8800,Fax:+886-7-7322402E-mail:chungjen@adm.cgmh.org.twReceived: April 20, 2010Revised: June 16, 2010Accepted: July 28, 2010

Objective:Myelitis isa rarebutsevereneurologicpresentationofpatientswithsystemic lupuserythematosus(SLE).Fewlarge-scaleretrospectivecohortstudieshavebeenconducted,especiallyinTaiwan;therefore,wedesignedaretrospectivestudytoinvestigatethediseaseparameters,treatment,andprognosisofmyelitisinsouthernTaiwan.Methods:WereviewedmedicalrecordsofpatientswithSLEwhowereevaluatedattheChangGungMemorialHospital-KaohsiungMedicalCenterbetweenJanuary1998andJanuary2009.Atotalof10patientswithmyelopathywereincludedinthestudy.NeurologicvariablesandserologicfeaturesofSLEwereassessed.Magneticresonanceimages(MRI)ofthespineandcerebrospinalfluidprofileswerecollected.Wealsoanalyzedthetreatmentandoutcomeofmyelitis.Results:Thecohortof10patientsincluded8females(80%)and2males(20%).Threepatients(30%)wereinitiallyadmittedunderthetentativeimpressionofurinarytract infection(UTI).In8patientsdiagnosedwithmyelitisusingMRI,7patients(88%)had increasedT2MRIsignal intensityoverthecervicalandupper thoracicspinalarea.Treatment regimens includedconventionalhigh-doseglucocorticoid,pulsemethylprednisolone,cyclophosphamide,andplasmaexchange.Sixpatients(60%)hadapooroutcome.Additionalcyclophosphamidewasusedin5patientsand3ofthem(60%)hadagoodoutcome.Conclusion:SLEpatients,whocontractedmyelitis,presentedwithpossibleurinarydifficultyandwereadmittedunderthetentativeimpressionofUTI.Besides,themostfrequentsiteoflupusmyelitisisthecervicaltoupperthoracicspinalarea.Treatmentwithhigh-doseglucocorticoidandcyclophosphamidemayberelatedtoabetteroutcomecomparedtothosewithoutusingcyclophosphamide.

Key words: Systemiclupuserythematosus,myelitis,myelopathy

Formosan Journal of Rheumatology 20�0;24:�6-4�

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Hsu et al

EspeciallyinTaiwan,onlycasereportsonmyelitisinSLEhavebeenreported[8];nolarge-scalecaseserieshavebeenreported thusfar.Therefore,wedesignedaretrospectivechart-reviewstudyto investigate thediseaseparameters,treatment,andprognosisofmyelitisinamedicalcenterinsouthernTaiwan.

Material and Methods

Wereviewed themedical recordsandmagneticresonance imaging (MRI) reports of all patientsdiagnosedwithbothSLEandmyelitiswhowereevaluatedat theChangGungMemorialHospital-KaohsiungMedicalCenterbetweenJanuary1998andJanuary2009.

Includedpatientshadtofulfillatleast4ofthe11AmericanCollegeofRheumatology(ACR)revisedclassificationcriteriaforSLE[9,10].Besides,theyhadtohavemyelopathyduetoacuteorsubacuteonsetofaspinalcordlesionwithassociatedmotororsensorydeficits,andsphincterdysfunction[11].Patientswithspinal cord injury secondary to trauma, tumor,orinfectionwereexcluded.

Wecollectedthedemographicdataofthesepatients,clinical and serologic featuresofSLE,neurologicparametersrelatedtomyelitis,spinalMRI,cerebrospinalfluid(CSF)studies,treatment,andoutcome:

Demographic data.Wedocumentedage,gender,andbodyweightofallparticipants.

Clinical and serologic features of SLE.WedocumentedthedurationandclinicalprofilesofSLE,theSystemicLupusErythematosusDiseaseActivityIndex(SLEDAI)atadmission,andlaboratorydataincludingwhitebloodcell(WBC),hemoglobin(Hb),andplatelet(Plt) count; erythrocyte sedimentation rate (ESR);C-reactiveprotein(CRP)level;creatinelevel(Cr).Thelevelsoftheseclinicalparameters,includingantinuclearantibody(ANA),complement,andanti-double-strandedDNAantibody(anti-dsDNA)werecollected.Presence/absencewascheckedinantiphospholipidantibody(aPLAb),anti-Roantibody(Anti-Ro),andanti-Laantibody(Anti-La).

Neurologic parameters related to myelitis.Wedocumentedprodromal syndrome, impairment inmusclepower, sensation,andsphincteric functionsat thetimeofnadirandat thetimeofbestrecovery.Wemeasureddisabilityusingtheexpandeddisabilitystatusscale(EDSS)[12]atnadir,whichisavalidatedscaletoevaluatemultiplesclerosis.AnEDSSscoreof6.0orgreatercorresponds tofunctionaldependence

on ambulatory assistivedevices towalkminimaldistances,whereasanEDSSscoreof8.0isindicativeofdependenceonawheelchair.Wealsorecordedthetreatmentregimen.

MRI of the spine.Wedocumented total lesionlocationandlength.

CSF studies.Lumbarpuncturestudieshadtobeperformedduringamyelitisattack.WedocumentedWBCcount,redbloodcells(RBC)count,andlevelsofprotein,glucose,andlactate.

Treatment and outcome.Wedocumented thetreatmentregimen,andrecorded theoutcomeat thenearestoutpatientdepartment,whichwasvisitedbeforeJanuary1,2010.Wedefinedagoodoutcomeas“fullabilitytoambulatewithoutassistance”.

Statistical analysisBecausethedatadidnotfollowanormaldistribution

in our cohort, valueswere expressed asmedian(interquartilerange,IQR).AllanalyseswereperformedusingtheSPSSprogram,version15(SPSS,Chicago,IL)forWindowsXPProfessional.

Results

Among1165differentSLEpatientsdiagnosedbetweenJanuary1998andJanuary2009,weidentified10patients(0.86%)withlupusmyelitis.Therewereatotalof15episodes.Thedescriptiononindividualcasesisasbelow:

Case 1.InJanuary2002,a70-year-oldmanpresentedwithprogressiveleftlowerlegweaknessandurinationdifficultyfor11days.PositiveANAandanti-dsDNAwere found incidentally.He also had leukopeniaand thrombocytopenia,andwasdiagnosedasSLEwithmyelitis.Hissymptomsprogressedrapidly,andquadriplegiaandrespiratoryfailuredevelopedinoneday.Pulsemethylprednisolone (1000mg/day for3days)wasprescribed,andfollowedbyoralprednisolone(1mg/kg/day for3weeks),but the treatmentwasineffective.Becauseofventilatordependence,hewassenttoalocalhospitalafterhospitalizationfor81days,andthenbecamelosttofollow-up.

Case 2.InApril2004,a43-year-oldwomandevelopedbilateral lower legsweakness andnumbness, andhaddifficultyinurinationanddefecationfor4days.ANAandanti-dsDNAwerepositive.Besides,shehadproteinuria,andwasdiagnosedasSLEwithmyelitis.Intravenous(IV)dexamethasone(5mgq6hfor7days)wasprescribed,andthentaperedtoprednisolone0.5

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Myelitis in SLE

mg/kg/day.Shewasdischargedwithmildparesthesiasensation.Oralcyclophosphamide(100mg/dayfor7dayspermonth)wasuseduntilJanuary2005.

InDecember2006,suddenrighteyeblurredvisiondeveloped.Pulsemethylprednisolone(500mgq6hfor3days)wasprescribed,buttheconditiondeterioratedtoblindness.Plasmapheresiswasperformedfor5times,followedwithIVcyclophosphamide(700mg),butwasineffective.Oralcyclophosphamide(100mg/dayfor7dayspermonth)wasuseduntilDecember2008.Shewasstillfollowedupinourhospital,livingindependently,butwithrighteyeblindness.

Case 3.InJanuary2008,a36-year-oldSLEwomanexperiencedprogressivenumbnessoverbilaterallegsfor4days.SpinalMRIrevealedC5-T3levelsmyelitis.Shefeltnumbnessimprovingafter25mgofprednisolonewasadministeredperdayforoneweek.

InFebruary2009,numbnessdevelopedagain. Itrecoveredafterprednisolone (40mgperday)wasadministeredforoneweek.

InSeptember2009, shedevelopedprogressivebilaterallowlimbsnumbnessandweaknessfor5days,andurinaryretention.Pulsemethylprednisolone(1000mg for3days)wasprescribed,and then followedwithplasma exchange for 5 times.However, hermusclepowerdidnot recover.After rehabilitation,shecouldambulatewith thehelpofawalker.Oralcyclophosphamide50mgperdayhasbeenusedsinceOctober2009.Now, she still hasparaparesis andparesthesia,butisfullyindependent.

Case 4.InNovember2004,a43-year-oldwomanpresentedwithleftsidenumbnessfor2months.PositiveANAwasfound.Besides,shehadoralulcerandmalarrash,andwasdiagnosedasSLEwithmyelitis.Shereceivedoralprednisolone40mgperday,butwithnoeffect.

InFebruary2005, leftsidenumbnessseemed toprogress.IVmethylprednisolone(40mgq12hforoneweek)wasused,butwasineffective.Plasmapheresiswas performed for 5 times, followingwith IVcyclophosphamide(500mg).Fortunately,herparesthesiarecoveredgradually.

InMay2005,anotherepisodeofleftsidenumbnessattacked.Plasmapheresiswasperformedagainfor5times,andthenIVcyclophosphamide(500mg).DuringOPDfollow,IVcyclophosphamide(500mgpermonth)wasuseduntilNovember2005.FollowingspinalMRIonMarch2007revealedregressivechange.Shehassincehadcompleteremissionwithoutsequelae.

Case 5. InJuly2004,a27-year-old femalehadprogressivebilateral legsweaknessfor3weeksand

urinationdifficulty.PositiveANAwasfound.Shealsohadmalarrashandphotosensitivity,andwasdiagnosedasSLEwithmyelitis.Pulsemethylprednisolone(1000mgfor7days)wasprescribed.Then, shestillhadparaparesis,butwasfoleyindependence.Shewaslosttofollow-upbyJanuary2007.

Case 6.InFebruary1998,a30-year-oldSLEfemalepresentedwithfeverfor2days,andthenacuteurineretentionwithmild bilateral legsweakness. Shewasadmittedunder impressionofUTI.However,consciousnessdisturbancedevelopedafteradmission.BrainCTrevealednospecific findings.CSFstudyrevealedproteinelevations,butnoincreasingWBC.Myelitiswas favored clinically.However, spinalMRIcouldn’tbeperformed,duetoincorporation.IVHydrocortisone(100mgq6hfor3days)wasused.Herconsciousnessandmusclepowerrecoveredgradually,butwithparesthesiasequelae.Sheisstillfollowedupatourhospital.

Case 7. InAugust2004,a37-year-oldSLEmandeveloped urination difficulty, recurrent fever,progressivebilateral legsweakness,andnumbnessfor4weeks.Initially,hewasadmittedwithtentativediagnosis of prostatitis orUTI.Unfortunately,paraplegiadeveloped.SpinalMRI revealedC7-T1enhancement,which favoredmyelitis.Therefore,pulsemethylprednisolone(1000mgfor3days)wasprescribed.Musclepowerseemedtoimprove,buthestillhasparaparesis.

Case 8. InJanuary2003,a22-year-oldSLEgirlexperiencedlowlimbsweaknessfor3days,associatedwithurineretention.ShereceivedlumbarspinalMRIwithoutaT2-enhancedlesion.Shedidn’treceivefurtherupperlevelspinalMRIorlumbarpuncture.However,myelitiswasstillfavoredbyclinicalpresentation.IVhydrocortisone(100mgq6hforoneweek)wastried.Shemadeamildrecovery,butstillhadparaparesis,andisfoleydependentafter7yearsoffollow-up.

Case 9.InMarch2009,a42-year-oldSLEwomanhadfeverfor2days,andthenacuteurineretention.ShewastreatedasUTIinitially.However,paraplegiadeveloped one day later. SpinalMRI revealedalmostwholespinalmyelitis lesion.ShereceivedIVhydrocortisone(100gq6hfor3days),followedbyIVcyclophosphamide(500g).Sherecoveredsmoothlywithnosequelae.

Case 10.InFebruary2009,a43-year-oldSLEwomanpresentedwithprogressivelowerlimbsweaknessfor3weeks,withurinationdifficulty.SpinalMRIrevealedC2-T6levelmyelitis.Therefore,prednisolone1mg/kg/daywasusedfor3weeks,accompaniedwithoral

�9

Hsu et al

cyclophosphamide(100mgperdayfor7dayspermonthfor4months).Musclepowerrecoveredgraduallyoneweeklateraftercyclophosphamidewasadministered,butdidnotachievestasis.Shestillneedsassistancetowalkuntilnow,butisfoleyindependent.

Demographic data and clinical characteristicsThedemographicandclinicalcharacteristicsare

showninTable1.Therewere8females(80%).Themedianageatdiagnosisofmyelitiswas39.5years.MyelitiswasthefirstmanifestationofSLEin4patients(40%).ThemedianSLEdurationatdiagnosisofmyelitiswas2years.

Themediantimefromtheonsetofsymptomstoaworsenedneurologicalstatuswas8days(range,3-65days).Thedevelopmentofneurologicalsymptomswasacute(within1month)in8patients(80%)andchronic(after1month)in2(20%).

Threepatients(30%)hadaprodromeoffeversomedaysbeforedevelopingneurologicsymptoms.Theother7patients(70%)hadnospecificprodrome.Urinarysphincterdysfunctionappeared in8patients (80%),paraplegia in6 (60%),paraparesis in8 (80%),andsensorydeficitsin9(90%).

ThemedianSLEDAIscoreatadmissionwasonly7.5.ThemedianEDSSscoreatnadirwas8.5.Nopatienthadahistoryofantiphospholipidsyndrome.

Diagnosisdelayoccursoften,and3patients(30%)wereinitiallyadmittedunderthetentativeimpressionof

UTI.

Laboratory findings, immunological features, and imaging techniques

TheresultsoftheCSFstudies,imagingtechniques,andtheimmunologicalpatternareshowninTables2&3.

TheCSFstudiesrevealedanincreasedWBCcountin2outof6patients(33%)tested,withpolymorphonuclearpredominance in1 case.Theotherpatientshadapredominanceof lymphocytes.Theproteinswerenoticeablyincreasedin5outof6patients(83%)tested.

Anti-dsDNAantibodieswerefoundin7outof10patients(70%)tested,withalowcomplementoflevelsin5outof10(50%).Fouroutofsixpatients(66%)testedwerepositiveforaPLAb.

Eightoutof9patients (88%)had increasedT2-signalintensityinthespinalcord,mostfrequentlyinthecervicaltoupperthoracicspinalsegments(Table2).

In8patientsdiagnosedwithmyelitisusingMRI,7patients(88%)hadlesionsovertheC-spineandupperTspinearea.Sixpatients(75%)hadlongitudinalmyelitiswhichinvolvedmorethan4spinallevels.PatientNo.8hadreceivedlumbarspinalMRIwithoutaT2-enhancedlesion.PatientNo.6didnotreceiveanMRIbecauseofpersonalreasons.Bothpatientswerediagnosedwithmyelitisbyaneurologistandhadclinicalimprovementunder treatment formyelitis. PatientNo. 9 hadinvolvementofalmosttheentirespinalcord.

Table 1. Demographic and clinical characteristics, treatment, and outcome of �0 SLE patients with myelitisNo Gender Age

(y)Recurrence SLE

Duration (y)

Urinary s/s

Impression SLEDAI s/s to nadir

EDSS Treatment beside CS

Outcome

� M 70 N 0 Y Stroke 22 �2 9.0 Pulse MP Poor, quadriplegia, on ventilator

2 F 4� Y 0 Y Myelopathy 8 � 6.0 Cy, plasmapheresis

Good, paresthesia, blindness (os)

� F �6 Y 24 Y Neurologia � 4 8.5 Pulse MP, Cy, plasma exchange

Poor, paraparesis

4 F 42 Y 0 N Brain tumor 4 65 8.5 Pulse MP, Cy, plasmapheresis

Good, CR

5 F 27 N 0 Y Myelopathy 0 24 8.5 Pulse MP Poor, paraparesis6 F �0 N � Y UTI �5 � 9.5 Pulse MP Good, paresthesia7 M �7 N � N UTI �6 �0 8.5 Pulse MP Poor, paraparesis8 F 2� N �0 Y Cauda equina

syndrome7 � 9.0 None Poor, paraparesis

foley dependence9 F 42 N �2 Y UTI �7 4 8.5 Cy Good, CR

�0 F 4� N �0 Y Polyneuropathy 4 2� 7.5 Cy Poor, paraparesisAbbreviations: M = male; F = female; Y = yes; N = no; s/s = symptoms and signs; susp = suspect; UTI = urinary tract infection; CS = corticosteroid; MP = methylprednisolone; Cy = cyclophosphamide; CR = complete remission

40

Myelitis in SLE

Treatment and OutcomeFourpatients (40%)hadagoodoutcome,and6

patients(60%)hadapooroutcome.Only2patientshadcompleteremission(Table3).Thedegreeofdisabilityranged frommildurinary sphincterdisturbanceorhypoesthesiaofthelowerextremitiestotetraplegia.

Fouroutof6patients (66%)with longitudinalmyelitishadapooroutcome.Oneoutof2patients(50%)withmyelitiswithoutlongitudinalpatternhadapoorprognosis.

Treatmentdatawereavailablefromallpatients(Table1).Corticosteroids,initiallyadministeredasintravenouspulsesofmethylprednisolone(500-1000mgperdayfor2to5days),wereusedin6patients,and2patients(33%)hadagoodoutcome.Cyclophosphamidewasusedin5patients,and3patients(60%)hadagoodoutcome.Plasmaexchange(PE)wasusedin3patients,and2patients(67%)hadagoodoutcome.

Fivecasesshowedtheonsetofsymptomsin thefirst7daysandtreatmentwasinitiatedearly.Twooutof5patients(40%)whoweretreatedearlyhadagoodoutcome.Theremaining5patientsweretreatedafter7

daysfromthestartofmyelitis.Twoofthese5patients(40%)hadagoodoutcome.

Sevenpatients(70%)hadonly1episodeofmyelitisduringtheperiodofobservation,whilethree(30%)hadrecurrentepisodes.Thehighestnumberofrecurrentepisodeswas4.

Discussion

Myelitiscouldbe thefirstmanifestationofSLE[7,11]. Inourcohort,40%ofpatientshadmyelitisas initialpresentationofSLE.Withoutappropriatetreatment,itmightresultindisabilityinwalking,foleydependence,paraplegia,bed-riddenstatus,respiratoryfailure,ormortality[7].Theremissionrateinourstudywas40%,andreportsintheliteraturerangebetween29to71%(Table4).

Identificationofsyndromesofmyelitismaypreventirreversibleparaplegia.Eightofthetenpatientswithmyelitis visited the emergency roomwith somesymptoms related to urinary retention insteadofparaplegia.Becauseofthepresenceoffever,3outof8

Table 2. Laboratory data of �0 SLE patients with myelitisNo WBC

(1000/uL)Hb

(g/dL)Plt

(1000/dL)Cr

(mg/dL)ESR

(mm/hr)CRP

(mg/L)C�

(mg/dL)C4

(mg/dL)Anti-ds DNA

(IU/mL)ANA aPL Anti-Ro Anti-La

� 2.9 9.� 6� �.6 45 NA 48.6 �6.� �60 �:640 + + +2 �.0 �2.2 �78 0.6 55 �.� 92.4 8.8 ��� �:�280 + + +� 4.9 �4.2 67 0.7 2� �.� ��4.0 �6.4 27 �:�20 + + -4 4.4 �0.9 2�4 0.5 �2 0.9 9�.0 2�.0 5 �:�20 - - -5 5.5 ��.9 20� 0.5 NA �.� �07.0 2�.7 4 �:�280 NA NA NA6 5.7 �0.6 �90 �.8 20 NA �7.7 4.4 NA �:�280 NA NA NA7 4.� 8.2 220 2.5 NA NA 70.9 6.5 �60 �:640 NA NA NA8 �.4 �0.6 6� 0.9 NA NA 24.5 4.� �506 �:640 NA + +9 9.� �0.6 �9� 0.9 NA �2.6 46.6 5.8 20� �:�20 - + -

�0 9.� �0.0 �44 0.5 �2 NA 72.9 �5.6 �47 �:�20 + NA NANA: no data available

Table 3. CSF study and MRI result of �0 SLE patients with myelitis

NoCSF MRI

CSF study WBC RBC Pro (mg/dL) Glu (mg/dL) Lactate (u/L) MRI evidence Lesion level Segments� Y � 0 78 7� 26.6 Y C2-T� 72 Y �4 0 66 67 27 Y C�-T5 �0� Y � 0 �0 ��6 29.7 Y C�-T7 �24 Y NA NA 45 67 �4.8 Y C�-� �5 Y 0 0 8� 4� �8.� Y T7-T�0 46 Y � 2 �92.7 42 NA NA7 NA Y C7-T� 28 NA NA9 NA Y Almost whole spine >�2

�0 NA Y C2-T6 �2NA: No data available

4�

Hsu et al

patients(38%)wereinitiallyadmittedunderthetentativeimpressionofUTIandlossofincipiency.Therefore,urinary difficultywithout evidence of pyuria orbacteruriainapatientwithSLE,especiallyaccompaniedwithfever,paraparesis,orsensorydeficit,shouldbeconsideredasacriticalsign.

Whenmyelitisissuspectedclinically,CSFstudiesandspinalMRIareimportantexaminationsfordiagnosis[7] .ElevationsintheCSFproteinconcentrationcanoccurininflammationconditions.NormalrangeWBCcountofCSFmayexcludepossibleinfection.ThespinalMRItypicallyshowsenhancingsignalabnormalityonT2sequences,extendingoveroneormorespinalcordsegmentsofmyelitis.

Thecasesofso-calledlongitudinalmyelitiswerebeyondimagination.Wehaveidentified75%(6/8)ofourpatientsofwhomaspinalcordMRIwasavailablethat showed this findingwhichwasmore frequentthanpreviousdata[13].AccordingtoEspinosaetal.,longitudinalmyelitisdevelopsmostfrequentlyinthecervicaltomid-lowerthoracicspinalsegments[14].Wenotedmyelitislesionsoftenoccurredinthesegmentsabovetheupperthoracicspine.ThelesionsatahigherspinallevelmaybecharacteristicformyelitisinSLE.Therefore,onlyalumbarMRIstudyisnotenoughforpatientswithsuspiciouslupusmyelitis.Unfortunately,urinarydysfunctionoftenleadsustofocusonlumbarlesionsandmakesusoverlookthoseatahigherspinallevel.

The immunopathogenesis ofmyelitis in SLEisuncertain, although immune-complex-mediatedvasculitisandarterialthrombosisresultinginischemiaweresuggested[15].ThepotentialroleofaPLAbinthepathogenesisofmyelitis inSLEhasbeenhighlydiscussed[16]. Inourcohort, thepositiveaPLratewas66%.However,becausemostofourcaseshadlongitudinalmyelitis,itseemsdifficulttoexplainhowa thromboticprocesscould involvedifferent levelsofspinalvessels.Our results suggest thatalternate

mechanismsotherthantheaPL-mediatedmodelsmaybeconsideredformyelitisinSLE.

Becauseofitsrarityandtheunclearpathogenesis,there are no randomized control trials to guidetreatmentformyelitisinSLE.Earlyaggressivetherapyisgenerallyrecommended[17,18]. Inothercohorts[11,19], thecombinationofmethylprednisoloneandcyclophosphamideappearedtobemoreeffectivethanmethylprednisolonealone.Inourcohort,thesubgroupthat receivedcyclophosphamide seemed tohaveabetteroutcomethanthosewhodidnot(60%vs.20%),however;pulsemethylprednisolonedidnotresult insuchagoodeffect.Therefore,besidestraditionalhigh-doseglucocorticoidtreatment(1mg/kg/day),additionalcyclophosphamidetreatment(500-700mgpermonthfor3to12months)isareasonablewaytotreatthesepatientsaccordingtotheexperienceandtheliterature.

It is equivocalwhether PE has an additionaltherapeutic benefit over glucocorticoids andimmunosuppressantagents in the treatmentofSLEpatientswithmyelopathy [11].However, a recentreviewofpatientswithSLEandcentralnervoussysteminvolvementshowedapotentialbenefitinacriticallyillcondition[20].BecauseofthemoreinvasivequalityofPEandpossibleeffect,wesuggestitbekeptasa“rescue”role.

Aggressive interventionwithin1weekofonsetofmyelopathyhasbeensuggested [21].However,accordingtoour limiteddata,patientswhoreceivedaggressive treatmentwithin1weekhadnodifferentoutcomecomparedwithpatientswhose symptomspresentedaftermorethan1week.InthestudyofdeSezeetal.,theyalsofoundthatthetimefromdiseaseonset to the initiationof treatmentdidnot influencetheresponseinidiopathictransversemyelitis[22].AsshowninthestudyofBirnbaumetal.[23],therearepossibly2myelitissubtypes,graymattermyelitisandwhitemattermyelitis,whichhaveadifferentclinicalcourseandseverity.Graymattermyelitisoftenpresents

Table 4. Cohort studies about myelitis in SLEAuthor Year Nation Cases Overall RR RR with Cy Treatment recommendationHsu (Current study) 20�0 Taiwan �0 40% 60% (3/5) IV CS + CyLiu [��] 2008 China �4 50% 38% (3/8) Early immunosuppressiveTellez-Zenteno [�9] 200� Mexico 6 33% 20% (1/5) No recommendationKovacs [��] 2000 USA �4 36% 22% (2/9) Dependent on severityMok [7] �998 China �0 50% 67% (4/6) CS + cytotoxic agentsHarisdangkul [2�] �995 USA 7 29% High-dose IV CSBarile [24] �992 Mexico 7 71% 67% (2/3) IV CS + Cy

Abbreviations: CS = corticosteroid; Cy = cyclophosphamide; RR = remission rate; IV = intravenousDefinition of remission: Full ability to ambulate without assistance

42

Myelitis in SLE

withemergentandseveresymptomsandapossiblypooroutcome.Ontheotherhand,whitemattermyelitismaydevelopslowlybutmighthaveabetteroutcome.Thedifferenttimepointatwhichpatientsvisitedthehospitalmayanexplanationforthedifferentsubtypes.Becauseoftheretrospectivedesignofthestudyandnumerousmissingdata,furthergroupingwasnotfeasibleinourcohort. Inconclusion,SLEpatientswhodevelopedmyelitis,presentedwithpossibleurinarydifficultyandwereadmittedunderthetentativeimpressionofUTI.Lupusmyelitisdevelopedmostfrequentlyatthecervicaltoupperthoracicspinalarea.Treatmentwithhigh-doseglucocorticoidandcyclophosphamidemayberelatedtoabetteroutcomecomparedtothosewithoutusingcyclophosphamide.

References1.SibleyJT,OlszynskiWP,DecoteauWE,SundaramMB.The

incidenceandprognosisofcentralnervoussystemdiseaseinsystemiclupuserythematosus.JRheumatol1992;19:47-52.

2.WongKL,WooEK,YuYL,WongRW.Neurologicalmanifestationsofsystemiclupuserythematosus:aprospectivestudy.QJMed1991;81:857-70.

3. BruynGA.Controversies in lupus: nervous systeminvolvement.AnnRheumDis1995;54:159-67.

4. FutrellN,SchultzLR,MillikanC.Centralnervoussystemdisease inpatientswith systemic lupuserythematosus.Neurology1992;42:1649-57.

5. JosephFG,LammieGA,ScoldingNJ.CNSlupus:astudyof41patients.Neurology200714;69:644-54.

6. WingerchukDM,HogancampWF,O'BrienPC,WeinshenkerBG.Theclinicalcourseofneuromyelitisoptica(Devic'ssyndrome).Neurology1999;53:1107-14.

7. MokCC,LauCS,ChanEY,WongRW.Acutetransversemyelopathy in systemic lupus erythematosus: clinicalpresentation, treatment, and outcome. JRheumatol1998;25:467-73.

8. ChenHC,LaiJH,JuanCJ,KuoSY,ChenCH,ChangDM.Longitudinalmyelitisasaninitialmanifestationofsystemiclupuserythematosus.AmJMedSci2004;327:105-8.

9. TanEM,CohenAS,Fries JF,MasiAT,McShaneDJ,RothfieldNF, et al.The1982 revised criteria for theclassificationofsystemic lupuserythematosus.ArthritisRheum1982;25:1271-7.

10.HochbergMC. Updating theAmerican College ofRheumatology revisedcriteria for the classificationofsystemiclupuserythematosus.ArthritisRheum1997;40:1725.

11.KovacsB,LaffertyTL,BrentLH,DeHoratiusRJ.Transversemyelopathyinsystemiclupuserythematosus:ananalysisof14casesandreviewof the literature.AnnRheumDis2000;59:120-4.

12.Kurtzke JF.Ratingneurologic impairment inmultiplesclerosis: an expandeddisability status scale (EDSS).Neurology1983;33:1444-52.

13.LuX,GuY,WangY,ChenS,YeS.Prognosticfactorsoflupusmyelopathy.Lupus2008;17:323-8.

14.EspinosaG,MendizabalA,MinguezS,Ramo-TelloC,CapelladesJ,OliveA,etal.Transversemyelitisaffectingmorethan4spinalsegmentsassociatedwithsystemiclupuserythematosus:clinical, immunological,andradiologicalcharacteristicsof22patients.SeminArthritisRheum2008Nov18.

15.AmmouriW,MezalekZT,HarmoucheH,AouniM,AdnaouiM,MaaouniA.Myelitis complicating systemic lupuserythematosus:successfullytreatedwithcorticosteroidsandcyclophosphamide.SouthMedJ2009;102:744-5.

16.D'CruzDP,Mellor-PitaS,JovenB,SannaG,AllansonJ,TaylorJ,etal.Transversemyelitisasthefirstmanifestationof systemic lupuserythematosusor lupus-likedisease:goodfunctionaloutcomeandrelevanceofantiphospholipidantibodies.JRheumatol2004;31:280-5.

17.Barile-FabrisL,Ariza-AndracaR,Olguin-OrtegaL,JaraLJ,Fraga-MouretA,Miranda-LimonJM,etal.ControlledclinicaltrialofIVcyclophosphamideversusIVmethylprednisolonein severeneurologicalmanifestations in systemic lupuserythematosus.AnnRheumDis2005;64:620-5.

18.ShererY,HassinS,ShoenfeldY,LevyY,LivnehA,OhryA,etal.Transversemyelitisinpatientswithantiphospholipidantibodies--theimportanceofearlydiagnosisandtreatment.ClinRheumatol2002;21:207-10.

19.Tellez-ZentenoJF,Remes-TrocheJM,Negrete-PulidoRO,Davila-MaldonadoL.Longitudinalmyelitisassociatedwithsystemiclupuserythematosus:clinicalfeaturesandmagneticresonanceimagingofsixcases.Lupus2001;10:851-6.

20.NeuweltCM.Theroleofplasmapheresisinthetreatmentofseverecentralnervoussystemneuropsychiatricsystemiclupuserythematosus.TherApherDial2003;7:173-82.

21.HarisdangkulV,DoorenbosD,SubramonySH.Lupustransversemyelopathy:betteroutcomewithearlyrecognitionandaggressivehigh-doseintravenouscorticosteroidpulsetreatment.JNeurol1995;242:326-31.

22.deSezeJ,LanctinC,LebrunC,Malikova I,PapeixC,WiertlewskiS,etal. Idiopathicacute transversemyelitis:applicationof the recentdiagnosticcriteria.Neurology2005;65:1950-3.

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全身性紅斑性狼瘡病人之脊髓炎

許鐘元 邱文燦 楊聰信 周靜蘭 蘇昱日 尤珊富 邱俊凱 陳英州

賴漢明 鄭添財 陳忠仁

長庚醫療財團法人高雄長庚紀念醫院 風濕過敏免疫科

目的：探討紅斑性狼瘡脊髓炎的臨床表現、治療、及癒後。方法：分析高雄長庚醫院1998至2009

年間，收錄符合美國風濕病學會全身性紅斑性狼瘡準則，且須發生脊髓炎的病人為研究對象。共收

錄10位全身性紅斑性狼瘡併脊髓炎病人。結果：本族群中，有80%病人為女姓，中位數年齡為39.5

歲。臨床表現為，90%病人有感覺異常，80%病人有下肢無力，80%病人有括約肌功能障礙。30%

病人先被診斷為尿道感染而住院。88%病人脊髓病灶於頸椎至上胸椎間。治療方式包括傳統高劑量

類固醇、脈衝類固醇、cyclophosphamide、血漿置換，60%病人癒後不佳。五位病人治療方式中，

包含了cyclophosphamide，其中60%得到較好的癒後。結論：全身性紅斑性狼瘡患者，發生脊髓炎

時，常表現解尿困難徵狀，而以尿道感染的診斷來住院。而最常出現病灶的位置為頸椎至上胸椎。

治療方面，高劑量類固醇併用cyclophosphamide可能有較好的癒後。

關鍵字：紅斑性狼瘡、脊髓炎、脊髓病變

Original Article

44

Introduction

Systemiclupuserythematosus(SLE),anautoimmune

disorderwhichpredominantlyaffectsyoungwomen,isfrequentlycomplicatedbyrenalinvolvement.Upto60%ofpatientsdevelopkidneyinvolvementduringthecourseoftheirdisease[1,2].AkidneybiopsyinanSLEpatientwithanydegreeofclinicalrenaldiseaseplaysan important role indiagnosisandmanagementhasbeenillustrated[3,4].Italsohasbeendemonstratedthatlong-termprognosisoflupusnephritis(LN)isrelatedtothehistopathologicalfindingsofrenalbiopsy[5,6].Sofar,proliferative lupusnephritisremainsamajorcauseofrenalfailureandmortalityamongpatientswithSLE[7,8].Inadditiontohistopathologicalfindings,the

Outcome of lupus nephritis – A 5-year analysis Tsong-Shing Yang, 1Shun-Chen Huang, Chung-Jen Chen, Chung-Yuan Hsu, Wen-Chan Chiu,

Ching-Lan Chou, Fu-Mei Su, Yu-Jih Su, Shan-Fu Yu, Chun-Kai Chiu, Ying-Chou Chen,

Han-Ming Lai, and Tien-Tsai ChengDivision of Allergy, Immunology and Rheumatology, and 1Division of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondingauthor:Tien-TsaiCheng,M.D.DivisionofRheumatology,AllergyandImmunology,ChangGungMemorialHospital-KaohsiungMedicalCenter,ChangGungUniversityCollegeofMedicine,Kaohsiung,Taiwan.No123,Ta-PeiRoad,Niao-SungHsiang,KaohsiungHsein,Taiwan833.Tel:+886-7-731-7123ext8800,Fax:+886-7-732-2402E-mail:tiantsai@ms2.hinet.netReceived: Feburary 22, 2010Revised: June 20, 2010Accepted: July 25, 2010

Objective:Toinvestigatethelong-termoutcomeofclassIVlupusnephritis(LN)andtoanalyzeitsprognosticfactors.Materials and Methods:Weperformedaretrospectivechartreviewstudyof157patientswithLNbetweenJanuary1986andJune2004inChangGungMemorialHospitalatKaohsiung.AlloftheseLNpatientsfulfilledthesystemiclupuserythematosusclassificationcriteriaoftheAmericanCollegeofRheumatologyandhadhistopathologicalfindingsofLN.Onlythosepathology-provedsubjectswithclassIVby2003ISN/RPSclassificationwererecruited.Wereviewedthechartsandcollectedthedemographicdata,serologicalparameters,andtreatmentcoursesofsubjectsrecruited.Theendpointofrenaloutcomeweredoublingofserumcreatinine(I)andendstagerenaldisease(ESRD)/death(II)within60monthsafterrenalbiopsyResults:Atotalof75subjectswererecruited,including13maleand62female.Meanagewas25.9±9.7year.Fiveyearsafterrenalbiopsy,16subjects(21.3%)developedoutcomeIand15subjects(20.0%)developedoutcomeII.ThosewhodidnotdevelopoutcomeIhadhighermean(14.5±2.1)activityindex(AI)thanthat(13.1±2.5)ofthosedid(HR=0.55,CI=0.35-0.87,p=0.01).ForthosewhodidnotdevelopoutcomeII,themeanAIwasalsohigherthanthosewhodid(14.4±2.2vs.13.5±2.3,HR=0.67,CI=0.44-1.00,p=0.05).Conclusions:The5-yearrenalsurvivalofcurrentseries,intermsofESRD/death,was80%andthiswasnotasfavorableasthosereportedintheotherinvestigations.Highactivityindexatbiopsyisapredictoroffavorableprognosisoflong-termrenaloutcomesincasethataggressivetreatmenthadbeengiven.

Key words:Lupusnephritis,prognosis,ISN/RPSclassification

Formosan Journal of Rheumatology 20�0;24:44-49

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Yang et al

determinantsthatmayinfluencetheprognosisofLNweremulti-factorial [9].WhytheprognosticfactorsreportedarediverseisnotonlybecausethepresentationofrenaldiseaseinSLEisproteanbutalsoduetotheconsiderableinter-investigationaldifferences.

Inthecurrentinvestigation,wesurveyedthelong-termoutcomeofsubjectswithISN/PRSclassification-basedclassIVLN.

Patients and methods

Weperformedaretrospectivechartreviewstudyof157patientswithLNbetweenJanuary1986andJune2004inChangGungMemorialHospitalatKaohsiung.AlloftheseLNpatientsfulfilledtheSLEclassificationcriteriaoftheAmericanCollegeofRheumatology(ACR)[10]andhadhistopathologicalfindingscompatiblewiththeInternationalSocietyofNephrologyandtheRenalPathologySociety (ISN/RPS)classificationofLN.OnlythosewithclassIV-SorclassIV-Gsubjects(n=75)revealedbyrenalbiopsywererecruited.AsFig.1,renalpathologyrevealedotherthanclassIV(n=7)andspecimenstoooldtoberead(n=75)wereexcluded.Themedicalrecordswerereviewedfordemographicdata,comorbidity,diagnosticdelaybetweenonsetoflupusandtimeofhistopathologicaldiagnosisofLN,ISN/RPS-basedhistopathologic findings includingactivity index (AI)andchronicity index (CI) [11],treatmentregimens/course,andlaboratorydataatthetimeofrenalbiopsy.AIandCIbelongstotheNationalInstitutesofHealth(NIH)-modifiedsemiquantitativehistologicscoringsystemforlupusnephritis[12].

TheendpointofrenaloutcomewasdefinedaseitherdoublingofserumCr(SCr)(I)orendstagerenaldisease(ESRD)/death(II)within60months[13,14].TheonsetofLNwasdefinedasthedateofbiopsy.WedefinedtherenaloutcomeasproposedbytheRenalSubcommitteeofRenal insufficiencyoftheACR[15].Inbrief, the

doublingofSCrandESRDwasdefinedaslastingforatleast6monthswithavalueofSCrofatleast2mg/dLandtheneedofdialysistherapy,respectively.

Statistical methodsMean±SDandmedian(25%to75%inter-quartile

range,IQR)wasusedforthedescriptionofvariableswithnormalandnon-normaldistribution,respectively.Afive-yearsurvivalcurvewasconstructedusingtheKaplan-Meiermethod.MultivariateproportionalhazardsCoxregressionanalysiswasused to investigate theprognosticvalueofcontinuousandbinaryvariables.Statisticalsignificancewasdefinedasap-valueoflessthan0.05.AllanalyseswereperformedusingtheSPSSprogram,version15(SPSS,Chicago,IL)forWindowsXPProfessional.

Results

Atotalof75patientsmet inclusioncriteria forclassIVLNoverthe18-yearstudyperiod,including2IV-Sand73IV-G.Therewere62femalesubjects.Themeanagewas25.9±9.7years.TheintervalbetweenSLEandthediagnosisofLNwas2years(IQR,0-5).C3andC4complementfractionsweredecreased in50and34patients,respectively.Therecordsofanti-dsDNAantibodyandanti-phospholipid(aPL)antibodylevelswere traceable in64 (85.3%)and24 (32%)subjects,respectively.Elevatedanti-dsDNAandaPLlevelswerefoundin50(78.1%)and3(4%)subjectsineachgroup,respectively.Theamountsofdailyproteinloss(DPL)wererecordedin31(41.3%)subjects.ThemedianDPLwas3.4g (IQR2.1-6.3).Tensubjectsrevealednephriticsyndrome.Atrenalbiopsy,themeanvalueofAIandCIindexwere14.2±2.3and2.5±1.9,respectively.Twenty-two(29.3%)subjectshadarterialhypertension.ThetherapyforLNincludedpulsesteroid(methylprednisolone,1g/dayforthreeconsecutivedays)in32(29.3%)andpulsecyclophosphamide(500-700mg/monthfor6consecutivemonths)in30(40%)ofthesubjectsrecruited.Othertreatmentregimensincludedoralcyclophosphamidein19(25.3%),oralazathioprinein 22 (29.3%) and cyclosporine in 10 (13.3%),respectively.Withinfiveyearsafterrenalbiopsy,16subjects(21.3%)developedoutcomeIand15subjects(20.0%)developedoutcomeII(Fig.2).TheclinicalcharacteristicsofsubjectsdevelopedoutcomeIandIIareshowninTable1and2.TheprognosticfactorsanalysisbyCoxregressionmodeldisclosedthat thesubjects,whodidnotdevelopoutcomeI,hadhighermean(14.5±Figure 1. Flow chart of case selection

46

Renal outcome of lupus nephritis

2.1)AIthanthat(13.1±2.5)ofthosedid(HR=0.55,CI=0.35-0.87,p=0.01).ForoutcomeII,themeanAIforthosedidnotdevelopwas14.4±2.2vs.13.5±2.3thosethatdid(HR=0.67,CI=0.44-1.00,p=0.05)

Discussion

SeveralpublicationshadreportedtherelationshipbetweenthehistopatologicalfindingsandprognosisofLN.However,thehistopathologicalfindingsofpreviousworkswerebasedontheWorldHealthOrganization

classification[16,17].Inordertostandardizedefinitionsof thepathologic lesions inLN, a revisionof theclassification,sponsoredbytheInternationalSocietyofNephrology(ISN)andtheRenalPathologySociety(RPS),hasbeenpostulatedin2003[18]andvalidatedsubsequently[19].Inthecurrentstudy,wereclassifiedthehistopathological findingbasedon ISN/RPSclassificationbyreviewingtheslidesofrenalbiopsyofLNpatientstoinvestigatetherelationshipbetweenhistopathologicalparametersandlong-termprognosis.

The 5-year renal survival of LN had beendemonstrated tobebetween83%and92% [7,9];however,itwas80%inourseries.Itseemsthatthelong-termrenalsurvivalofcurrentseriesisworsethanthatofpreviousworks.However, theobviousdifferenceinoutcomeofserialreportsissubjecttothedefinitionofLN,racesofpopulation,criteriaof inclusion,andtreatmentmodality. ItwaswellknownthatclassIIIandIVglomerulonephritisinWHOclassificationwerethemajorcategoriesofLNandthesehistopathologicalfindingswerethemajordeterminantsofprognosisofLN[3,20,21].Inordertoenrollahomogenouspopulation,onlythosesubjectswithIVLN(ISN/RPS)wereenrolledincurrentstudy.Inaddition,thedateofrenalbiopsywasselectedastheonsettimingoffollow-up,whenthepatientshadfrankrenalpresentations.Allofthesemayexplainwhytheoutcomeofcurrentserieswasnotasgoodaspreviousstudies.

Okuyamaetal.reportedlong-termoutcomeof15LNsubjectswithclassIV(ISN/RPS)inrenalpathology.

Table 1. Clinical characteristics of subjects for end point I at initial renal biopsySCr 2×

All + – pn 75 �6 59Age at biopsy (y) 25.9 ± 9.7 25.� ± 8.7 26.� ± �0.0 0.�92SLE→LN (y)# 2(0;5) 2(0.�;6) �.5(0;5) 0.74�Gender, female n(%) 62(82.7) �0(62.5) 52(88.�) 0.�08Albumin# (g/dL) 2.�(�.7;2.8) 2.�(2;2.�) 2.�(�.6;2.8) 0.�60Creatinine# (mg/dL) 0.9(0.8;�.�) �.2(0.8,2.�) 0.9(0.8,�.2) 0.�76C3# (mg/dL) 5�.2(��.�; 86.0) 5�.9(29.�;6�.) 5�.2(��;92.7) 0.996C4# (mg/dL) 9.6(6.0; �7.8) 8.4(4.7;�6.5) �0.�(6.5;�8) 0.�9�Anti-dsDNA(+), n(%) 50(78.�) �0(8�.�) 40(76.9) 0.202Activity index(0-24) �4.2 ± 2.� ��.� ± 2.5 �4.5 ± 2.� *0.0�Chronicity index(0-�2) 2.5 ± �.9 �.6 ± 2.� 2.2 ± �.7 0.056Hypertension, n(%) 22(29.�) 8(50) �4(2�.7) 0.7�6Pulse steroid, n(%) 22(29.�) �0(62.5) �2(20.�) 0.46Pulse Cyc, n(%) �0(40) 8(50) 22(�7.2) 0.262

Abbreviations: SLE→LN = Interval between SLE diagnosis and LN; # = median(IQR); SCr 2× = doubling of serum creatinine ; Cyc = Cyclophosphamide *p:the Cox proportional hazard regression model

Figure 2. Sixty months renal survival rate

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Yang et al

Hedemonstratedtherenalsurvivalratewere100%at10-yearand80%at20-year,respectively[22].However,theresultsweresubject toasmallsamplesizeinhisseries.Tothebestofourknowledge,thecurrentseriesisthelargestpopulationofclassIVLNbasedonISN/RPSclassification.However,theclinicalimplicationsofourresultsshouldbevalidatedinfutureinvestigations.

AsshownisFig.2,thesurvivalcurveofoutcomeImatched thatofoutcomeII inourseries.And thesubjectswhodevelopedoutcome IalsodevelopedoutcomeII.Thissuggests that ifdoublingofSCr isfoundafter renalbiopsy inasubject,pooroutcomeseemsinevitable.

Furthermore, for theclassof ISN/RPS in renalpathology, severaldeterminantsofpoorprognosticfactorsofLN[7,23,24]havebeenpostulated.Theseincludedmale in gender, elevated baseline SCr,persistentarterialhypertension,andelevatedbaselineCI.However, inourseries,wedidnot findanyoftheabove tohave impactionon theprognosis.Anexplanationregardingthedifferencesbetweenourseriesandpreviousworksseemstoberelatedtothereasonspreviouslymentioned.However,other reasonsmayresultfromoursamplesizeissmallerthanothersandthefactorsenrolltocoxregressionaredifferent.IthadbeendemonstratedthatAIofrenalhistologywasapoorprognosticfactorofrenalsurvival[25-27].ButFiehnetal.describedhigherAIagoodprognosticfactorofrenaloutcome[4].AsshowninTableIandII,lowerAIisanindependentpoorprognosticfactorofeitheroutcomeIorIIinthecurrentseries.Schwartzetal.proposedthathigh

AIstoodforpotentiallyreversiblerenalpathology[17].Hence,theroleofAIonrenaloutcomeiscontroversialatpresent.TheAIhadbeenpostulatedtoberelatedtothelevelsofcirculatingγ-interferonandelevatedurinaryinterleukin-8[28,29].Thesecytokinesrepresent theacute inflammatoryprocessoccurringin thekidney.Therefore,wespeculatethathigherAImightindicateacuteinflammationinthekidneyandsuggestreversiblerenalhistopathologyifadequate therapyis initiated.However,thishypothesisneedstobeconfirmedinthefuture.

The limitationof this investigation is that it isaretrospectivechartreviewstudy,andnotallofthedatacouldbe retrieved.Therefore,notallofprognosticfactorspotentiallyassociatedwith long-termrenaloutcomecouldbeanalyzed.Thosefactorsincludeddailyproteinuria,aPLpositive,otherregimenssuchasoralendoxan,azathioprone,cyclosporinewereexcluded.Inaddition,asthedefinitionofLNwasdifferentineachofthestudiesandtheonsetofLNcouldnotbetraced,thesemayexplainthevastdifferencesbetweenourresultsandthoseofothersurveys.Regardless, this investigationoffers theexperienceof long-termrenaloutcomeofclassIVLNbasedonnewISN/RPSclassificationandsuggests thathigherAI isagoodprognostic factor.Whetheraggressive treatmentfor thoseLNsubjectsrevealinghighAIcouldimprovetheprognosisneedsfurtherinvestigation.

References1. CameronJS.Lupusnephritis. JAmSocNephrol1999;

Table 2. Clinical characteristics of subjects for end point II at initial renal biopsyESRD/death

All + – pn 75 �5 60Age at biopsy (y) 25.9 ± 9.7 22.2 ± 6.2 26.8 ± �0.2 0.�0�SLE→LN (y)# 2(0;5) 2(0;6) 2(0;5) 0.984Gender, female n(%) 62(82.7) ��(7�.�) 5�(85) 0.5�8Albumin# (g/dL) 2.�(�.7;2.8) 2.�(�.7;2.�) 2.2(�.7;2.9) 0.�89Creatinine# (mg/dL) 0.9(0.8;�.�) 0.9(0.8;�.9) 0.9(0.8;�.�) 0.�02C3# (mg/dL) 5�.2(��.�,86.0) 49(29;59.6) 60.4(��.7;9�.�) 0.702C4# (mg/dL) 9.6(6.0;�7.8) 8.6(5.4;�2.9) �0.�(6.2;�8.�) 0.46�Anti-dsDNA(+), n(%) 50(78.�) �0(90.9) 40(75.5) 0.48�Activity index(0-24) �4.2 ± 2.� ��.5 ± 2.� �4.4 ± 2.2 *0.05Chronicity index(0-�2) 2.5 ± �.9 �.0 ± �.9 2.4 ± �.9 0.76�Hypertension(+), n(%) 22(29.�) 5(��.�) �7(28.�) 0.9�4Pulse steroid(+), n(%) 22(29.�) 8(5�.�) �4(2�.�) 0.746Pulse Cyc(+), n(%) �0(40) 6 (40) 24(40) 0.�90

Abbreviations: SLE→LN = Interval between SLE diagnosis and LN; # = median(IQR); Cyc = Cyclophosphamide *p:the Cox proportional hazard regression model

48

Renal outcome of lupus nephritis

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12.WernickRM,SmithDL,HoughtonDC,PhillipsDS,BoothJL,RunckelDN,etal.Reliabilityofhistologicscoringforlupusnephritis:acommunity-basedevaluation.AnnInternMed1993;119:805-11.

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紅斑性狼瘡腎炎的預後-五年分析報告

楊聰信 黃純真� 陳忠仁 許鐘元 邱文燦 周靜蘭 蘇富美 蘇昱日

尤珊富 邱俊凱 陳英州 賴漢明 鄭添財

長庚醫療財團法人高雄長庚紀念醫院 過敏免疫風濕科 �解剖病理科

目的：調查第四期紅斑性狼瘡腎炎的長期預後並分析影響預後因子。方法：本研究回溯性調閱本院

157位過去經診斷為紅斑性狼瘡腎炎病人之病歷，他們都符合美國風濕病醫學會紅斑性狼瘡分類標

準並於1986-2004期間在本院接受過腎臟切片，經確認為狼瘡性腎炎。但我們只收集符合2003 ISN/

RPS 第四期紅斑性狼瘡腎炎病患之人口統計學，血清學資料及治療內容。主要觀察重點為60個月內

達到兩倍血中肌酸酐（Cr）（I）及末期腎病變（ESRD）/死亡（II）的比率。結果：我們總共收錄

75位符合2003 ISN/RPS第四期紅斑性狼瘡腎炎病患之資料，其中包含13位男生，62位女生。平均

年齡25.9±9.7歲。五年後16人（21.3%）達到觀察重點（I），15人（20%）達到觀察重點（II）。

其中沒有發展成兩倍Cr者比達到兩倍Cr者，有較高（14.5±2.1）活動指數（activity index，AI）

（HR=0.552，CI=0.351-0.870，p=0.01）。沒有發展成ESRD/death者比達到者的AI為14.4±2.2

vs.13.5±2.3（HR=0.666，CI=0.443-1.000，p=0.05）。結論：第四期紅斑性狼瘡腎炎在末期腎

病變/死亡方面達到五年長期存活預後的比率為80%，略低於其他的調查。另外腎臟切片時有較高的

AI是好的腎臟預後因子。

關鍵字：狼瘡腎炎、長期預後、ISN/RPSclassification

Original Article

50

Introduction

Goutisaninflammatorydisorderandcharacterizedbythepresenceofacute-onsetmonoarthritis.Chronicgoutmaycontributetotophiformation,boneerosionandevenmusculoskeletaldisability.Monosodiumurate(MSU)caninducecaspase-1-activatingNALP3inflammasome,whichhasbeenproventoplaymajorroleinthepathogenesisofgout[1].

Ahighprevalenceofgout inTaiwanesehasbeenreported.Laietal.analyzed3397peoplewhoreceiveda

healthexaminationandshowedthat5%ofthemaleshadahistoryofgout[2].Possibleexplanationsareageneticassociation,ahighprevalenceofchronickidneydiseaseandpoorcompliance.Therelationshipbetweengoutandhyperuricemiaandcardiovasculardiseaseshasbeenwelldocumented.Recentstudieshavedemonstratedthathyperuricemiaisasignificantpredictorforstrokeinwomenandmyocardial infarction[3,4].Adequatetreatmentforhyperuricemianotonlyprotectspatientsfromgoutattack,butalsocardiovasculardiseases.

C-reactiveprotein(CRP),oneof theacute-phasereactants, isnamedfor itscapacitytoprecipitate thesomaticC-polysaccharideofStreptococcuspneumonia[5].SerumCRP is producedbyhepatocytesonlyandpredominantlyunder transcriptionalcontrolbyinterleukin-6,which isproducedpredominantlybymacrophages, aswell as adipocytes [6,7].AhighsensitivityCRP(hsCRP)assayhasbeendevelopedtomeasure lowlevelsofCRPusing thenephelometry

Association of high sensitivity C-reactive protein with hyperuricemia in Taiwanese patients with gout Ming-Han Chen, Wei-Sheng Chen, Hui-Ting Lee, Chang-Youh Tsai, Chung-Tei ChouDivision of Allergy, Immunology & Rheumatology and Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan

Correspondingauthor:Chung-TeiChou,M.D.DivisionofAllergy,Immunology&Rheumatology,TaipeiVeteransGeneralHospital.112,Sec2,Shih-PaiRoad,Taipei112,Taiwan.Tel:+886-2-28712121ext7130,Fax:+886-2-28742518E-mail:ctchou@vghtpe.gov.twReceived: June 25, 2010Revised: August 26, 2010Accepted: Septemter 5, 2010

Objective:Toanalyze the relationshipbetweenhighsensitivityC-reactiveprotein (hsCRP)andhyperuricemiaingoutpatientsinaTaiwanpopulation.Methods:Fortygoutpatientsand25normalhealthycontrolsubjectswererecruited.TheserumhsCRP,uricacid,anderythrocytesedimentationrate(ESR)levelsofeachparticipantweremeasured.Thediseaseduration,visualanaloguescale(VAS)painscoreandpresenceorabsenceoftophiwererecorded.ThecorrelationsbetweenhsCRPlevelsandclinicalfeaturesor laboratoryprofilesingoutpatientswereanalyzed.Results: ThefindingsdemonstratedstatisticalsignificanceinhsCRPlevelsingoutpatientscomparedwithnormalhealthycontrolindividuals(p<0.001).HsCRPcorrelatedwithserumESR(r=0.549,p<0.001),uricacid(r=0.381,p=0.020)andtheVASpainscore(r=0.385,p=0.014),butnotwithdiseasedurationandpresenceoftophi.Conclusion:HsCRPwasassociatedwithhyperuricemia,highESRlevelsandhighVASpainscoresingoutpatientsinTaiwan,suggestingincreasedhsCRPmaybeanindicatorofuncontrolledhyperuricemiaorgoutyarthritis.

Key words:Gout,hyperuricemia,highsensitivityC-reactiveprotein

Formosan Journal of Rheumatology 20�0;24:50-55

5�

Chen et al

method.SerumhsCRPconcentrationsincreaseduringinflammatoryprocesses, including inflammation,infection,connectivetissuediseaseandtissuedamage[8].

Goutyarthritis is alsoan inflammatorydiseasewhichcan increaseCRP.However, thecorrelationbetweenhsCRPandgouthasseldombeenaddressed.Thus,theobjectiveofthecurrentstudywastocomparetheserumlevelsofhsCRPbetweengoutpatientsandnormalhealthycontrols.Inaddition,weinvestigatedtheassociationbetweenhsCRPandclinicalparameters,includingerythrocytesedimentationrate(ESR),uricacid(UA)levels,diseaseduration,visualanaloguescale(VAS)painscore,andthepresenceof tophi ingoutpatients.

Materials and methods

PatientsThisstudywasapprovedbytheethicscommitteeof

TaipeiVeteransGeneralHospital.Informedconsentwasobtainedfromtheparticipantsbeforetheyenteredthestudy.TomeasureserumhsCRPlevels,40goutpatientswhohadsufferedagoutyarthritisattackandvisitedtheoutpatientdepartmentof theDivisionofAllergy,ImmunologyandRheumatologyatTaipeiVeteransGeneralhospitalwere recruitedandbloodsampleswereobtainedwhentheacuteattackhasresolved.ThediagnosisofgoutwasprovenbyjointaspirationwithpositiveMSUcrystalsinthesynovialfluidorapresenceoftophi.Bloodsampleswerealsoobtainedfrom25age-andsex-matchedhealthyTaiwanesecontrols.Clinicalandlaboratoryassessmentswereperformedonthesameday.Thediseaseduration,VASpainscoreandpresenceorabsenceof tophiwererecorded.TheserumESRandUAlevelsofthegoutpatientswerealsomeasured.IndividualswereclassifiedashavinghyperuricemiawhentheirUAvaluesweremorethan7.2mg/dL.Allgoutyarthritissubjectsweremaleandtheirmeanagewas52.0years.Ofthisgroup,18patients(45%)hadhyperuricemiaand21(52.5%)hadtophi.

Laboratory analysisSamplesofperipheralbloodwereobtainedfrom40

goutpatientsand25normalhealthycontrols.SerumlevelsofhsCRPweremeasuredusingacommercialELISAkit (R&DSystem,Minneapolis,MNUSA).ESRwasmeasuredusing theWestergrenmethod(VACUETTE®ESRtubes;BangkokInterProductsCo.,Ltd,Khannayao,Bangkok,Thailand).Apatentedkinetic

uricase-peroxidasemethodwasused toevaluate theserumuricacidassay(UAShinotest®kit;Shino-testCo,Tokyo,Japan).

Statistical analysisToanalyzegroupdifferences, theMann-Whitney

U-testwasused.CorrelationsbetweenvariablesweredeterminedusingtheSpearman’srankcorrelationtest.Thepvaluewas2-tailedandinterpretedassignificantwhenthevaluewaslessthan0.05.AllstatisticalanalyseswereperformedusingSPSSsoftware,version17(SPSS,Chicago,Illinois,USA)

Results

Serum levels of hsCRP in gout patients and healthy controls

WecomparedtheserumlevelsofhsCRPbetweenthe40goutpatientsand25healthycontrols.SerumlevelsofhsCRPweresignificantlyhigherinthe40goutpatientsthaninthe25healthycontrols(mean±standarderrorofmean,3700±604vs.352±57ng/mL;p<0.001).

CorrelationbetweenserumlevelsofhsCRPandclinicalparametersingoutpatients

ThecorrelationsbetweenserumlevelsofhsCRPandclinicalparametersingoutpatientsareshowninTable1.SerumlevelsofhsCRPshowedasignificantcorrelationwithESR(r=0.549,p<0.001),UAlevels(r=0.381,p=0.020)andVASpainscores(r=0.385,p=0.014),butnotdiseaseduration(r=0.362,p=0.097)orpresenceof tophi (r=0.171,p=0.291). Inaddition,wealsoinvestigatedtheinterrelationshipsbetweenotherclinicalparameters.Ourdatashowednosignificantcorrelation,althoughserumlevelsofESRrevealeda trend thatcorrelatedwithVASpainscore(r=0.295,p=0.080).Moreover,thehighlevelsofhsCRP(>3000ng/mL)in20goutpatientswereassociatedwithhigherESR(26.21±4.85vs.8.82±2.10mm/hour,p=0.003),VASpainscores(6.15±0.70vs.2.65±0.74,p=0.002)andUAlevels(8.23±0.54vs.5.93±0.53mg/dL,p=0.003),whencomparedwithlowerlevelsofhsCRP(Table2).

Whenwedividedthegoutpatientsintotwogroups,highUAlevels(>7.2mg/dL)andnormalUAlevels(≤7.2mg/dL),thepatientswithhyperuricemiahadhigherVASpainscoresandhigherserumhsCRPlevelasopposedtothosewithout(6.06±0.90vs.2.91±0.67,p=0.009;4773.39±896.17vs.2839.91±807.93ng/mL,p=0.013,respectively)(Table3).SimilarresultswerenotobservedinESR,age,anddiseaseduration.

52

High sensitivity CRP and hyperuricemia

Discussion

Goutisthemostcommoncrystal-inducedarthritis.AnepidemiologicalstudyshowedthattheprevalenceofhyperuricemiaandgoutintheTaiwanpopulationwas19.82%and2.13%,respectively,whichwassignificantlylower than amongTaiwan aborigines [9-11].Thepossibleexplanationsweredifferentgenetics,alcoholconsumptionanddietaryintake.Inthisstudy,wefoundthatupto45.0%ofgoutpatientswerehyperuricemic,and52.5%ofthisgrouphadtophi, implyingthatthelaboratoryandclinicalconditionofmostpatientswasnotwellundercontrol.Inalargecohortstudyofuricacid-lowering therapy,Solomonetal. foundovera1-yearstudyperiodthatthehyperuricemiain64%ofgoutpatientswaspoorlycontrolled[12].Withoutregularandadequatehypouricemictherapy,patientswithacutegoutmaydevelopchronicortophaceousgoutandthesechronicinflammatorystatuseswillincreaseCRPlevels.

CRPisanacute-phasereactantanditsrelationshipwithgoutandhyperuricemiahasseldombeenreported.EvrinandcolleaguesdemonstratedthattheserumlevelofCRPwasassociatedwithuratelevels,andIl’inaetal.reportedthattheCRPlevelsweresignificantlyhigherin

goutpatientswithatherosclerosisthaninthosewithoutthiscondition[13,14].Ourstudydemonstratedthesamefinding,inthatgoutypatientshadsignificantlyhigherhsCRPlevels,andtheirserumUAlevelscorrelatedwithhsCRP.Moreover,thedatashowedapositivecorrelationbetweenserumUAandhsCRPlevels.RecentstudieshaveshownthatMSUcrystalswereakindof"dangersignal",andinducedinterleukin(IL)-1betaproductionbyactingon inflammasome. IL-1had theability tostimulateliversynthesisofCRP,andthisisthereasonwhyhighhsCRPlevelswereobservedingoutpatients[1,15,16].

Inthisstudy,wefoundthatoverhalfofpatientshadtophi,whichisadepositofMSUcrystalsformedinmanyplacesthroughoutthebody,includingthejoints,cartilageandsoft tissues.WhentheconcentrationofserumUAchanges,tophiwillberesolvedandUAwillbereleasedintothebloodandmaybedepositedinthejoints,inducingarthritisandaninflammatoryreactioninperiarticulartissues.OurstudyshowedthatVASpainscoreswerehigher in thehyperuricemiagroup thaninthenormouricemiagroup.Therefore,thetreatmentof tophiorhyperuricemia isnecessary toattenuatesymptomsofgoutytophiwithchronicpain.

Table 1. Correlation of serum hsCRP and clinical parameters in gout patientsESR UA level VAS pain score Disease duration Tophi

hsCRP r = 0.549p<0.00�*

r = 0.�8�p=0.020*

r = 0.�85p=0.0�4*

r = 0.�62p=0.097

r = 0.�7�p=0.29�

ESR r = 0.2�4p=0.225

r = 0.295p=0.080

r = 0.�64p=0.��9

r = 0.��0p=0.52�

UA level r = 0.257p=0.�25

r = - 0.�9�p=0.258

r = -0.244p=0.�46

VAS pain score r = 0.044p=0.788

r = -0.�24p=0.449

Disease duration r = 0.�94p=0.2�2

Abbreviations: n = number; NA = not applicable; ESR = erythrocyte sedimentation rate; hsCRP = high sensitivity C-reactive protein; UA = uric acid; VAS = visual analogue scale; *p<0.05.

Table 2. Comparison of the high and low hsCRP groups of gout patients

hsCRP

p value<3000 ng/mL

n = 20>3000 ng/mL

n = 20ESR, mm/hour 8.82 ± 2.�0 26.2� ± 4.85 0.00�*Age, years 52.25 ± 4.89 5�.75 ± 4.45 0.84�VAS pain score 2.65 ± 0.74 6.�5 ± 0.70 0.002*DD, years ��.�� ± 2.44 ��.�5 ± 2.06 0.696UA, mg/dL 5.9� ± 0.5� 8.2� ± 0.54 0.00�*

Abbreviations: ESR = erythrocyte sedimentation rate; hsCRP = high sensitivity C-reactive protein; UA = uric acid; VAS = visual analogue scale; DD = disease duration; *p<0.05.

Table 3. Comparison of hyperuricemia and normouricemia groups of gout patients

UA <7.2 mg/dL >7.2 mg/dL p value

ESR, mm/hour �2.2� ± 2.70 2�.56 ± 5.7� 0.�6�hsCRP, ng/mL 28�9.9� ± 807.9� 477�.�9 ± 896.�7 0.0��*Age, years 5�.00 ± 4.00 5�.6� ± 5.97 0.69�VAS pain score 2.9� ± 0.67 6.06 ± 0.90 0.009*DD, years �2.7� ± 2.4� 9.6� ± �.88 0.596Abbreviations: ESR = erythrocyte sedimentation rate; hsCRP = high sensitivity C-reactive protein; UA = uric acid; VAS = visual analogue scale; DD = disease duration; * p< 0.05.

5�

Chen et al

Thehighermortalityofpatientswithhyperuricemiaorgout than thosewithnormouricemiawasprovenrecently[10].Individualswithgoutorhyperuricemiahaveahighprevalenceofmetabolicsyndrome[17,18],diabetesmellitus[19]andchronickidneydisease[20],andalloftheseconditionscontributetoatheroscleorosisandincreasecardiovascularmortality.ThelinkbetweenhighUAlevelsandcardiovascularmortalityhasnotbeenentirelyunderstood,butCRPmayplayapivotalroleincardiovasculardisease.Daneshetal.comparedtheCRPlevelsof2459patientswithnonfatalmyocardialinfarctionor thosewhohaddiedofcoronaryheartdisease(CHD)with3969controlsfrom22prospectivestudies,andshowedthatafteradjustingformajorCHDriskfactors,patientswithCRPlevelsat thetopthirdhada45%increasedchanceofCHDeventsoccurringcomparedwiththoseatthebottomthird[21].Ridkerandcolleagueshaveshown thatpatientswithmorecharacteristicsofmetabolicsyndromehadhigherCRPlevels[22].GoutpatientsinthisstudyhadhigherhsCRPlevels,indicatingthathighhsCRPmayberesponsiblefor the increasedcardiovascular risk.Therefore,wesuggestthataggressivehypouricemictherapyshouldbegiveninasymptomatichyperuricemiapatientswithhighhsCRPinordertoreducecardiovascularmortality.

ThisstudydidnotdemonstrateacorrelationbetweenserumESRlevelsandUAlevels,VASpainscoresanddiseaseduration.ThiswasbecausemanyfactorscaninfluenceserumESRlevels,includingage,sex,anemia,congestiveheartfailure,etc.Theresults impliedthattheserumhsCRPlevelsaremoresensitivethanESRinevaluatinggoutseverityandtreatmentoutcome.

Thelimitationofthestudywasthesmallnumberofcases.LackofbaselinedataoftheserumlevelsofhsCRP,ESRanduricacidforcomparisonwasanotherlimitation.

Inconclusion, thehigherserumlevelsofhsCRPwere strongly related tohyperuricemia,highESRlevelsandhighVASpainscores inTaiwanesegoutpatients.High serum levelsofhsCRPmay reflecttheseverityof inflammatorystatus ingoutpatients.Successful treatmentofhyperuricemiacannotonlyreducethehsCRPlevel,whichisresponsibleforahighcardiovascularrisk,butalsoattenuatechronicgoutyattacksandtophiformation.

References1.MartinonF,PetrilliV,MayorA,TardivelA,TschoppJ.Gout-

associateduricacidcrystalsactivatethenalp3inflammasome.Nature2006;440:237-41.

2.LaiSW,LiuCS,LinT,LinCC,LaiHC,LiaoKF.PrevalenceofgoutandhyperuricemiainTaiwan:Ahospital-based,cross-sectionalstudy.SouthMedJ2009;102:772-3.

3.ChienKL,HsuHC,SungFC,SuTC,ChenMF,LeeYT.HyperuricemiaasariskfactorforcardiovasculareventsinTaiwan:TheChin-Shancommunitycardiovascularcohortstudy.Atherosclerosis2005;183:147-55.

4.ChenSY,ChenCL,ShenML.Severityofgoutyarthritisisassociatedwithq-wavemyocardialinfarction:Alarge-scale,cross-sectionalstudy.ClinRheumatol2007;26:308-13.

5.PepysMB,BaltzML.AcutephaseproteinswithspecialreferencetoC-reactiveproteinandrelatedproteins(pentaxins)andserumamyloidaprotein.AdvImmunol1983;34:141-212.

6.PepysMB,HirschfieldGM.C-reactiveprotein:Acriticalupdate.JClinInvest2003;111:1805-12.

7.LauDC,DhillonB,YanH,SzmitkoPE,VermaS.Adipokines:Molecularlinksbetweenobesityandatheroslcerosis.AmJPhysiolHeartCircPhysiol2005;288:H2031-41.

8.ClyneB,OlshakerJS.TheC-reactiveprotein.JEmergMed1999;17:1019-25.

9.ChouCT,LaiJS.TheepidemiologyofhyperuricaemiaandgoutinTaiwanaborigines.BrJRheumatol1998;37:258-62.

10.KuoCF,SeeLC,LuoSF,KoYS,LinYS,Hwang JS,et al.Gout:An independent risk factor for all-causeand cardiovascularmortality.Rheumatology (Oxford)2010;49:141-6.

11.RoddyE.Hyperuricemia,gout, and lifestyle factors. JRheumatol2008;35:1689-91.

12.SolomonDH,AvornJ,LevinR,BrookhartMA.Uricacidloweringtherapy:Prescribingpatternsinalargecohortofolderadults.AnnRheumDis2008;67:609-13.

13.EvrinPE,NilssonSE,ObergT,MalmbergB.SerumC-reactiveproteininelderlymenandwomen:Associationwithmortality,morbidityandvariousbiochemicalvalues.ScandJClinLabInvest2005;65:23-31.

14. Il'inaAE,Varfolomeeva EI,VolkovAV,Mach ES,AleksandrovaEN,NovikovAA,etal.Relationshipbetweenthe intima-mediacomplex thickness, the risk factorsofcardiovasculardiseases,andthelevelofC-reactiveproteiningoutypatients.TerArkh2009;81:45-9.

15.GanterU,ArconeR,ToniattiC,MorroneG,CilibertoG.DualcontrolofC-reactiveproteingeneexpressionbyinterleukin-1andinterleukin-6.EMBOJ1989;8:3773-9.

16.MoshageHJ,RoelofsHM,vanPeltJF,HazenbergBP,vanLeeuwenMA,LimburgPC,etal.Theeffectofinterleukin-1,interleukin-6and its interrelationshipon thesynthesisofserumamyloidandC-reactiveproteininprimaryculturesofadulthumanhepatocytes.BiochemBiophysResCommun1988;155:112-7.

17.ChoiHK,FordES,LiC,CurhanG.Prevalenceof themetabolicsyndromeinpatientswithgout:Thethirdnational

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healthandnutritionexaminationsurvey.ArthritisRheum2007;57:109-15.

18.LeeMS,LinSC,ChangHY,LyuLC,TsaiKS,PanWH.HighprevalenceofhyperuricemiainelderlyTaiwanese.AsiaPacJClinNutr2005;14:285-92.

19.ChoiYH,LeeDC,LeeI,LeeMG.Changesinmetforminpharmacokineticsafterintravenousandoraladministrationtoratswithshort-termandlong-termdiabetesinducedbystreptozotocin.JPharmSci2008;97:5363-75.

20.CameronJS,SimmondsHA.Uricacid,goutandthekidney.J

ClinPathol1981;34:1245-54.21.DaneshJ,WheelerJG,HirschfieldGM,EdaS,Eiriksdottir

G,RumleyA,etal.C-reactiveproteinandothercirculatingmarkersofinflammationinthepredictionofcoronaryheartdisease.NEnglJMed2004;350:1387-97.

22.RidkerPM,BuringJE,CookNR,RifaiN.C-reactiveprotein,themetabolicsyndrome,andriskofincidentcardiovascularevents:An8-year follow-upof14719 initiallyhealthyAmericanwomen.Circulation2003;107:391-7.

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探討台灣痛風病人的高尿酸血症與高敏感性C-反應蛋白的關係

陳明翰 陳瑋昇 李惠婷 蔡長佑 周昌德

台北榮民總醫院 內科部 過敏免疫風濕科

國立陽明大學

目的：探討台灣痛風病人的高尿酸血症與高敏感性C-反應蛋白（hsCRP）的關係。方法：門診收

集四十位確定痛風患者和二十五位正常健康者之血清，以酵素連結免疫吸附分析法（ELISA）去

測定血清的hsCRP，另外尚檢測血中尿酸及紅血球沈降速率，同時紀錄每位參與者的病程長短，

視覺類比量表疼痛分數（VASpain score）和痛風石的有無。最後針對痛風患者，進行hsCRP和臨

床特徵或實驗室數據的相關性的分析。結果：痛風患者血清的hsCRP的值明顯地高於正常健康對

照者（p<0.001）。且此血清hsCRP和紅血球沈降速率（r=0.549，p<0.001），尿酸（r=0.381，

p=0.020）及視覺類比量表疼痛評分成正相關（r=0.385，p=0.014），但與病程的長短與痛風石的

存在與否無關。結論：在台灣的痛風患者，hsCRP與高尿酸血症，紅血球沈降速率及視覺類比量表

疼痛分數高低有關。未來擬探討增加的hsCRP是否可作為控制不佳的高尿酸血症或痛風性關節炎的

指標。

關鍵詞：痛風、高尿酸血症、高敏感性C-反應蛋白

Original Article

56

Introduction

Pulmonary arterial hypertension (PAH) is oneof the life-threateningcomplications thatoccur in

connectivetissuediseases.StudiesofPAHhavebeenmainlyfocusedonsystemicsclerosis (SSc)patientsbecauseoftheirhigherPAHprevalence(estimated12-17.9%)[1,2].TheprevalenceofPAHinSLEhasawiderangeofestimationsbetween0.5%and14%.Thisreflectsnotonlythelackofavailabilityofareliableandsensitivescreeningmethod,thedifficultyinidentifyingriskfactorsassociatedwithPAH,butalsothebiasindetectingPAHinlupuspatientsintertiarycenters[3].SLEwithPAHmaybeunder-diagnosedoroverlookedbecause thesymptomsofPAHin lupus (exertionaldyspnea, fatigueandweakness)aregenerallynon-specificandcouldbeattributedtoserositisorinterstitial

Angiopoietin-1 and endoglin are not associated with pulmonary arterial hypertension in patients with systemic lupus erythematous Ling-Jung Yen, Hsiu-Man Keng, Chin-Chang Cheng1, Jiung-Jun Chu, Chieh-Mei Hsu,

Xin-Tian Lin, Jui-Cheng Tseng, Jui-Chieh Hu, Ling-Ying LuDivision of Allergy, Immunology and Rheumatology, and 1Cardiovascular Medical Center, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

Correspondingauthor:Ling-YingLu,M.D.DivisionofAllergy,ImmunologyandRheumatology,KaohsiungVeteransGeneralHospital.No386,Ta-Chung1stRoad,Kaohsiung813,Taiwan.Tel:+886-7-3422121ext2055,Fax:+886-7-3478962E-mail:lylu@vghks.gov.twReceived: June 30, 2010Revised: August 14, 2010Accepted: September 20, 2010

Objective:Angiopoietin(Ang)-1,anangiogenicfactor,hasbeendemonstratedtoregulatepathologicsmoothmusclecellhyperplasia.Endoglin(Eng)playsaroleincardiovasculardevelopment,vascularremodelingandactiveangiogenesis.Bothwerereported tobeassociatedwith thedevelopmentofpulmonaryarteryhypertension(PAH)inscleroderma.Therefore,wehypothesizedthatserumlevelsofAng-1andEngwouldbeassociatedwithPAHinpatientswithsystemiclupuserythematous(SLE).Methods:SerumAng-1andEnglevelsweremeasuredbyenzyme-linkedimmunoassayin22SLEpatientswithPAH,80patientswithoutPAHand16healthycontrols,andwerecorrelatedwithdiseaseactivities.Results:Ang-1levelsweresignificantlylowerinSLEpatients(19.37±8.02ng/mL)comparedwithhealthycontrols(32.00±9.89ng/mL,p<0.001).AmongSLEpatients,Ang-1levelswerelowerinpatientswithoutPAH(18.75±7.90ng/mL)comparedwiththosewithPAH(21.60±8.24ng/mL,p=0.394).However,thedifferencedidnotreachastatisticalsignificance.TherewasnodifferenceofEnglevelsbetweenSLEpatients(4.62±1.60ng/mL)andhealthycontrols(4.78±0.99ng/mL,p=0.400)andbetweenSLEpatientswithoutPAH(4.69±1.69ng/mL)andwithPAH(4.37±1.20ng/mL,p=0.441).Inaddition,Ang-1andEnglevelsdidnotcorrelatewithC3,C4andanti-dsDNAAbinpatientswithSLE.Conclusion:SerumAng-1andEnglevelswerenotgoodbiomarkersinpredictingPAHinpatientswithSLE.

Key words:Angiopoietin-1,endoglin,pulmonaryarterialhypertension,systemiclupuserythematous

Formosan Journal of Rheumatology 20�0;24:56-6�

57

Yen et al

lungdisease, therebymaking it difficult for earlydiagnosingPAHonclinicalgrounds.EarlydiagnosisisessentialbecauseearlyaggressiveinterventionofPAHwith immunosuppressivesfor lupuspatientsmaybehelpfulinprolongingtheirsurvival[4].

Up to date, echocardiography and right heartcatheterizationremaintobetheessentialsinscreeningofPAH.Echocardiographyisnoninvasive,butitmayyieldfalsepositiveresultssincepulmonaryarterysystolicpressure(PASP)increaseswithageandbodymassindex(BMI).RightheartcatheterizationisconsideredthegoldstandardindiagnosingPAH,itishoweverimpracticalasascreeningtoolbecauseitisnotonlycostlybutalsoholdshighproceduralrisks.Therefore,inconjunctionwithechocardiography,additionalscreeningtestsforidentifyingPAHmaybeimportant.

ThepathogenesisofPAHisstillnotwellunderstood.SeveralattributablecausessuchasabnormalvasospasmorRaynaud’sphenomenon,pulmonaryvasculitis,thromboembolicdisease,hypoxiaandfibrosis frominterstitiallungdiseasehavebeensuggested.IdentifyingthebiomarkersmayhelpinpredictingthedevelopmentofPAHinthosesusceptiblepopulations,enhancetheunderstandingoftheunderlyingbiologicsandpathologicmechanismandassist in thefollowupof treatmentresponses.

Angiopoietin-1(Ang-1)isasecretedglycoproteinthatbelongstoafamilyofgrowthfactors(Ang-1toAng-4).Ang-1andAng-2bothshareasimilarTIE-2(tyrosinekinasewithIgandEGFhomologydomains-2)transmembrane receptor expressedonendothelialcells.Ang-1,madeandsecretedbyvascularsmoothmusclecells[5],actsasapositiveregulatorofbloodvesseldevelopment,remodelingandmaturationintheembryonic lung.Ang-1expression inadult lungs isminimal.EvidencehavesuggestedthatAng-1regulatesthepathologicsmoothmusclecellhyperplasiainPAHandAng-1isupregulatedinthelungparenchymalofmostformsofnonfamilialPAH[5,6].Onthecontrary,Ang-1hasalsobeenreported toprotectagainst thedevelopmentofPAH in the ratmonocrotolineandhypoxiamodelsofdisease[7].

Endoglin (Eng) is aglycoproteinexpressedbyhumanvascularendothelialcells.EvidencesuggeststhatEngplaysacrucialroleincardiovasculardevelopment,vascular remodeling and active angiogenesis.Anincreased expression of Eng in fibroblasts andendothelialcellshasbeendemonstrated inSSc, thatsuggestsanalterationintheregulationoftheexpressionorfunctionofEngisrelatedtovascularmanifestationsofSSc[8].

The role ofAng-1 and Eng in SLE patientsdevelopingPAHhasnotbeen investigatedbutmaybepotentially significant. In this study,weaim toinvestigateonAng-1andEngfortheirrolesinadditionalscreeningmethodsaspotentialbiomarkerstopredictPAHinSLE.

Materials and methods

PatientsAtotalof102SLEpatients,whofulfilledthe1997

classificationcriteriaof theAmericanRheumatismassoc ia t ion for SLE and had ever rece ivedechocardiographyforunexplainedexertionaldyspneaintheabsenceofcardiaccausesorprominentpulmonarydiseaseonchestradiography,fromDecember2007toDecember2009,wereenrolled.92(90%)ofthepatientswerefemalesandallwereHan’sdescent.Themedianagewas38years(ranged20-76years),meanageofonsetwas30.2±13.9years,andmediandiseasedurationwas11.0years (ranged1-26years).Demographic,clinicalandlaboratoryfindingswereobtainedfromthepatients’charts.DiseaseactivitywasassessedbytheSLEDiseaseActivityIndex(SLEDAI)andpatientsweresubdividedintoactive(SLEDAI≥7)andinactive(SLEDAI<7)group.Sixteenyounghealthydonorswereselectedforthecontrolgroup.

Detection of PAHPAHwasdefinedasanestimatedPASPofmore

than40mmHg,atrest,onDopplerechocardiography.Inwhich,peakvelocityoftricuspidregurgitationwasassessed incontinuouswavemodeat theapexandtricuspidgradientwascalculatedusingthesimplifiedBernoulliequation,4v2,wherev isthevelocityofthetricuspid jet inmeterspersecond.EstimatedPASPwasderivedbyadditionofrightatrialpressure(RAP)tothetricuspidgradient(PASP=4v2+RAP).RAPisanestimatedvaluebasedontheverticalheightofthejugularvenouspulseonphysicalexamination.Forpatientswithprominentsignsof rightheart failure,withpatients’writtenconsentobtained,ourcardiologistperformedrightheartcatheterizations.Patientswithmoderatetosevereleftsidedventricularorvalvularheartdiseasesandchronicobstructivepulmonarydiseasewereexcluded.Consequently,atotalof22patients(22/102,21.6%)weredisclosedtohavePAH.

Measurement of Ang-1 and EngHemogram,serumcreatinineandurinalysiswere

58

Angiopoietin-� and Endoglin with PAH

measuredbyroutine techniques.Complementswerequantifiedbynephelometrymethods(BeckmanCoulterIMMAGEImmunochemistrySystem)andantibodiesagainstds-DNAandextractiblenuclearantigenswereanalyzedby immunoassay(PharmaciaUnicap-100).Serumlevelsofanti-cardiolipin,anti-β2-glycoprotein-1(β2-GP1),Ang-1 and Engwere quantitativelymeasuredusingenzyme-linkedimmunosorbentassays(ELISAs)accordingtothemanufacturer'sinstructions(INOVADiagnostics, Inc,SanDiego,CA,USAforanti-cardiolipin, anti-β2-GP1; andR&DSystems,Minneapolis,MN,USAforAng-1andEng).Serafrom16healthyvolunteerswithoutcardiacorpulmonarydiseasewerecollectedasnormalcontrolsforcomparisonofbiomarkers.

Statistical AnalysisDifferencesintheclinicalandlaboratoryfeatures

betweenpatientgroups(SLEwithorwithoutPAH)andhealthycontrolswerecomparedusingchi-squareanalysisandMann-WhitneyU-testasappropriate.CorrelationsofserumC3,C4,anti-dsDNA,Ang-1andEnglevelsbetweenthepatientgroupsandhealthycontrolgroupswereevaluatedusingPearson’scorrelation.Astatistical

differencewasconsideredsignificantifthepvaluewaslessthan0.05.DataanalysiswasperformedusingSPSS12.0forWindows.

Results

Comparisons of Clinical Characteristics between SLE patients with or without PAH

Amongtheclinicalmanifestationsinthe102SLEpatients(Table1),renalinvolvement(49.6%),arthritis(46.3%)and rash (42.1%)were themostcommon.Raynaud’sphenomenonwaspresent in28.9%andthromboticeventsoccurredin12.4%.ComparingtheclinicalmanifestationsbetweenSLEpatientswithPAHandwithoutPAH,thromboticeventtendedtoincreaseinPAHgroup(27.3%vs.11.3%,p=0.086),howeveritdidnotreachastatisticalsignificance.TheroleofautoimmuneprocesshasfrequentlybeenspeculatedinthepathogenesisofPAHassociatedwithconnectivetissuedisease.However, therewasno significantdifference in thepresenceofSSA,SSB,Sm,RNP,anticardiolipin,β2-GP1andanti-dsDNAantibodiesbetweenSLEpatientswithandwithoutPAH.

Table 1. Clinical features and laboratory findings in SLE patients with and without PAHSLE patients

All (n = �02)n (%)

With PAH (n = 22)n (%)

Without PAH (n = 80)n (%)

p

Clinical featuresRash 5� (42.�) �� (50.0) 40 (50.0) �.000Oral ulcer 22 (22.9) 5 (22.7) �7 (2�.�) �.000 Arthritis 57 (46.�) �5 (68.�) 42 (52.5) 0.2�0Serositis 40 (�9.2) 9 (40.9) �� (�8.8) �.000Renal involvement 60 (49.6) �4 (6�.6) 46 (57.5) 0.6�5 Neurological involvement �2 (9.9) � (��.6) 9 (��.�) 0.7�8Hematological involvement 42 (�4.7) 8 (�6.4) �4 (42.5) 0.6�5Vasculitis �5 (�4.7) 2 (9.�) �� (�6.�) 0.5�4Raynaud’s phenomenon �5 (28.9) 8 (�6.4) 27 (��.8) 0.805 Thrombotic event �5 (�2.4) 6 (27.�) 9 (��.�) 0.086Avascular necrosis �� (9.�) 2 (9.09) 9 (��.�) �.000

Laboratory findingsAnti-SSA 5� (50.0) �� (59.�) �8 (47.5) 0.�0�Anti-SSB �7 (�6.7) 5 (22.7) �2 (�5.0) 0.��7Anti-Sm �4 (��.7) � (4.6) �� (�6.�) 0.285Anti-RNP 24 (2�.5) 6 (27.�) �8 (22.5) 0.568Anti-cardiolipin 6� (6�.8) �2 (54.5) 5� (6�.8) 0.574Anti-β2-GP1 8 (7.84) � (4.54) 7 (8.64) 0.665Anti-dsDNA 56.07 ± �20.�6 74.79 ± 45.2� 50.92 ± 8.92 0.5��C� (Mean ± SD) 77.85 ± 24.5� 75.46 ± 26.�2 78.5� ± 24.�5 0.278C4 (Mean ± SD) �6.28 ± 8.04 �4.6� ± 6.29 �6.74 ± 8.4� 0.609

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Yen et al

The associations of Ang-1 and Eng with PAHAsshowninFig1A,Ang-1levelsweresignificantly

lowerinSLEpatients(19.37±8.02ng/mL)comparedwithhealthycontrols(32.00±9.89ng/mL,p<0.001).AmongSLEpatients,Ang-1 levelswere lower inpatientswithoutPAH(18.75±7.90ng/mL)comparedwiththosewithPAH(21.60±8.24ng/mL).However,thedifferencedidnotreachastatisticalsignificance(p=0.394).

InFig1B, therewasnodifferenceofEnglevelsbetweenSLEpatients(4.62±1.60ng/mL)andhealthycontrols(4.78±0.99ng/mL,p=0.400)andbetweenSLEpatientswithoutPAH(4.69±1.69ng/mL)andwithPAH(4.37±1.20ng/mL,p=0.441).

The correlations of Ang-1 and Eng with lupus disease activity

AsshowninTable2,bothAng-1andEnglevelsshowednocorrelationwiththelevelsofC3,C4andanti-dsDNAAbinSLEpatients.

Discussion

PAHisadevastatingcomplicationofSLEbecauseof itspoorer treatment responsecomparing toothermanifestations.ThemortalityrateofSLEpatientswith

PAHismorethan50%after3yearsfromdiagnosis[9].TheprognosisofPAHinSLEisreportedtobeworsethanthatofidiopathicPAH[10].

ArangeofbiomarkerssuchasN-terminalfragmentofbrainnatriureticpeptide(NT-proBNP),endothelin-1(ET-1),TroponinT,nitricoxide,cGMPandD-dimerhadbeenstudiedforpulmonaryhypertensioninliterature[11].However,eachofthesepotentialmarkershasitslimitations.

AnelevatedplasmaNT-proBNPlevelreflectsthedegreeofrightventricularstress,alatepresentationofPAH,thereforeanormalNT-proBNPlevelcannotbe

Figure 1. Angiopoietin-� (Ang-�) and endoglin (Eng) levels in SLE patients and controls. (box and whisker plots show Ang-� (A) and Eng (B) levels between �02 SLE patients and �6 controls, and between SLE patients, 22 with PAH and 80 without PAH.) Ang-1 levels are decreased in SLE patients compared with healthy controls (A). No significance difference in Eng levels between �6 controls and �02 SLE patients (B).

Table 2. Correlation tests between angiopoietin-� and endoglin levels and C�, C4, and anti-dsDNA in patients with SLE C� C4 Anti-ds DNAAng-� r 0.�60 -0.044 -0.��4 p (Double tail) 0.��� 0.662 0.256 Case number �0� �0� �0�

Eng r 0.044 0.06� -0.085p (Double tail) 0.66� 0.545 0.�98Case number �02 �02 �02

Abbreviations: Ang-� = angiopoietin-�; Eng = endoglin; C� = complement �; C4 = complement 4; anti-dsDNA = anti-dsDNA antibodyWhen p<0.05 (double tail), correlation is statistically significant.

60

Angiopoietin-� and Endoglin with PAH

usedtoexcludethepresenceofPAH[11].ET-1isapotentendogenousendothelium-derived

vasoconstrictorandproliferativecytokine.PAH isassociatedwiththeincreasedexpressionofendothelin-1invascular endothelial cells [12].However,ET-1is clearedby thepulmonaryvascularbed,makingperipheralvenoussamplesomewhatunreliable[13].

TroponinT is a regulatoryproteinof the thinactin filamentsof cardiacmuscles releasedwhencardiomyocyte injuryoccurred.ElevatedtroponinT,however, isnotasensitivemarkerofearlydiseasesinceitmaybeindicativeofmyocardialischemiaandisaffectedbyconcurrent leftheartdiseaseandrenalimpairment[11].

Pulmonary hypertension is believed to be aconsequenceof reducedproductionofvasodilatorsubstancessuchasnitricoxide.However,nitricoxideisaverylabilemolecule,itsdirectmeasurementofitsgaseousforminbloodisverydifficultandthereforenotfeasibleforroutinescreening.Inaddition,therearetoomanyinfluencingfactorsaffectingthefractionalexhalednitricoxidemeasurement,theyincludeage(higherinolderadults),gender(lowerinfemales),height(elevatedintallerindividuals),race(higherinAsianthanthatofWhiteorBlacks),smoking(lowerinsmokers),dietaryfactors(ingestionofnitraterichfoodsuchaslettuceandradishes,drinkingofwaterandingestionofcaffeine,andalcohol)andmedications(suchascorticosteroidsandbronchodilators)[14].StudiesoncGMPandD-dimerhadbeendone,buttheirrolesasbiomarkersforPAHstillrequirefurtherinvestigations[15,16].

Two families of growth factors, the vascularendothelialgrowthfactor(VEGF)andtheangiopoietinfamiliesareknown toactspecificallyon thebloodvasculature.Ang-1isapotentendothelialcellsurvivalfactorvia inhibitionofendothelialcellapoptosis inresponsetocytokines,Ang-1/TIE2(receptortyrosinekinases forAng) interaction is likely tocontributetowardsthemaintenanceofvascularhomeostasisunderphysiologicalcondition.Ang-1hasbeenimplicatedinPAH,however,therewerecontroversiesonitsroleinthepathogenesisofPAH.ThestudyofpatientswithPAHundergoingembolectomy reported increasedAng-1expressioninthelungparenchymawhichwasproportionaltotheincreaseinpreoperativepulmonaryvascularresistanceandmedialwallhypertrophy[5].This finding suggests either a causal relationshipbetween theactivationof theangiopoietin systemanddevelopmentofPAH,orpossibly the increasedAng-1productionrepresentsacompensatoryresponsetovasculardamageinthisdisease[7].Thistlethwaite

andcolleaguesdemonstratedincreasedexpressionofAng-1andincreasedlevelsofactivatedTIE2inpatientswithPAHwhichstimulatedproliferationofsmoothmusclecellsaroundpulmonaryarterioles, leadingtotheirconstrictionandinabilitytodilate,andeventuallyincreasedpulmonaryvascularresistance[17].However,Stewartandcolleagueshypothesizedtheendothelialcellapoptosismayleadtovessellossthatdecreasesthepulmonaryvascularbed,leadingtoincreasedresistance.TheyadministeredAng-1into theratmonocrotalinemodel,andweresuccessful inpreventingmortality,improvedallmeasuresofpulmonaryhemodynamics,and rescuedendothelial cells fromapoptosis [18].CommentarybyRudgeandcolleaguessuggestedthattheobservedincreasedAng-1inPAHbyThistlethwaitemightbeareflectionofaninsufficientcompensatoryresponseratherthanacause.Inseveralrodentmodels,smoothmusclehyperplasiawasnotobservedafteradministrationofAng-1.Therefore, according totheabove findings,althoughAng-1andTIE2maybe required fornormalendothelial-smoothmuscleinteractions,butanexcessactivationofthispathwayneednotleadtosmoothmusclehyperplasia[19].

Our results showed that serumAng-1 levelwassignificantlyhigherforthehealthycontrolscomparedwithSLEpatients(p<0.001), inaccordancewiththeclinicalstudiespointingtowardstheprotectiveeffectsofAng-1/TIE2signaling[20].ThedecrementofAng-1levelinSLEwasmorepronouncedinthepresenceofactivelupusdiseaseactivity,butdidnotreachstatisticalsignificance(p=0.151).Inaddition, thedifferenceofAng-1levelswasnotassociatedwithdiseaseactivityofSLE.ThesefindingscoincidedwiththeresultsofKumpersandcolleaguesthatindicatedcirculatingAng-1levelsweresignificantlyloweramongbothactiveandinactiveSLEpatientscompared tohealthycontrols,with lowestAng-1level inactiveSLEpatients.ThedifferenceinAng-1levelsbetweenpatientswithactiveand inactiveSLE,however,didnot reachstatisticalsignificance[21].Surprisingly,serumAng-1levelsforSLEpatientswithPAH,althoughwerelowercomparedwiththehealthycontrols,werehigherthanthatofSLEpatientswithoutPAH.Eventhoughthedifferencedidnot reachstatisticalsignificance(p=0.360), thisup-regulationofserumAng-1probablyisanotherreflectionofaninsufficientcompensatoryresponsetovasculardamageorinflammation.

The transforming growth factor (TGF) is amultifunctional cytokine, its vascular effect inangiogenesisaremainlymediatedbyEng,aTGF-βreceptorpreferentiallyexpressedonendothelialcells.

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Itresultsinactivationofendothelialcellsandvascularsmoothmusclecells.Engplaysa role invascularintegrityandendotheliumfunctioningwhereassolubleEngactsasananti-angiogenicproteinthat interfereswiththebindingofTGF-βtoitsreceptor.FujimotoandcolleaguesshowedthatserumsolubleEnglevelsweresignificantlyelevatedinpatientswithlimitedcutaneousSSc (lcSSc)comparedwithdiffusecutaneousSSc.PulmonaryarterypressurewaspositivelycorrelatedwithsolubleEnglevelsinpatientswithlcSSc[22].WipffandcolleaguesfirstdiscoveredanassociationbetweenanEnggenepolymorphismandSSc-relatedPAH[23]andwentonfurthertoshowincreasedvaluesofsolubleEnginalargeSSccohortandarelevantassociationwithavascularphenotypethatintegratesthepresenceofdigitalulcersandalteredDLCO/VA[24].UnlikeSScpatients,serumEnglevelsbetweenourSLEpatientsandhealthycontrolshadnosignificantdifference.

Inconclusion,wehaveyet toidentifyapotentialbiomarkerforPAHinSLEpatients.ChangeinserumconcentrationsofAng-1orEng inpatients inSLEpatientswithandwithoutPAHwereofnostatisticalsignificance.

References1.MukerjeeD,StGeorgeD,ColeiroB,etal.Prevalenceand

outcomeinsystemicsclerosisassociatedpulmonaryarterialhypertension:applicationofaregistryapproach.AnnRheumDis2003;62:1088-93.

2. LaunayD,MouthonL,HachullaE,etal.Prevalenceandcharacteristicsofmoderatetoseverepulmonaryhypertensioninsystemicsclerosiswithandwithoutinterstitiallungdisease.JRheumatol2007;34:1005-11.

3. BijlM,BootsmaH,KallenbergCG.Pulmonaryarterialhypertensioninsystemiclupuserythematosus:shouldwebother?Rheumatology(Oxford)2009;48:1471-2.

4. SanchezO,SitbonO, JaisX,SimonneauG,HumbertM. Immunosuppressive therapy in connective tissuediseases-associatedpulmonaryarterialhypertension.Chest2006;130:182-9.

5. Thistlethwaite PA, Lee SH, Du LL, et al. Humanangiopoietingeneexpression isamarkerforseverityofpulmonaryhypertensioninpatientsundergoingpulmonarythromboendarterectomy. JThoracCardiovasc Surg2001;122:65-73.

6. SullivanCC,DuL,ChuD,etal.Inductionofpulmonaryhypertensionbyanangiopoietin1/TIE2/serotoninpathway.ProcNatlAcadSciUSA2003;100:12331-6.

7. ZhaoYD,CampbellAIM,RobbM,NgD,StewartDJ.Protectiveroleofangiopoietin-1inexperimentalpulmonary

hypertension.CircRes2003;92:984-91.8. Coral-AlvaradoP,QuintanaG,GarcesMF,etal.Potential

biomarkersfordetectingpulmonaryarterialhypertensionin patientswith systemic sclerosis. Rheumatol Int2009;29:1017-24.

9. ChungSM,LeeCK,LeeEY,YooB,LeeSD,MoonHB.Clinicalaspectsofpulmonaryhypertension inpatientswithsystemic lupuserythematosusand inpatientswithidiopathicpulmonaryarterialhypertension.ClinRheumatol2006;25:866-72.

10.MariaJR-C,PilarE,RafaelA,etal.Comparisonofbaselinecharacteristicsandsurvivalbetweenpatientswithidiopathicandconnective tissuedisease relatedpulmonaryarterialhypertension.Jheartlungtransplant2009;28:621-7.

11.WarwickG,ThomasPS,YatesDH.Biomarkersinpulmonaryhypertension.EurRespirJ2008;32:503-12.

12.GiaidA,YanagisawaM,LanglebenD,etal.Expressionofendothelin-1 in the lungsofpatientswithpulmonaryhypertension.NEnglJMed1993;328:1732-9.

13.HeresiGADR.Biomarkersinpulmonaryhypertension.PVRIReview2010;2:12-6.

14.AbbaAA.Exhalednitricoxideindiagnosisandmanagementofrespiratorydiseases.AnnThoracMed2009;4:173-81.

15.WiedemannR,GhofraniHA,WeissmannN,etal.Atrialnatriuretic peptide in severe primary andnonprimarypulmonaryhypertension:responsetoiloprostinhalation.JAmCollCardiol2001;38:1130-6.

16.KiatchoosakunS,UngkasekvinaiW,WonvipapornC,etal.D-dimerandpulmonaryarterialhypertensioninsystemicsclerosis.JMedAssocThai2007;90:2024-9.

17.DuL,SullivanCC,ChuD, et al.Signalingmoleculesinnonfamilialpulmonaryhypertension.NEngl JMed2003;348:500-9.

18.ZhaoYD,CampbellAI,RobbM,NgD,StewartDJ.Protectiveroleofangiopoietin-1inexperimentalpulmonaryhypertension.CircRes2003;92:984-91.

19.RudgeJS,ThurstonG,YancopoulosGD.Angiopoietin-1andpulmonaryhypertension: causeor cure?CircRes2003;92:947-9.

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21.KumpersP,DavidS,HaubitzM,etal.TheTie2receptorantagonistangiopoietin2facilitatesvascularinflammationin systemic lupus erythematosus.Ann RheumDis2009;68:1638-43.

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23.WipffJ,KahanA,HachullaE,etal.Associationbetweenan

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endoglingenepolymorphismandsystemicsclerosis-relatedpulmonaryarterialhypertension.Rheumatology(Oxford)2007;46:622-5.

24.WipffJ,AvouacJ,BorderieD,etal.Disturbedangiogenesisin systemic sclerosis: high levelsof soluble endoglin.Rheumatology2008;47:972-5.

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Angiopoietin-1,endoglin與紅斑性狼瘡肺高壓的相關性研究

顏伶容 耿秀曼 鄭錦昌� 曲敬正 林新田 許介眉 曾瑞成 胡瑞潔

呂聆音

高雄榮民總醫院 過敏免疫風濕科 �心臟內科

目的：Angiopoietin（Ang）-1為血管新生因子，可調節病變平滑肌細胞的增生，而endoglin（Eng）

則在心臟血管生成、血管重塑、及活化血管新生扮演重要角色。兩者均證實與硬皮症引起的肺高壓

相關。本研究主要探討Ang-1及Eng是否與紅斑性狼瘡併發的肺高壓相關。方法：共收集80位紅斑

性狼瘡未合併肺高壓病患與22位紅斑性狼瘡合併肺高壓病患，藉由酵素免疫分析法測定病患血清

Ang-1與Eng濃度，並評估與臨床疾病活性（C3、C4與anti-dsDNA）之相關性。結果：紅斑性狼瘡

病患的Ang-1血清濃度明顯低於正常人（分別為19.37±8.02及32.00±9.89ng/mL，p<0.001），而在

紅斑性狼瘡的族群中，未合併肺高壓的Ang-1濃度雖低於合併肺高壓病患，但未達顯著差異（分別

為18.75±7.90及21.60±8.24ng/mL，p=0.394）。而Eng濃度在無論是紅斑性狼瘡病患與正常人（分

別為4.62±1.60及4.78±0.99ng/mL，p=0.400）或是紅斑性狼瘡病患有無合併肺高壓（分別為4.37

±1.20及4.69±1.69ng/mL，p=0.441）之間，皆無顯著差異。此外，紅斑性狼瘡病患的Ang-1與Eng

血清濃度與狼瘡活性指標C3、C4及anti-dsDNAAb均未呈現顯著相關性。結論：Ang-1與Eng無法作

為紅斑性狼瘡病人是否併發肺高壓之生物指標。

關鍵詞：Angiopoietin-1、endoglin、肺高壓、全身性紅斑性狼瘡

Original Article

64

Introduction

Rheumatoidarthritis (RA) iswellknownasaninflammatoryandchronicarticulardiseasethataffects0.5-1.0%ofthepopulationworldwide[1].RApatientshavehigherratesofacceleratedcoronaryarterydisease,

cerebrovascularatherosclerosisandheartfailure[2,3].Recently,RAhasalsobeenreportedtobeassociatedwithmetabolicdisordersincludingobesity,dyslipidemia,hypertension, increasedwaist circumference anddiabetes[4].

Lifestyleinthisarticledescribedasregularphysicalactivity and consumptionof foods cooked inoil.Obesity,physicalinactivity,andhighfatdietmaybethemajorfactors thatcontribute to thisunfavorablecardiovasculardisorder(CVD)riskprofileinRApatients[5]. Inaddition, some therapeuticagents includingcorticosteroidsusedforRApatientsmayincreasetheCVDriskfactorforsuchdisordersashyperlipidemia,hypertensionandhyperglycemia.

The metabolic syndrome (MS), including

Metabolic syndrome in patients with rheumatoid arthritis: association of lifestyle with anthropometric measurements Ming-Fu Chen1, Yi-Ming Chen1,2, Der-Yuan Chen1,2,3,4, Joung-Liang Lan1,2,3,4

1Department of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taiwan 2Faculty of Medicine, National Yang-Ming University, Taiwan 3Institute of Biomedical Science, National Chung-Hsing University, Taiwan4School of Medicine, Chung-Shan Medical University, Taiwan

Correspondingauthor:Der-YuanChen,M.D.,Ph.D.DivisionofAllergy,ImmunologyandRheumatology,DepartmentofInternalMedicine,TaichungVeteransGeneralHospital.No160,Sec3,Taichung-KangRoad,TaichungCity,40705,Taiwan.Tel:+886-4-23592525ext3330,Fax:+886-4-23503285E-mail:dychen@vghtc.gov.twReceived: June 18, 2010Revised: September 16, 2010Accepted: October 01, 2010

Objective: Metabolicsyndrome(MS) isaclusteringofmajor risk factors for theoccurrenceofcardiovasculardisease(CVD).Rheumatoidarthritis(RA)isachronicinflammatorydiseaseassociatedwithanincreasedCVDrisk.Inthisprospectivestudy,weevaluatedtherateofMSandtheassociationoflifestylewithanthropometricmeasurementsinRApatients.Method:Weenrolled86RApatientswhoattendedahypertension,hyperglycemia,hyperlipidemiaquestionnaireassessmentclinicbetweenDecember2008andJune2009.Inaddition,werandomlyselected172age-andsex-matchedcontrolsfromthedatabaseoftheBureauofHealthPromotion,theDepartmentofHealth,inTaiwan.Results:TherateofMSwashigherinRApatients(26.7%)thanincontrols(22.1%),buttherewasnostatisticalsignificance.AsignificantlyhigherDAS28wasobservedinRApatientswithMSthaninthosewithoutMS(4.66±0.17vs.4.00±0.12,p<0.05).Significantlyhigherlevelsoftotalcholesterol,HDL-C,andsystolicbloodpressure,andsignificantlylowerlevelsoffastingglucose,LDL-CandTGwereobservedinRApatientsthanincontrols.TheoccurrencerateoffamilyhistoryofdiabetesandhypertensionwashigherinRApatientswithMSthaninthosewithoutMS.Conclusion:ChronicinflammationstatusofRAplaysanimportantroleintheriskofdevelopingMS.OurresultssuggestthatRApatientsshouldbecontroltheirdiseaseactivityaggressively.

Key words:Metabolicsyndrome,rheumatoidarthritis,lifestyle,anthropometricmeasurements

Formosan Journal of Rheumatology 20�0;24:64-7�

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Chen et al

dyslipidemia, hypertension, hyperglycemia andabdominalobesity,isaclusteringofriskfactorsofCVD[6-9].MSisaconstellationofriskfactorsofmetabolicoriginandphysicalconditionsthatareassociatedwithan increasedriskof type2diabetesmellitus (DM),atherosclerosis, andCVD[10].AccumulatingdatasupporttheincreasedpresenceofMSininflammatoryrheumaticdiseasesuchasRA[11].MSwasalsofoundtobeassociatedwithatherosclerosisinRApatients[12].

Theaimofthisstudywastoinvestigatetheimpactoflifestyle,MScomponentinRAcomparedwiththegeneralpopulation,anddiseaseandlifestylecomponentintheRAwithMScomparewithRAwithoutMS.

Patients and methods

SubjectsAtotalofeighty-sixpatients (77 femalesand9

males;meanage±SD,55.4±1.2years),whofulfilledthe1987AmericanCollegeofRheumatologycriteriaforRA[13],wereenrolledbetweenDecember2008andJune2009.TheyattendedaquestionnaireassessmentclinicandtooktheTaiwaneseSurveyonthePrevalenceofHyperglycemia,HyperlipidemiaandHypertension(TwSHHH),whichwasdevelopedin2001[14].ThestudyprotocolwasapprovedbytheInstitutionalReviewBoard(IRB)ofTaichungVeteransGeneralHospitalandallpatientsgaveinformedconsent.

Onehundredandseventytwosex-andage-matchedcontrols(154femalesand18males;55.4±0.9years)wererandomlychosenfromtheTwSHHHdatabaseoftheBureauofHealthPromotion,theDepartmentofHealth,inTaiwan.Thedatabaseincludedatotalof7566subjectswhoparticipatedinanationwidecross-sectionalpopulation-basedsurvey in2002 inTaiwan.ThesecontrolswereselectedbecausetheyhadtheadvantageofbeingpredominantlyfromthegeneralpopulationandwereassessedinthesamewayasRApatients.

Data collection Datawerecollectedbyusingaquestionnaireon

sociodemographiccharacteristics, includingsex,age,physicalactivity,menopausalstatus,dietaryhabits,familyhistoryof cardiovascular-relateddiseases,physician-diagnoseddiseasesandmedicationhistory.Thedatacollectbyquestionnairebypatientsself,thephysicalactivitydefinedregularexerciseforbodyhealthandinexerciseatleastthreetimesaweekthatincreasestheheartbeatandinducessweating.

Duringtheassessmentclinic,sittingbloodpressure

(BP)andanthropometricmeasurementswereperformed.Waistcircumferencewasmeasuredat thenarrowestpointwithatapemeasureplacedparalleltothefloorattheendofarelaxedexpirationwiththeparticipantsstandingakimbo.Assessmentswereundertakenbyanexperiencednurse.Bloodsampletestsincludedfastingtotalcholesterol,triglyceride(TG)andfastingplasmaglucose (FPG).Electrophoresiswasperformed todeterminehigh-densitylipoproteincholesterol(HDL-C)andlow-densitylipoproteincholesterol(LDL-C).

Diagnostic criteria for MSIn this study,classificationofMSaccording to

themodifiedATP III criteria forAsians [15] andfurthermodifiedbytheBureauofHealthPromotion,DepartmentofHealth,Taiwanin2006,requiredmeetingatleastthreeofthefollowingcomponentriskfactors:(1)Waistcircumference>90cmformenand>80cmfor

women;(2)TG≥150mg/dL;(3)HDL-C<40mg/dLformenand<50mg/dLfor

women;(4)SystolicBP(SBP)≥130mmHgordiastolicBP(DBP)

≥85mmHgorcurrentuseofantihypertensivedrugs;(5)FPG≥100mg/dLorcurrentuseofantihyperglycemic

drugs.Thedefinitionofabdominalobesitywasmodified

accordingtothe2000WHOAsiaPacificGuidelines[16],asawaistcircumferencehigherthan90cminmenandhigherthan80cminwomen.

Statistical analysesResultsarepresentedwithmean±standarddeviation

ormedian (range), andwereanalyzedusingSPSS12.0 forWindows (SPSSInc.,Chicago, IL,USA).Differencesbetweenthetwogroupsweretestedusingtheindependentsamplesttest.Pearson'schi-squaretestwasusedtocomparecategoricalvariables.Apvalueoflessthan0.05wasconsideredstatisticallysignificant.

Results

Demographic data, clinical characteristics, and laboratory findings of study groups

As illustrated inTable1, themeanerythrocytesedimentationrate(ESR)was34.6±2.2mm/hr, themeanlevelofC-reactiveprotein(CRP)was0.74±0.12mg/dL,andthemeandiseaseactivityscorein28joints(DAS28)was4.13±0.10,indicatingactivestatusofRApatients.

66

Metabolic syndrome in RA

After stratification for thecholesterol-loweringmedicationsandantihypertensivemedicationsused,significantlyhigherlevelsoftotalcholesterol,HDL-C,andSBP,andsignificantlylowerlevelsofFDG,LDL-CandTGwereobservedinRApatientsthanincontrols.ThewaistcircumferencewasnotsignificanthigherinRApatientsthancontrols(p=0.054).Therewasnosignificantdifferencein therateofMSbetweenRApatients(26.7%)andthecontrolgroup(22.1%).

Components of lifestyle in RA patients and the control group

As illustrated inTable 2, significantly lowerfrequenciesofconsumptionofmeatcookedwithahigh

amountofoilorsaltwereobservedinRApatientswhencomparedwiththecontrolgroup(p=0.048).TherewerenosignificantdifferencesinregularphysicalactivityormeannumberofyearssubjectsengagedinregularphysicalactivitybetweenRApatientsandthecontrolgroup.ThenumberofRApatientswithfamilyhistoryofdiabetes,hyperlipidemia,CADorCVAwassignificantlylowerthanthatinthecontrolgroup(Table2).

Comparison of the components of metabolic syndrome between RA patients with MS and controls with MS

AmongthecomponentsofMS,asignificantlyloweroccurrenceoflowHDL-CwasobservedinRApatientsthaninthecontrolgroupwithMS(21.7%vs.63.2%,p=0.003,Fig.1).

Table 1. Demographic data, clinical characteristics and laboratory findings of RA patients and the control group

RA patients(n = 86)

Controls(n = �72)

Age, years 55.4 ± �.2 55.4 ± 0.9Sex, F/M 77 (89.5) �54 (89.5)Glucose, mg/dL 9�.5 ± 2.� �0� ± 2.9 *Cholesterol, mg/dL 2�0.9 ± 4.� �95.5 ± 2.7 **Triglyceride, mg/dL 94.7 ± 6.8 ��4.0 ± 6.7 ***HDL-C, mg/dL 78.8 ± 2.5 59.� ± �.� **LDL-C, mg/dL ���.� ± �.8 �22.6 ± 2.0 *SBP, mmHg ��2.� ± �.7 �22.0 ± �.4 ***DBP, mmHg 78.0 ± �.� 76.2 ± 0.9Waist circumference, cm 8�.4 ± 2.� 79.5 ± 0.7Metabolic syndrome 2� (26.7) �8 (22.�)ESR, mm/hr �4.6 ± 2.2 NACRP, mg/dL 0.74 ± 0.�2 NADAS28 4.�� ± 0.�0 NAPrednisolonea 6.24 ± 0.�0 NAMethotrexateb �2.� ± 0.�7 NAHydrochloroquine 29 (��.7) NASalazopyrine �4 (�6.�) NAArheuma �4 (�6.�) NACyclosporine �0 (��.6) NANSAID 80 (9�.0) NAEtanercept �9 (22.�) NAAdalimumab �4 (�9.5) NARituximab 6 (7.0) NAOcrelizumab �(�.�) NA

Abbreviations: HDL-C = high density lipoprotein; LDL-C = low density lipoprotein; SBP = systolic blood pressure; DBP = diastolic blood pressure; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS28 = disease activity score in 28 joints; NSAID = non-steroid anti-inflammatory drug; NA = not applicable.*p<0.05, **p<0.005, ***p<0.00�, analyzed by Pearson’s chi-square test. a8� patients in the RA groupb54 patients in the RA group

Table 2. Physical activity, dietary habits and cardiac-associated disease history of RA patients and the control group

RA patients(n = 86)

Controls (n = �72)

Regular physical activity (no. of subjects)

59 (68.6) �25 (72.7)

Regular physical activity (years) 5.�8 ± �.25 8.78 ± �.55Diet high in salt 70 (8�.4) �40 (8�.4)Consumption of foods cooked in oil (no. of subjects)

Vegetables 75 (87.2) �5� (89.0)Meat �7 (4�.0) 97 (56.4)*Eggs 66 (76.7) �47 (85.5)Bean �� (�6.0) 5� (29.7)Fish 56 (65.�) ��2 (76.7)rice �5 (�7.4) 2� (�2.2)Daily consumption of vegetables 77 (89.5) �62 (94.2)Vegetarian 7 (8.�) �0 (5.8)Hyperuricemia 5 (5.8) 7 (4.�)CAD 6 (7.0) �9 (��.0)Hypertension 22 (25.6) �9 (22.7)Diabetes � (�.5) �4 (8.�)Hyperlipidemia �� (�5.�) �0 (�7.4)CVA � (�.2) 4 (2.�)FH Diabetes 26 (�0.2) 74 (4�.0)*FH Hyperlipidemia 20 (2�.�) 8� (47.�)***FH Hypertension 4� (50.6) �08 (62.8)FH CAD �8 (20.9) 7� (42.4)**FH CVA 20 (2�.�) 66 (�8.4)*

Abbreviations: FH = family history (at least one person); CAD = coronary artery disease; CVA = cerebral stroke. *p<0.05, **p<0.005, ***p<0.00�, analyzed by Pearson’s chi-square test, Fisher’s exact test, Mann–Whitney test, Student’s t-test, as appropriate.

67

Chen et al

Comparison of lifestyle and cardiovascular-associated disease in RA patients with and without MS

WestratifiedRApatientsintotwosubgroups:thosewithorwithoutMS(Table3).RApatientswithMShadsignificantlyhigherDAS28scoresthanthosewithoutMS(4.66±0.17vs.4.00±0.12,p<0.05). In termsoffamilyhistory,asignificantlyhigherrateoffamilyhistoryofdiabeteswasobservedinRApatientswithMSthaninthosewithoutMS(60.9%vs.19.0%,oddsratio[OR]=6.61,95%confidenceinterval[CI]2.32-18.8,p<0.001).Similarly,asignificantlyhigherrateoffamilyhistoryofhypertensionwasobservedinRApatientswithMS(73.9%vs.41.9%,OR=3.92,95%CI1.36-11.3,p<0.05).Nosignificantdifferenceinage,proportionoffemales,ESR,CRPlevel,physicalactivity,dietaryhabitsandtheusageofbiologicagentswasobservedbetweenRApatientswithMSandthosewithoutMS.

Discussion

Thepresent studydemonstrateda substantiallyelevatedprevalenceofMSinRApatientscomparedtothatintheage-andsex-matchednormalpopulation,butwithoutasignificantdifference(26.7%vs.22.1%).OurresultswereconsistentwiththoseofpreviousstudiesreportingprevalenceratesofMSrangingfrom14%to44%inRApatients[17-19].Inaddition,weshowedthatsignificantlyhigherdiseaseactivityscores(DAS28)werenotedinRApatientswithMSthaninthosewithout

MS.OurdatawereconsistentwiththoseinthestudybyS.A.Karvounarisetal.showingthatRApatientswithDAS28>3.2hadsignificantlyhigherprevalenceratesofMScomparedwiththosewithnoMScomponents[17].RecentstudiesindicatedthepresenceofMSincreasestheriskforafutureCVDevent[20],andasystematicreviewrevealedthatmiddle-agedindividualswithMShavea1.5foldincreasedriskforcardiovascularevents[21].ADutchcommunity-basedstudydemonstratedthatindividualswithMShadatwo-foldhigher10-yearriskof incidentcardiovasculardisease [22].Takentogether,thesurveyofMSservesasasimplemethodfor identifying high-risk subjects predisposed tocardiovasculardisease[23,24].

MShas been shown to affect primarily oldersubjects in thegeneralpopulation,asaconsequenceofage-relatedmodificationofsomeofitscomponents[25].Inourstudy,olderage(meanagewas54years)mayexplain the lackofsignificantdifferencein therateofMSinbothRApatientsandthecontrolgroup.Obesityisapro-inflammatorystateandadiposetissueisa rich sourceof inflammatorymediatorsknownasadipocytokines,whichmayinterfacebetweentheimmunesystemandMS.Inthepresentstudy,thefindingthat therewasnosignificantdifference in thewaistcircumferencebetweenRApatientsandcontrolsmayberelatedtoweightlossandcachexia[26].Inourstudy,RApatientshadhighwaistcircumference.

OurresultsshowedthatRApatientshadsignificantlyhigher levels ofHDL-C and lower levels ofTG

Figure 1. Comparison of the components of metabolic syndrome between RA patients with MS and controls with MS. RA patients with MS had significantly lower levels of HDL-C (p=0.003) than controls with MS.

68

Metabolic syndrome in RA

comparedwiththecontrolgroup.ApossibleexplanationmaybeRA-relatedinflammationandmedicationsthataffect lipidprofiles.OurresultswereconsistentwiththefindingsofarecentstudyshowingthathighHDL-Cwasapro-inflammatoryHDL-CinRApatientswithactivediseasethatincreasescardiovascularmorbidityandmortality[27].Morerecently,chronicinflammationhasbeensuggestedasapartoftheinsulin-resistancesyndrome [28].Therapeutic interventionbasedon

methotrexateandTNF-αantagonistsseemstodiminishtheinsulinresistancestate[29].

PhysicalinactivityisalsoanimportantriskfactorforMS[30].OurresultsshowedthatRApatientsdonotengageinregularexerciseasfrequentlyasthecontrols.ThereasonforthisfindingmaybeRA-relatedfunctionaldisabilities, joint stiffnessandpain.OurdatawasconsistentwiththefindingsofastudybySharmayneR.E.etal.[31].Theinverseassociationbetweenphysicalactivityand thepercentageof individualswithMSsuggeststhatmoreactivitymayprotectthemagainstthedevelopmentofMS.

Thesignificant lowerratefamilyhistoryofDM,hyperlipidemia,CADandCVA inRApatientwaspresentinourstudy.Significantlowerfamilyhistoryofcardiovasculardiseaseswaspresent in thestudyofSharmayneR.E. [31]. In thepresent study,wedemonstratedthatasignificantlyhigherrateoffamilyhistoryofdiabetesandessentialhypertensionmayleadtoahigherriskofMS.OurresultswereconsistentwiththoseofastudybyGhoshA.etal.indicatingthatthepercentageofindividualswithahighfamilialriskofdiabetesandahighriskofdevelopingMSwasbetween1.4and1.6,and1.6and1.8times,respectively,thatofpeoplewithaveragefamilialrisk[32].

RApatientswithMShavesignificantlowerHDL-CthancontrolswithMS.Thehigh levelHDL-CmayexplainastheHDL-CasproinflammatoryHDL-C,theincreasedriskofatherosclerosisinpatientswithRAwasdemonstrated[33].

ThemajorlimitationishigherrateofusebiologicagentinRApatient,mayresultfromasinglecenter,outpatientdepartmentbasedstudy.Theothertwoofthelimitationsaretothedurationofuseofbiologicagent,andlackofcomparisonofpre-andpost-medicationinourstudy.

Inconclusion,ahighrateofMSmaybepredictiveoffurthercardiovasculareventsinRApatients.ChronicinflammationstatusofRAplaysanimportantroleintheriskofdevelopingMS.Ourresultssuggest thatRApatientsshouldbecontrol theirdiseaseactivityaggressively.FurtherlongitudinalstudiestoconfirmtheroleoflifestyleinthedevelopmentofMSareneeded.

References1. WeinblattME,KuritzkyL.RAPID:rheumatoidarthritis.J

FamPract2007;56:S1-7.2. KaplanMJ.Cardiovasculardiseaseinrheumatoidarthritis.

CurrOpinRheumatol2006;18:289-97.3. McEntegartA,CapellHA,CreranD,RumleyA,Woodward

Table 3. Physical activity, dietary habits and cardiac-associated disease history of RA patients with and without metabolic syndrome (MS)

RA with MS (n = 2�)

RA without MS(n = 6�)

Age, years 58.9 ± 2.2 54.2 ± �.5Sex, F/M 19/4 58/5ESR, mm/hr �6.4 ± 5.� ��.2 ± 2.4CRP, mg/dL 0.47 ± 0.�4 �.52 ± 0.7DAS28 4.46 ± 0.�7 4.00 ± 0.�2*Biologic agent �7 (7�.9) 47 (74.6)Regular physical activity (no. of subjects)

6 (26.�) 2� (��.�)

Regular physical activity (years)

7.2� 5.04

Diet high in salt �9 (82.6) 46 (7�.0)Consumption of foods cooked in oil (no. of subjects)

Vegetables 22 (95.7) 5� (84.�)Meat 8 (�4.8) �2 (�9.0)Eggs �7 (7�.9) 49 (77.8)Bean 9 (�9.�) 22 (�4.9)Fish �7 (7�.9) �9 (6�.9)Rice 6 (26.�) 9 (�4.�)Daily consumption of vegetables

5 (2�.7) 5 (7.9)

Vegetarian � (��.0) 4 (6.�)Hyperuricemia � (4.�) 4 (6.�)CAD 2 (8.7) 4 (6.�)Hypertension 6 (26.�) �6 (25.4)Diabetes 0 (0) � (4.8)Hyperlipidemia 4 (�7.4) 9 (�4.�)CVA 0 (0) � (�.6)FH Diabetes �4 (60.9) �2 (�9.0)**FH Hyperlipidemia 5 (2�.7) �5 (2�.8)FH Hypertension �7 (7�.9) 26 (4�.9)*FH CAD 4 (�7.4) �4 (22.2)FH CVA 7 (�0.4) �� (20.6)

Abbreviations: FH = family history (at least one person); ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS28 = disease activity score in 28 joints; CAD = coronary artery disease; CV = cerebral stroke. *p<0.05, **p<0.00�, analyzed by Pearson’s chi-square test, Fisher’s exact test, Mann–Whitney test, Student’s t-test, as appropriate.

69

Chen et al

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4. ChungCP,OeserA,SolusJF,Avalos I,GebretsadikT,ShintaniA,RaggiP,SokkaT,PincusT,SteinCM.Prevalenceof themetabolic syndrome is increased in rheumatoidarthritisand isassociatedwithcoronaryatherosclerosis.Atherosclerosis2007;196:756-63.

5. ElkanAC,EngvallIL.Rheumatoidcachexia,centralobesityandmalnutrition inpatientswith low-activerheumatoidarthritis: feasibilityofanthropometry,MiniNutritionalAssessmentandbodycompositiontechniques.EurJNutr2009,48:315-22.

6. GrundySM.Hypertriglyceridemia,atherogenicdyslipidemia,andthemetabolicsyndrome.AmJCardiol1999;83:25-9.

7. ExecutiveSummaryof theThirdReportof theNationalCholesterolEducationProgram (NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII).JAMA2001;285:2486-97.

8. HansenBC.ThemetabolicsyndromeX.AnnNYAcadSci1999;892:1-24.

9. LieseAD,Mayer-DavisEJ,HaffnerSM.Developmentofthemultiplemetabolicsyndrome:anepidemiologicperspective.EpidemiolRev1998;20:157-72.

10.WilsonPW,D’AgostinoB,PariseH,SullivanL,MeigsJB.Metabolicsyndromeasaprecursorofcardiovasculardiseaseandtype2diabetesmellitus.Circulation2005;112:3066-72.

11.RatermanHG,vanEijk, IC.Themetabolicsyndrome isamplifiedinhypothyroidrheumatoidarthritispatients:across-sectionalstudy,AnnRheumDis2010;69:39-42.

12.DesseinPH,JoffeBI,VellerMG,etal.Traditionalandnontraditionalcardiovascular risk factorsareassociatedwithatherosclerosis inrheumatoidarthritis.JRheumatol2005;32:435-42.

13.ArnettFC,EdworthySM,BlochDA,etal.TheAmericanRheumatismAssociation1987 revised criteria for theclassificationof rheumatoid arthritis.ArthritisRheum1988;31:315-24.

14.LeeCH,BaiCH,ChenCJ.Prevalenceofobesity andmetabolic syndrome inTaiwan. JFormosMedAssoc2006;105(8)

15.WorldHealthOrganization.TheAsia-Pacificperspective:redefiningobesityanditstreatment.WHO:Geneva,2000.

16.TanCE,MaS,WaiD,etal.Canweapply theNationalCholesterolEducationProgramAdultTreatmentPaneldefinitionofthemetabolicsyndrometoAsians?DiabetesCare2004;27:1182-6.

17.KarvounarisSA,SidiropoulosPI,PapadakisJA,SpanakisEK,BertsiasGK,GanotakisS,BoumpasDT.Metabolicsyndromeiscommonamongstmiddle-to-olderagedMediterranean

patientswithrheumatoidarthritisandcorrelateswithdiseaseactivity:aretrospective,cross-sectional,controlledstudy.AnnRheumDis2007;66:28-33.

18.DesseinPH,TobiasM,VellerMG.Metabolicsyndromeandsubclinicalatherosclerosis in rheumatoidarthritis. JRheumatol2006;33:2425-32.

19.Zonana-NacachA,Santana-SahagunE,Jimenez-BalderasFJ,Camargo-CoronelA.Prevalenceandfactorsassociatedwithmetabolic syndrome inpatientswith rheumatoidarthritisandsystemiclupuserythematosus.JClinRheumatol2008;14:74-7.

20.CabreJJ.Metabolicsyndromeasacardiovasculardiseaseriskfactor:patientsevaluatedinprimarycare.BMCPublicHealth2008;8:251.

21.GamiAS,WittBJ,HowardDE,ErwinPJ,GamiLA,SomersVKetal.Metabolicsyndromeandriskofincidentcardiovasculareventsanddeath:asystematicreviewandmeta-analysisoflongitudinalstudies.JAmCollegeCardiol2007;49:403-14.

22.SidiropoulosP,KarvounarisS,BoumpasD.Metabolicsyndrome in rheumat ic d iseases : epidemiology,pathophysiology,andclinicalimplications.ArthritisResTher2008;10:207.

23.WannametheeSG,ShaperAG,LennonL,MorrisRW.Metabolic syndrome vs. FraminghamRiskScore forPredictionofCoronaryHeartDisease,Stroke,andType2DiabetesMellitus.ArchInternMed2005;165:2644-50.

24.SattarN,McConnachieA,ShaperAG,BlauwGJ,BuckleyBM,deCraenAJetal.Canmetabolicsyndromeusefullypredictcardiovasculardiseaseanddiabetes?Outcomedatafromtwoprospectivestudies.Lancet2008;371:1927-35.

25.AlexanderCM,LandsmanPB,GrundySM.Theinfluenceofageandbodymassindexonthemetabolicsyndromeanditscomponents.DiabetesObesMetab2008;10:246-250.

26.ElkanAC,HåkanssonN.Rheumatoidcachexiaisassociatedwithdyslipidemiaandlowlevelsofatheroprotectivenaturalantibodiesagainstphosphorylcholinebutnotwithdietaryfatinpatientswithrheumatoidarthritis:across-sectionalstudy.ArthritisRes&Ther2009;11:108.

27.Charles-SchoemanC,WatanabeJ.Abnormalfunctionofhigh-densitylipoproteinisassociatedwithpoordiseasecontrolandanalteredproteincargoinrheumatoidarthritis.ArthritisRheum2009;60:2870-9.

28.Fernandez-Real JM,RicartW. Insulin resistance andchroniccardiovascularinflammatorysyndrome.EndocrRev2003;24:278-301.

29.KiortsisDN,MavridisAK,VasakosSet al.Effectsofinfliximabtreatmentoninsulinresistanceinpatientswithrheumatoidarthritisandankylosingspondylitis.AnnRheumDis2005;64:765-6.

30.MelindaLI,BarbaraEA,Elizabeth JM-D,CherylLA,

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RussellRP,andLarryJD.Physicalactivityandthemetabolicsyndromeinatri-ethnicsampleofwomen.ObesRes2002;10

31.Sharmayne RE, Courten B.The role of traditionalcardiovascularriskfactorsamongpatientswithrheumatoidarthritis.JRheumatol2009;36:1;doi:10.3899/jrheum.080404.

32.GhoshA,LiuT,KhouryMJ,ValdezR.FamilyhistoryofdiabetesandprevalenceofthemetabolicsyndromeinU.S.adultswithoutdiabetes:6-year results fromtheNational

HealthandNutritionExaminationSurvey(1999-2004).PublicHealthGenomics2009.

33.MaureenM,JenniferG,JohnF,ErikaD,DanielJW,BernardYT,HumeiraB,KennethK,ChristinaC,MohamadN,AlanMF,BevraHH.ProinflammatoryHigh-DensityLipoproteinasaBiomarkerforAtherosclerosisinPatientsWithSystemicLupusErythematosusandRheumatoidArthritis.ArthritisRheum2006;54:2541-9.

7�

Chen et al

類風濕性關節炎病人的代謝症候群與生活習慣及體位測量相

關性之研究

陳銘夫� 陳一銘�,2 陳得源�,2,�,4 藍忠亮�,2,�,4

�台中榮民總醫院 過敏免疫風濕科

2國立陽明大學醫學院

�國立中興大學 醫學科技研究所

4中山醫學大學醫學院

目的：代謝症候群是心血管疾病的危險因子，類風濕性關節炎是一種慢性發炎性疾病同時也增加了

心血管疾病的危險性，本研究探討類風濕性關節炎病人的代謝症候群與生活習慣及體位測量相關

性。方法：本研究於2008年12月至2009年6月間於門診收集86位類風濕性關節炎病人有關高血壓、

高血糖、高血脂的問卷，另外又由國民健康局的資料庫中隨機抽樣172位年齡與性別吻合的對照

組。結果：類風濕性關節炎病人的代謝症候群盛行率（26.7%）較對照組高（22.1%），類風濕性

關節炎病人有代謝症候群的DAS28較無代謝症候群者高（4.66±0.17vs.4.00±0.12,p<0.05），類

風濕性關節炎病人比起對照組有較高的總膽固醇、高密度膽固醇及收縮血壓，較低的低密度膽固醇

及三酸甘油酯，類風濕性關節炎病人中有代謝症候群的家族有糖尿病或高血壓較無代謝症候群的病

人高。結論：類風濕性關節炎造成的慢性發炎反應可能是代謝症候群盛行率高的原因，應該多鼓勵

類風濕性關節炎病人積極的控制疾病。

關鍵詞：代謝症候群、類風濕性關節炎、生活習慣、體位測量

Original Article

72

Introduction

Thekneejointsareoneofthemostcommonsitesofmusculoskeletalpain,withtheprevalenceofkneepainrangingfrom20%to52%inindividuals55yearsoldandolder[1].Baker'scyst (BC)wasoneof thedifferentialdiagnosesasthesourceofkneepain.BCwasfirstreportedbyAdamsin1840[2]andwastheorizedasanenlargedgastroenemius-semimembranosusbursathat

communicatedwiththekneeandtrappedsynovialfluid.ABaker'scyst isseenasaswellingbehindthekneeandformswhenfluidcollectsinthejoint.Thisexcessofsynovialfluidmaybecausedbytissueinflammationassociatedwith increasedintraarticularpressureduetoanunderlying jointdisease suchas rheumatoidarthritis(RA)orosteoarthritis(OA)[3,4].BCsmaybeasymptomaticorsymptomaticwithafeelingofmass,atensefeelingwithunevenjointmovement,orlowerlegswelling.ComplicationsofBCincludecystinfection,rupturecausedpseudothrombophlitis [3],deepveinthrombosis[5],andacutecompartmentsyndrome[6].Owing to its lowercost,noninvasiveness,andeaseofoperation,musculoskeletalultrasound(MSU)isagoodtoolforevaluatingkneepain.Thepurposeofthisretrospectivestudywastoanalyzeassociateddiseases,lesionsizes,andinflammatorymarkersinnon-rupturedandrupturedBCs.

Ruptured Baker’s cyst in patients with rheumatic diseases: analysis of 235 Baker’s cysts in 198 patients Song-Feng Yeh1, Deh-Ming Chang1, Jenn-Haung Lai1, Chen-Hung Chen1, Tsung-Yun Hou1,

San-Yuan Kuo1, Chi-Sheng Chiou2, Chi-Ching Chang2

1Division of Rheumatology, Immunology and Allergy, Department of Internal medicine, Tri-serve General Hospital, National Defense Center, Taiwan2Division of Rheumatology, Immunology and Allergy, Taipei Medical University Hospital, Taiwan

Correspondingauthor:Chi-ChingChang,M.D.DivisionofRheumatology,ImmunologyandAllergy,TaipeiMedicalUniversityHospital.No252,Wu-HsingStreet,Taipei,Taiwan.Tel:+886-2-2737181ext3903,Fax:+886-2-27363051E-mail:ccchang@tmu.edu.twReceived: June 30, 2010Revised: November 20, 2010Accepted: November 26, 2010

Purpose: Weretrospectivelyanalyzedpatients'characteristics,underlyingdiseases,andsizeoflesionbetweenrupturedandnon-rupturedBaker'scysts(BC).Method:Weretrospectivelyreviewedthehospitalrecordsof198patientswith161unilateraland37bilateralBCsthatwerediagnosedbymusculoskeletalultrasound(MSU)atarheumatologydepartmentfromJune2006toJune2009.Result: Wefound235BCsofwhich22wereruptured(11rightand11leftknees).Non-rupturedBCandassociateddiseasesoccurancewereasfollows:Osteoarthritis(OA)(125),gout(41),rheumatoidarthritis(RA)(21),pseudogout(13),andspondyloarthropathy(SpA)(13).RupturedBCswereassociatedwiththefollowingdiseases:RA(11),OA(4),gout(3),SpA(1),systemiclupuserythematosus(1),pseudogout(1),andpolymyositis(1).Conclusion:OAwastheleadingcauseofnon-rupturedBaker'scystswhileRAwithactivearthritiswerethemajorcausesofrupturedBCs.MSUwasfoundtobeausefultoolforidentifyingthesediseasesinrheumatologicclinics.

Key words:Musculoskeletalultrasound,Baker'scyst,arthritis

Formosan Journal of Rheumatology 20�0;24:72-77

7�

Yeh et al

Patients and methods

Patients and dataThehospitalrecordsof198patients(78menand120

women)withunilateralorbilateralBC(161unilateraland37bilateral)whowerereviewedbetweenJune2006andJune2009atarheumatologydepartment.WithMSUexamination,BCwasdiagnosedbyfindingahypoechoicor anechoic cystic lesionbehindknee joints andrupturedcystmeanextensionoffluidoutofthecystintosurroundingtissue.OAwasdiagnosedusingthecriteriadevelopedbytheAmericanCollegeofRheumatology(ACR)in1981[8].RAwasdiagnosedusingthe1988ACRrevisedcriteria[9].Crystalassociatedarthritiswasdiagnosed throughpolarizedmicroscopy.Diagnosisof systemicerythematosus lupus (SLE)wasmadeaccording to the1997ACR revised classificationcriteria[10].Spondyloarthropathy(SpA)wasdiagnosedusingthe1991EuropeanSpondyloarthropathyStudyGroupClassificationCriteria[11].PolymyositiswasdiagnosedaccordingtothediagnosticcriteriaproposedbyBohanandPeter [12].Therewasnohistoryoftraumaticeventsaffectingtheleg,orexcessivephysicalactivityprecedingtheonsetofsymptoms.Diagnosisoftheserheumaticdiseaseswasmadeorhadalreadybeenmadewhenourpatientswerehospitalized.Themedicalrecordsofthesepatientswerereviewedandthefollowingclinicalconditionswereevaluated:associateddiseases,C-reactiveprotein(CRP)levels,andthesizeoftheBC.CRPlevelswerealsocollectedatthetimeofBCdiagnosis.Thisretrospectiveobservationstudywasapprovedbytheethicalcommitteeofourhospital.

MethodAllMSUandpowerDopplerevaluationsoftheBC

wereexaminedbyanexperiencedseniorrheumatologist.AllultrasoundinvestigationswereperformedusinganultrasoundsystemandpowerDopplertechniquewitha7~12MHzreal-timelineararraytransducer(Model2356,Envisor,Philips). Initially,patientswere inasupinepositionwiththekneejointatzerodegreesofflexionfor theexamination.Thesizeof theBCwasdetermined.

Results

Patient characteristicsPatients'demographicsaresummarizedinTable

1.Wefound235BCs inwhich rupturedBCswereobservedin22knees(9.4%)(11rightand11left).Non-rupturedBCassociateddiseaseswereasfollows:OA(125),gout(41),RA(21),pseudogout(13),andSpA(13).ThediseasesassociatedwithrupturedBCwereRA(11),OA(4),gout(3),SLE(1),pseudogout(1),polymyositis(1),andSpA(1).ThemeanageofBConsetwas63(range23-94yrs).ThemeanageofrupturedBConsetwas57.8(range22-85yrs).

Clinical presentationNew-onsetswellingofthekneewaspresentinall

patients.Tendernesswaspresent in36%of thenon-rupturedBCgroupand82%oftherupturedcystgroup.Localheatandtendernesswerepresentin42%ofthenon-rupturedBCgroupand76%oftherupturedcystgroup.FourrupturedBCpatientsrequiredawheelchair.Meandurationofkneesymptomswas4.7days.

Table 1. Clinical manifestation and disease associated non-ruptured Barker's cyst and ruptured Baker’s cyst Non-ruptured Barker’s cyst

n: 213 (%)Ruptured Baker’s cyst

n: 22 (%) Mean age (yrs) 62.98 57.75Mean size (length x width) �.66 cm x �.27 cm 9.65 cm x 2.50 cm OA �25 (58.7) 4 (�8.2)Gout 4� (�9.2) � (��.6)RA 2� (9.8) �� (50.0)SpA �� (6.�) � ( 4.5)Pseudogout �� (6.�) � (4.5 ) SLE 0 � ( 4.5)Polymyositis 0 � ( 4.5)Mean level CRP (mg/dL) in RA �.�6 7.99**

Abbreviations: OA = osteoarthritis; RA = rheumatoid arthritis; SpA = spondyloarthropathy; SLE = systemic lupus erythematosus; CRP = C- reactive protein **p value <0.05.

74

Ruptured Baker’s cyst in rheumatic diseases

Sonographic and laboratory findingsOfthetotal235BCsevaluatedinthisstudy,198

rheumatologicpatientswerediagnosed.213BCs(90.6%)werediagnosedasnon-rupturedand22BCs(9.4%)werediagnosedasruptured.Noadversereactionswereobserved.Thesonographicappearanceofnon-rupturedBCswasasananechoicorhypoechoiclesion(Fig.1)withasharplydefinedoutersurfaceandvariablewall-lumeninterface.RupturedBCs(Fig.2)demonstratedextensionoffluidoutofthecystintothefacialplaneadjacenttothemuscle.

Themeansizeofnon-rupturedBCswas3.66cm×1.27cmandrupturedBCswere9.65cm×2.50cm.ThemeanlevelofCRPinnon-rupturedBCswas1.16mg/dL(range0.38-3.83mg/dL)andinrupturedBCswas7.79mg/dL(range0.33-27.2mg/dL).

Discussion

Inourstudy,inflammatoryarthritissuchasRAwithhigherCRPlevelhadhighincidenceofrupturedBCthatdifferentiatedthemfromthenon-rupturedBCgroup.

EarlydetectionofBCsaspossiblemayavoidseverecomplications[3,4].WefoundthefrequencyofrupturedBCsinrheumaticpatientswithBCwas9.4%andthesepatientsdidrequiremoreaggressivetreatment.OAwasthemostcommoncauseofBCandRAwastheleadingcauseofrupturedBC.SwellingmaynotbenoticeableduringphysicalexaminationsthatmayleadphysicianstomissBCinOAwhenkneepainisthepredominantfeature.Manystructuresaroundthekneehavebeenshowntocontainpainfibersincludingthejointcapsule,theperiosteumandotherbonesites,theinsertionsitesofligamentsandmuscles,andpossiblythesynovium.WiththehelpofMSU,BCcanbefoundtobethecauseofkneepaininOA.ThepresenceofBCseemstocausepainfulflare-upsinOAoftheknee[13].

Inourstudy,crystal-associatedarthritiswas thesecondleadingcauseofBC.Goutandpseudogoutwereallfoundinourstudy.BCincrystal-associatedarthritismayeasilybemisdiagnosedinclinicalpractice.Inouropinion,thepresenceofBCshouldbeconsideredasasignofchronicarthritisandanindicationthataggressivehypouricemictreatmentisnecessary.Moreover,MSUcanbeusedtodelineatepatientswithchondrocalcinosisandcrystalarthropathy[14].

BCmaybeseeninpatientswithRAwhereitconsistsofasynovium-linedsac that iscontinuouswith thejointspace.Inouropinion,RAistheleadingcauseofrupturedBCthatmayescapeclinicaldetection[15].Therefore,BCshouldbemorewidelyconsideredbycliniciansintheRApatientswithkneepain,whichmaysometimesbeaccompaniedbysignificantmorbiditysuchasdeepvenousthrombosis[16].Thus,MSUshouldbeusedinthefirstlineofinvestigationwhendiagnosingRApatientswithkneepain.

The clinical diagnosis of knee pain in therheumatologic department is often based on ourphysicalexaminationandthepatient'shistorythatmaynotaccuratelydiagnoseSpApatientswithkneepain.OzgocmenhadreportedacaseofReiter'ssyndromeinwhichasynovialcystofthepoplitealspace,mimickingsymptomsofdeepvenousthrombosis,complicatedthecourseofthearthritis[17].RupturedBCanddeepveinthrombosisneedaccuratelydifferentiateddiagnosisbecausemistakenlyanticoagulanttherapyinapatientwitharupturedcystmaycausehemorrhage.

TashjianandLoporealsoreportedapsoriaticarthritiswithBaker's cyst [18,19]. Inourobservation,BCwaspossiblecauseofkneepaininSpA,eventhoughitwasunusual.BCisalsoararecauseofkneepaininSLEandpolymyositis.Wefoundapatient in theinitialperiodofSLEwitharupturedBCwitharapidly

Figure 1. Longitudinal medial scan of popliteal fossa: anechoic,echogenicity of Baker's cysts in a 72-year-old female with knee osteoarthritis.

Figure 2. (A) Longitudinal medial scan of popliteal fossa and calf: 55 year-old female with rheumatoid arthritis with large, “S” form Baker's cysts. (B) Incontinuous wall contour indicates Baker’s cyst which rupture into the calf.

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Yeh et al

progressingandpotentiallydestructivekneeinfectionthatwascomplicatedbyseverenecrotizingfascitis.WealsofoundanotherpatientwitharupturedBCwithpolymyositiswhohadundergonelong-termtreatmentwithmediandosecorticosteroids.ThesynovialfluidculturesofbothpatientscontainedStaphylococcusaureus.After aggressive treatment, including theadministrationofantibioticsandemergencydebridementbothpatientsrecoveredwithoutkneecomplications.Pseudothrombophlebitis is awell-knownentity inwhicharupturedordissectingpoplitealcystclinicallymimicsthrombophlebitis[20]andtreatinganecrotizingfascitiswhichrestingandintra-articulrcortocosteroidpredisposes to severe sepsis. These two casesdemonstratetheimportanceofearlydiagnosisBC.Inaddition,theincidenceofarupturedBCbecomesgreaterwithincreasingsizeoftheBCandhigherlevelsofCRP,whichisconsistentwiththehypothesisthatincreasedintra-articularpressure forces joint fluid throughaweakenedposteromedialjointcapsuleintothepotentialspaceofthepoplitealbursa[3,4].

Thepresentstudydoeshavesomelimitations.ThefirstoneisrelatedtoMSUanalysisthatcanberegardedaspoorlystandardizedandhighlyoperatordependent.However,ourexaminationswereperformedbythesamephysician,havingmorethan10yearsofexperienceandallpatientswereevaluatedbythesameoperator.Thesecond,thisretrospectiveanalysisdidnotincludeothercausesofkneepainliketraumatickneeinjuryandsepticarthritis.Wealsodidnotanalyzethetherapeuticeffectinnon-rupturedandrupturedgroup.Futureprospectivestudiesarealsonecessarytoanalyzedifferenttherapeuticstrategies,otherradiographicexaminationsanddiseaseactivityscoresthatcomparewithMSUfindings.

Conclusion OurstudyshowsOAaretheleadingcauseofnon-

rupturedBCandRAwithactivearthritisarethemajorcausesofrupturedBCs.Forearlydetectionofnon-rupturedandrupturedBC,MSUshouldbemorewidelyemployedbyrheumatologistsandcliniciansindiagnosisofBC.

DisclosuresWeensurethatnoconflictsofinterestordisclosures

areincludedinthismanuscript.

References 1.AoyagiK,RossPD,HuangC,etal.Prevalenceofjointpain

ishigheramongwomeninruralJapanthanurbanJapanese-

AmericanwomeninHawaii.AnnRheumDis1999;58:315-9.2. CurlWW.Poplitealcysts:histaricalbackgroundandcurrent

knowledge.JAmAcaOrthpSurg1996:4:129-33.3. WolfeRD,ColloffB.Poplitealcysts:Anarthrographic

study and reviewof the literature. JBone JointSurg1972;54:1057-63.

4. RauschningW.Poplitealcystsand their relation to thegastrocnemio-semimembra-nousbursa: studieson thesurgical and functional anatomy.ActaOrthopScand1979;179(Suppl):9-13.

5. Mangia f i co RA, San tonoc i to M, Manda la ML.PseudothrombophlebitisduetoanexpansivepoplitealcystassociatedwithReiter'ssyndrome.1995;86:391-4.

6. OlcottC,MehiganJT.PoplitealarterystenosiscausedbyaBaker'scyst.JVascSurg1986;4:403-5.

7. ScottWN,JacobsB,LockshinMD.Posteriorcompartmentsyndromeresultingfromadissectingpoplitealcyst.ClinOrthop1977;122:189-92.

8. AltmanR,AschE,BlochD,etal.Developmentofcriteriafor the classification and reporting of osteoarthritis.Classificationofosteoarthritisoftheknee.DiagnosticandTherapeuticCriteriaCommitteeoftheAmericanRheumatismAssociation.ArthritisRheum1986;29:1039-49.

9. Arnett FC,EdworthySM,BlochDA.TheAmericanRheumatismAssociation1987 revised criteria for theclassificationof rheumatoidarthritis.ArthritisRheum1988;31:315-24.

10.HochbergMC. Updating theAmerican College ofRheumatology revisedcriteria for the classificationofsystemiclupuserythematosus.ArthritisRheum1997;40:1725.

11.DougadosM,vanderLindenS,JuhlinR,etal.TheEuropeanSpondylarthropathyStudyGrouppreliminarycriteriafortheclassificationofspondylarthropathy.ArthritisRheum1991;34:1218-27.

12.BohanA,PeterJB.Polymyositisanddermatomyositis.NEnglJMed1975;292:344-37.

13.deMiguelMendietaE,CoboIbáñezT,UsónJaegerJ,etal.Clinicalandultrasonographicfindingsrelatedtokneepaininosteoarthritis.OsteoarthritisCartilage2006;14:540-4.

14.FoldesK.Kneechondrocalcinosis:anultrasonographicstudyofthehyalincartilage.ClinImage2002;26:194-6.

15.AndonopoulosAP,YarmenitisS,SfountourisH, et al.Baker'scyst in rheumatoidarthritis:anultrasonographicstudywithahighresolutiontechnique.ClinExpRheumatol1995;13:633-6.

16.McQueenAS,ElliottST,KeirMJ.Ultrasonography forsuspecteddeepveinthrombosis:howusefulissingle-pointaugmentation?ClinRadiol2009;64:148-55.

17.OzgocmenS,Kaya,AKocakoc,E,etal.RupturedofBaker'scystproducingpseudothrombophlebitis inapatientwithReitersyndrome.KaohsiungJMedSci2004;20:600-3.

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18.TashjiRZ,Nickisch,DennisonD.Rupturedsepticpoplitealcyst associatedwith psoriatic arthritis.Orthopedics2004;27:231-3.

19.LeporeL,RabusinM,PennesiM.BilateralBaker'scystinapatientwithpsoriaticarthritisofpediatriconset.ClinExp

Rheumatol1996;14:109-10.20.MunkPL,LeeMJ,MsrchinkowLO.Musculoskeletalcase

11.RupturedBaker'scystproducingpeudothrombophlebitissyndrome.CanJSurg2000;43:310-1.

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貝克氏囊腫破裂於風濕性疾病患者：分析198位病人發現235個貝克氏囊腫

葉松峰� 張德明� 賴振宏� 陳政宏� 侯宗昀� 郭三元� 邱啟勝2 張棋楨2

�三軍總醫院 風濕免疫過敏科

2台北醫學大學附設醫院 風濕免疫過敏科

目的：我們回顧性分析non-ruptured與 rupturedBaker's cyst病人臨床特性，潛在的疾病與囊腫大

小。方法：從2006年6月至2009年6月以回顧性方式分析在本院風濕免疫過敏科接受肌肉骨超音波診

斷為Baker'scyst病患。結果：我們發現其中235個Baker'scyst，rupturedBaker'scyst有22人（右側

11位，左側11位）。non-rupturedBaker'scyst的相關疾病有：退化性關節炎125位，痛風關節炎41

位，類風濕性關節炎21位，假性痛風13位，血清陰性關節炎13位；RupturedBaker'scyst的相關疾

病有：類風濕性關節炎11位，退化性關節炎4位，痛風關節炎3位，血清陰性關節炎1位，全身性紅

斑性狼瘡4位，假性痛風1位，多發性肌炎1位。結論：我們發現潛在膝關節病變是Baker's cyst的主

要原因，且越嚴重的發炎性關節炎越有可能造成rupturedBaker'scyst；肌肉骨骼超音波對於早期發

現Baker'scyst是一個有用的工具，以避免Baker'scyst造成的併發症。

關鍵字：肌肉骨骼超音波、Baker'scyst（貝克氏囊腫）、關節炎

Original Article

78

Introduction The anti-Jo-1 antibodywas first describedbyNishikaiandReichlinin1980andwasnamedafterapatientwithpolymyositisandpulmonaryfibrosis.Theseresearchers found theanti-Jo-1antibodymainly inpatientspolymyositisanddermatomyositis,andnotinpatientswithotherrheumaticdiseases[1].Subsequentstudieshaveshownthattheanti-Jo-1antibodytargetshistidyl-tRNAsynthetaseinthecytoplasmofcells,andthisbindinginhibitstheincorporationofhistidineintothegrowingpolypeptidechaininproteinsynthesis[2-4].Dueto theheterogeneityof idiopathic inflammatory

Clinical and serological features of patients with anti-Jo-1 antibodies Ting-Hui Chang1, Song-Chou Hsieh2, Chia-Li Yu2,3

1Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan2Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan3Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Correspondingauthor:Chia-LiYu,M.D.,Ph.D.DivisionofAllergy,ImmunologyandRheumatology,DepartmentofInternalMedicine,NationalTaiwanUniversityHospital.No7,Chung-ShanSouthRoadTaipei100,Taiwan.Tel:+886-2-23123456ext65011,Fax:+886-2-23957801E-mail:Chialiyu@ntu.edu.twReceived: August 10, 2010Revised: October 11, 2010Received: October 17, 2010

Objective: Toelucidatetheclinicalandserologicalfeaturesofpatientswithanti-Jo-1antibodies.Methods:Between2007and2010,patientswithpositiveanti-Jo-1antibodieswereenrolledinastudyconductedatNationalTaiwanUniversityHospital.Theirclinicalandserologicalfeatureswereobtainedbyreviewingmedicalrecords,laboratorydatabases,andimagestudies.Results:Onthebasisoftheinformationreview,45patientswithpositiveanti-Jo-1antibodieswereidentified.Sevenpatientshadpolymyositis,2patientshaddermatomyositis,and2patientshadinterstitiallungdisease(ILD)withoutevidenceofmyositis.Themostfrequentsymptomswerejointmanifestationandsiccasyndrome:90.9%patientsinthemyositis/ILDgroupand32.3%patientsinthenon-myositis/ILDgroupshowedjointmanifestation,and45.5%patientsinthemyositis/ILDgroupand44.1%patientsinthenon-myositis/ILDgrouphadsiccasyndrome.Raynaud’sphenomenon,fever,andskinrashoccurredin27.2%,45.5%,and36.4%ofthepatientsinthemyositis/ILDgroup,andin20.5%,17.6%,and17.6%ofthepatientsinthenon-myositis/ILDgroup.Serologicalprofilesofthepatientsshowedpositiveantinuclearantibodyin22patientsandpositiverheumatoidfactorin10patients.Theinitialpresentationsof34patientswithoutmyositisorILDwererecorded;thepresentationswereveryheterogeneous.Conclusion:Anti-Jo-1antibodyisoneofthemostimportantautoantibodiesinidiopathicinflammatorymyopathies.Inourstudy,patientswithanti-Jo-1antibodieshadhighlyvariableclinicalpresentations.Ourfindingsalsorevealedthatnegativeorlowtitersinantinuclearantibodytestingcouldnotexcludethepresenceofanti-Jo-1antibody.

Key words: Anti-Jo-1antibody,anti-synthetasesyndrome,myositis,interstitiallungdisease,arthritis,siccasyndrome

Formosan Journal of Rheumatology 20�0;24:78-8�

79

Chang et al

myopathy(IIM),Loveetal.proposedaclassificationscheme based on the status ofmyositis-specificautoantibodies[anti-aminoacyl-tRNAsynthetase,anti-signalrecognitionparticle(SRP),anti-Mi-2,andanti-MAS].Patientswithanti-aminoacyl-tRNAsynthetaseautoantibodieswere found tohavemore frequentarthritis,fever,interstitiallungdisease(ILD),Raynaud'sphenomenon,andmechanic'shands[5].Thus, thesepresentationswerecollectivelynamedanti-synthetasesyndrome[6].Anti-Jo-1antibodyhasbeenreportedtobe themostcommonmyositis-specificautoantibody[7,8].Thesensitivityofanti-Jo-1antibodyforIIMwas19-33%andthespecificitywasupto99%[9].

Indailypractice, testingforanti-Jo-1antibodyisindicatedinpatientsaffectedwithidiopathicmyositisandinthosewithidiopathic interstitial lungdisease.However, agreat amountof clinicalvariability inpresentationhasbeenreported,andsomepatientswithanti-Jo-1antibodiesdonotpresentwithmyositis[10,11].Inthisstudy,wedescribedtheclinicalandserologicalfeaturesofpatientswithanti-Jo-1antibodies,includingthosewithtypicalanti-synthetasesyndromeandotherpresentations.

Patients and Methods

Between2007and2010,weidentifiedpatientswithpositivetitersofanti-Jo-1antibodiesfromthelaboratorydatabasesofNationalTaiwanUniversityHospital.Autoimmunetestswereperformedsincethepatientspresentedwithvariousrheumaticsignsandsymptoms.Wedidnotenrollpatientsinwhompositivetitersofotherantinuclearantibodiesweredetected inanti-extractablenuclearantigen(ENA)screening.Theanti-ENAscreeningincludeddetectionofanti-Sm,anti-RNP,anti-SSA,anti-SSB,anti-histone,anti-dsDNA,anti-Scl-70,anti-CENP,andanti-Jo-1antibodies.

Anti-Jo-1antibodiesweredetectedbyenzyme-linkedimmunosorbentassay(ELISA;AtheNAMulti-Lyte®TestSystem).Avalueabove120AU/mLwasinterpretedasapositiveresultandavaluebetween100and120AU/mLasindeterminate.

Clinicalandserologicalfeaturesweredeterminedbyaretrospectivereviewofthepatients'medicalrecords,laboratorydatabases,andimagingstudies.Symptomsofanti-synthetasesyndrome,includingfever,myositis,ILD,Raynaud's phenomenon, polyarthritis, andmechanic'shands,wereexamined.Otherpresentationsthatcouldbeattributedtoautoimmunemanifestationswerealso recorded.Thediagnosisofautoimmune

diseaseswasmadeinaccordancewiththecurrentlyusedclassificationcriteria.

Results

Forty-fivepatients(36womenand9men;age,18-88years)withanti-Jo-1autoantibodieswere identified.Among these45patients, 11patients had typicalmanifestationsofanti-synthetasesyndrome:7patientshadpolymyositis,2patientshaddermatomyositis,and2patientshadILDwithoutevidenceofmyositis.Theother34patientsdidnotpresentmyositisorILDduringfollow-up.Theclinicalandserologicalfeaturesofpatientsinmyositis/ILDgroupandinnon-myosiits/ILDgrouparelistedinTable1.Jointsymptomsandsiccasyndromewerethemostprevalentpresentationinbothgroups.Tenpatients(90.9%)inthemyositis/ILDgroupand11patients(32.3%)inthenon-myositis/ILDgrouphadjointsymptoms,includingarthralgia,arthritisanderosivearthropathies.Siccasyndromewasfoundin5patients(45.5%)in themyositis/ILDgroupandin15patients(44.1%)intheothergroup.Raynaud'sphenomenonwas reported in3patients (27.2%) inmyoitis/ILDgroupandin7patients(20.5%)innon-myosiits/ILDgrouprespectively.Fivepatients(45.5%)inthemyositis/ILDgroupand6patients(17.6%)inthenon-myositis/ILDgrouphadfeverwithoutidentifiableinfectionfocus.Fourpatients(36.4%)inthemyositis/ILDgroupandin6patients(17.6%)inthenon-myositis/ILDgroupdevelopedskin rashes; rashes includedGottron'spapules,malar rash,urticaria-like lesions,photosensitivityorvasculitislesions.Mechanic'shandsandmuscleweaknesswerefoundexclusively in the

Table 1. The incidence of clinical and serological features in patients with positive anti-Jo-� antibodies

Myositis/ILD(n = ��)

With no myositis or ILD (n = �4)

Arthralgia or arthritis 10 (90.9%) 11 (32.3%)Sicca syndrome 5 (45.5%) 15 (44.1%)Raynaud’s phenomenon 3 (27.2%) 7 (20.5%)Fever 5 (45.5%) 6 (17.6%)Skin rash 4 (36.4%) 6 (17.6%)Mechanic’s hands 2 (18.2%) 0 Muscle weakness 7 (63.6%) 0ILD 8 (72.7%) 0Relation of malignancy 1 (9%) 2 (5.8%)Positive ANA 7 (63.6%) 15 (44.1%)Positive RF 3 (27.2%) 7 (20.5%)Deceased 2 2

Abbreviation: ILD = intertitial lung disease

80

Features of patients with anti-Jo-� antibodies

myositisgroup.Theserologicalreviewshowedthatonly22outof

these45patientsshowedantinuclearantibodies(ANA)onHep-2cells.ThetitersofANArangedfrom1:40to1:2560,mostlybelow1:160(n=17).Thepatternswerequitevariable, includingspeckled,cytoplasmic,homogeneous, and nucleolar patterns.Themostcommonpatternwasthespeckledpattern;itwasfoundin15patients.Thenextmostcommonpatternwasthecytoplasmicpattern;itwasdetectedin7patients.Positiverheumatoidfactor (RF)wasdetected in10patients.

Theinitialpresentationsofthe34patientswithoutmyositisorILDarelistedinTable2.Elevenpatients

in thenon-myositis/ILDgrouphadananti-Jo-1titergreater than180AU/mL.Thesymptomswereveryheterogeneous: relapsingpolychondritis,vasculitis,idiopathic thrombocytopenicpurpura, thromboticthrombocytopenic purpura, chronic pancreatitis,psychosis,confusion,andculture-negativeendocarditiswerereported.

Therewere4deaths among these45patients.The causeswere hypoxemic respiratory failuredue toprogressing ILD, respiratory failuredue toILD superimposed on pulmonary tuberculosis,cytomegaloviruspneumonitiswithrespiratoryfailure,andsepticshockafterhearttransplantationinthecaseofculture-negativeendocarditis.

Table 2. Presentations of anti-Jo-� positive patients without myositis or interstitial lung disease

No. Gender Age at diagnosis Initial presentations Anti-Jo-�

level ANA

� F 45 Pulmonary hypertension, pulmonary embolism, sicca syndrome �4� Negative2 F 50 Polyarthritis with deforming arthropathy �78 Negative� F 47 Multiple oral ulcers Trace �:404 F 2� Polyarthralgia with alopecia Trace �:405 M �� Relapsing polychondritis �7� Negative6 F 46 Chronic abdominal pain, suspect chronic pancreatitis �24 Negative 7 F �2 Infertility, sicca syndrome �70 Negative8 F 6� Polyarthralgia, sicca syndrome �65 �:809 F 4� Myasthenia gravis, painful neuropathy ��6 �:40

�0 F �8 Sicca syndrome �65 �:40�� F 22 Cutaneous vasculitis on lower legs Trace Negative�2 F �8 Acute psychosis with low-grade fever �6� Negative�� F 66 Painful neuropathy, sicca syndrome �77 �:40�4 F 88 Nephrotic syndrome Trace �:80�5 F 58 Polyarthralgia, sicca syndrome, recurrent oral ulcer �54 �:�60�6 M 4� Recurrent oral ulcer Trace Negative�7 M �8 Fever of unknown origin Trace Negative�8 F �5 Dry mouth, polyarthritis, oral ulcer Trace Negative�9 F 6� Numbness on digits ��8 �:4020 F 78 Sicca syndrome, polyarthralgia �29 Negative2� F 44 Recurrent oral ulcer, polyarthralgia �24 Negative 22 F 68 Recurrent oral and genital ulcer, sicca syndrome ��4 Negative2� M �� Thrombotic thrombocytopenic purpura �54 �:�2024 M 5� Pontine hemorrhage with coma, fever of unknown origin �94 Negative25 M 58 Ischemic retinopathy, polyarthralgia 57� �:256026 F 2� Chronic pancreatitis with pancreatic atrophy ��2 �:�2027 F 56 Palindromic rheumatism ��9 �:8028 F 25 Polyarthritis �48 Negative29 F �7 Recurrent spontaneous abortion 20� �:40�0 F 20 Idiopathic thrombocytopenic purpura �98 �:�20�� F 57 Sicca syndrome, polyarthralgia, skin rash with itching 496 �:40�2 F 8� Confusion, multiple white matter lesions in the brain and spinal cord �46 Negative�� F 27 Spleen rupture, eosinophilic vasculitis involving spleen and liver ��6 Negative�4 F 47 Culture-negative endocarditis with valvular heart disease and heart failure,

sicca syndrome4�5 Negative

8�

Chang et al

Discussion

In these45patientswith anti-Jo-1 antibodies,the incidence of jointmanifestation,Raynaud'sphenomenon,andsiccasyndromewashigh(46.6%,22.2%,and44.4%, respectively).Thesesymptomswerealsoquitefrequentinthe231patientswithanti-Jo-1antibodiesinastudybySchmidtetal.[10].Tooursurprise,thespecificmanifestationsofanti-synthetasesyndrome,suchasmyositis,ILD,andmechanic'shands,occurredrelativelylessfrequentlyinourpatients(20%,17.7%,and4.4%,respectively).Thespecificityofanti-Jo-1antibodyformyositiswasreportedtobehighintheliterature[5,12].Inareview,anti-Jo-1antibodywasnotfoundin124healthydonors,andpositiveresultwasfoundinonly1patientoutofthe668patientswithotherconnectivetissuediseases[9].Thisdiscrepancybetweenourandothers'observationmaybeduetothefollowingreasons.

First,weusedanti-ENAtestsasoneofthescreeningtoolsinpatientswithrheumaticmanifestations,notonlyinthosewithsuspectedmyositisandILD.Secondly,myositisor lungmanifestationmaynotbetheinitialpresentationofIIM.InthereportbySchmidtetal.,61%ofthe66anti-Jo-1positivepatientspresentedmyositisand/oralveolitisas thefirstsymptoms,and32%ofpatientshadonlyarthritis initially[10].Casereportsofarthritisprecedinganti-synthetasesyndromewerenotrare[13,14].Inourstudy,wealsofoundsymptomswithsimilarcourseintwopatients.Oneisa33-year-oldman;hecametoourhospitalduetopolyarthritis,andacorticosteroidandsulfasalazinewithmethotrexatewereprescribedforthiscondition.Hedevelopedprogressingdyspneaafter6years; fever andproximalmuscleweaknesswithahighcreatinekinaselevelwerefound.Hewasdiagnosedwithdermatomyositis.Theotheroneisa49-year-oldwoman;shepresentedwithpolyarthritisatourrheumatologyclinic.Polymyositiswasfoundafter3years.Extendedfollow-upmaydiscoveranti-synthetasesyndromeinmoreofourpatients.Thirdly,thespecificityofanti-Jo-1antibodytoanti-synthetasesyndromemay be influenced by an inadequatecutoffpoint.Gomard-Mennessonetal.reportedhighprevalence(19%)ofotherautoimmunediseaseswithnomyositisorILDinacohortof45patientsdisplayinganti-Jo-1antibody[11].Theyfoundthattheanti-Jo-1titersinthisgroupweregenerallylowerthanthatintheanti-synthetasesyndromegroup.Similarly,wefoundthatall11patientswithmyositisand/orILDhadhightitersofanti-Jo-1antibody.

Another finding inour studywas thatonly22outof45patients(48.8%)showedpositiveresultsofantinuclearantibodyonHep-2cells.Thisisareminderthattestingforanti-Jo-1antibodyshouldbeconsideredifthereishighclinicalsuspicion,eveniftheANAtestisnegativeorinthecaseoflowtiter.

Insummary,anti-Jo-1antibodyisapromisingtestindiagnosinganti-synthetase syndrome.However,thecutoffvalueinclinicaldiagnosisandthepossibleroleinotherautoimmunemanifestationsremaintobeinvestigated.

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antibodies in polymyositis and dermatomyositis.CharacterizationoftheJo-1antibodysystem.ArthritisRheum1980;23:881-8.

2. MathewsMB.Myositis autoantibody inhibitshistidyl-tRNA synthetase:Amodel for autoimmunity.Nature1983;304:177-9.

3. DangCV,BellWR.Histidyl-tRNAsynthetase,themyositisJo-1antigen, iscytoplasmicandunassociatedwith thecytoskeletalframework.ExpCellRes1986;164:261-6.

4. RabenN,DohlmanJ,McPhieP,SridharV,HydeC,etal.Amotifinhumanhistidyl-tRNAsynthetasewhichissharedamongseveralaminoacyl-tRNAsynthetasesisacoiled-coilthatisessentialforenzymaticactivityandcontainsthemajorautoantigenicepitope.JBiolChem1994;269:24277-83.

5. LoveLA,etal.Anewapproach to theclassificationofidiopathic inflammatorymyopathy:myositis-specificautoantibodiesdefineusefulhomogeneouspatientgroups.Medicine(Baltimore)1991;70:360-74.

6. TargoffI.N.Immunemanifestationsofinflammatorymuscledisease.RheumDisClinNorthAm1994;20:857-80.

7. BrouwerR,etal.AutoantibodyprofilesintheseraofEuropeanpatientswithmyositis.AnnRheumDis2001;60:116-23.

8. GunawardenaH,BetteridgeZE,McHughNJ.Myositis-specific autoantibodies: their clinical andpathogenicsignificanceindiseaseexpression.Rheumatology(Oxford)2009;48:607-12.

9. ZampieriS, et al.Anti-Jo-1antibodies.Autoimmunity2005;38:73-8.

10.SchmidtWA,etal.Clinicalandserologicalaspectsofpatientswithanti-Jo-1antibodies--anevolvingspectrumofdiseasemanifestations.ClinRheumatol2000;19:371-7.

11.Gomard-MennessonE,etal.Clinicalsignificanceofanti-histidyl-tRNAsynthetase(Jo1)autoantibodies.AnnNYAcadSci2007;1109:414-20.

12.HirakataM,et al.Autoantibodies to smallnuclearandcytoplasmic ribonucleoproteins in Japanese patientswith inflammatorymuscle disease.ArthritisRheum

82

Features of patients with anti-Jo-� antibodies

1992;35:449-56.13.NagashimaT,MinotaS.Antisynthetasesyndromeassociated

withlong-standingrheumatoidarthritis.RheumatolInt2010.

14.ParkCK,etal.Developmentofantisynthetasesyndromeinapatientwithrheumatoidarthritis.RheumatolInt2009.

8�

Chang et al

Jo-1抗體陽性病人之臨床特徵及血清學表現

張婷惠� 謝松洲2 余家利2,�

�亞東醫院 過敏免疫風濕科

2台大醫院 過敏免疫風濕科

�國立台灣大學 醫學系 分子醫學研究所

目的：研究Jo-1抗體陽性病人之臨床徵及血清學表現。方法：本研究收錄在一醫學中心自2007年至

2010年間測得Jo-1抗體陽性之病人。回溯其病歷記載、檢驗資料及影像檢查結果分析臨床特徵及血

清學表現。結果：總共有45名病人收入此研究。其中7名診斷為多發性肌炎，2位為皮肌炎，2位為

無肌炎表現的間質性肺炎。臨床症狀表現上最多的是關節症狀和乾燥症候：在肌炎/間質性肺炎病

人群分佔了90.9%及45.5%，在非肌炎/間質性肺炎病人群分佔32.3%及44.1%。雷諾氏現象、發燒和

皮膚紅疹表現在肌炎/間質性肺炎病人群有27.2%、45.5%和36.4%；在非肌炎/間質性肺炎病人群則

有27.2%、17.6%和17.6%。此45名病人在血清學上總共有22名呈抗核抗體陽性，10名呈風濕因子陽

性。在34名非肌炎/間質性肺炎的病人中，臨床表現相當多樣化。結論：本研究發現Jo-1抗體除了典

型表現在特發性發炎性肌炎，亦可能有其他多樣性的臨床表現。此外，抗核抗體陰性無法排除Jo-1

抗體之存在。

關鍵詞：Jo-1抗體、synthetase抗體、肌炎、間質性肺炎、關節炎、乾燥症

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Case report

Case report

A47-year-oldTaiwanesewomansuffered frommultiplepainfullumps,1-3cminsize,withintermittentfeverupto38.5degreecentigradeforoneweek.Thelumpsweredistributedinbothbreasts,trunkandfourextremities.Onphysicalexamination,multiplecropsof1-3cm,painful,palpable,fixedmasseswerefoundinbothbreasts,abdominalwallandfourextremities.Laboratorydatadisclosedperipheralbloodwhitecellcount:2400/mm3;hemoglobin:12.8g/dL;platelet:203000/mm3; erythrocyte sedimentation rate: 37mm/hr;C-reactiveprotein:0.4mg/dL;and lactatedehydrogenase:515u/L(normal,<240u/L).However,alanineaminotransferase,aspartateaminotransferase,alkalinephosphatase, lipaseandantinuclearantibodywerewithinnormallimit.Sonographicassessmentof

bothbreastswasperformedwithaGeneralElectricLOGIQ500unit(GeneralElectricMedicalSystems,Milwaukee,WI,USA)usinga6-13MHzlineararraytransducer.TheB-modefrequencywassetat11MHz.Gray-scale ultrasonography (US)was performedover the breast lumps. Severalwell-demarcatedhyperechoicplaque-like lesions,measuredupto1-2cminsize,withmildlyirregularmarginwhichwereshown in thesubcutaneous tissuecorresponding tothepalpablenodules(Fig.1). Insomeof thelumps,increased thicknesswithhomogenously increased

Sonographic findings of Weber Christian disease involving the breasts: a case report Kuang-Yung Huang1, Yi-Ming Chen2,3,4, Der-Yuan Chen2,3,4, Hsin-Hua Chen2,3,4

1Department of Allergy, Immunology and Rheumatology, Buddhist Tzu Chi Dalin General Hospital, Taiwan2Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taiwan3National Yang-Ming University, Taiwan4National Chung-Hsing University, Taiwan

Correspondingauthor:Hsin-HuaChen,M.D.DivisionofAllergy,ImmunologyandRheumatology,DepartmentofInternalMedicine,TaichungVeteransGeneralHospital.No160,Sec3,Taichung-KangRoad,TaichungCity,40705,Taiwan.Tel:+886-4-23592525ext3336,Fax:+886-4-23503285E-mail:shc5555@hotmail.comReceived: June 30, 2009Revised: August 14, 2009Accepted: September 20, 2009

Weber-Christiandisease,whichisatypeofpanniculitis,isarareconditioncharacterizedbyidiopathicinflammationoffatty tissuealongwithfebrilestatus. Inmostcases,panniculitis is located in thesubcutaneouslayeroffourextremitiesandtrunk.Herein,wereportedacaseofWeber-Christiandiseaseinvolvingthesubcutaneouslayerofthebreastswiththesonographicfindingsbeforeandaftertreatment.

Key words:Weber-Christiandisease,ultrasonography,breast,panniculitis

Figure 1. Dual image of transverse sonogram of a breast lump. Left side: Note two well-demarcated hyperechoic plaque-like lesions with mildly irregular margin (arrows) located in the subcutaneous layer corresponding to the palpable nodules. Right side: Note few Doppler signals over the ovoid plaque-like lesion with power Doppler image.

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echogenecity in theskin layeroverlyingtheplaque-likelesionswasshown(Fig.2A).PowerDopplerUS(PDUS)examinationwasalsoperformedover thebreastlumps.FewDopplersignalswerefoundwithintheplaque-like lesionsonpowerDoppler images(Fig.1B).Excisionalbiopsyofanoduleinleftbreastshowed infiltrationof inflammatory cells,mainlymononuclearandfoamycells,withinsubcutaneousfatlobules,whichwerecompatiblewithchroniclobularpanniculitis(Fig.3).Methylprednisolonepulsetherapy(750mgfor3consecutivedays)wasadministeredduringhospitalizationandfeversubsidedgradually.Oralcolchicine0.5mgdaily,hydroxychloroquine200mg twicedailyandprednisolone20mgdailyweregiven.Sixweekslater, thelumpsinfourextremitiesandbothbreastsweresignificantlyreduced.Follow-upultrasonographicstudyover thebreast lumpwassubsequentlyperformed.Whencomparedwith thepreviousstudy(Fig.2A),completedisappearanceofsubcutaneousnoduleswasobserved(Fig.2B).

Discussion

Weber-Christ ian disease (WCD) was f irstdescribedbyPfeiferin1892asararediseasewiththepathognomonic featuresof relapsing inflammatorynecrosis in thesubcutaneousfat[1].In1925,Weberdelineated it as a newentitywith relapsingnon-suppurativenodularpanniculitis [2]whileChristiancharacterizedfeveraspartofthisdiseasein1928[3].Theusualclinicalmanifestationispainfulsubcutaneousnodules but constitutional symptoms includingfever,polyarthralgiaandmyalgiaarealsofrequentlyencounteredinWCD.Systemicinvolvementofliver,kidney,spleen,visceraladiposetissueandbonemarrowhasbeenmentionedinpreviousreportsofWCD[4].However,breastinvolvementinWCDhasseldombeendiscussed.

Thefemalebreastconsistsofskin,adiposeglandulartissue, looseanddenseconnectivetissue,andbreastmassesof different etiologies canoriginate fromdifferent layers.However,breast lumpsarethemostcommonpresentationofbreastcancerinwomenandmen.Fromclinicalhistoryandphysicalfindingsaloneitmaybedifficultforphysicianstodifferentiatebetweenbenignandmalignantdiseases.Inourcase,thecardinalsonographicfindingswerelimitedtothesubcutaneoustissuewith intact glandular tissue, suggestingpanniculitis.Acutepanniculitisinvolvingthebreastsisrareandlesscommonlyreportedintheliteraturewithmostcasesassociatedwithunderlyingautoimmunediseasessuchassystemiclupuserythematosus[5]ordermatomyositis[6].Additionally,somesubjectsmightdevelopbreastpanniculitisfollowingprior traumaticevents[7].Inourcase,therewereneitherskinrashesnorprevioushistoryoftrauma,andseveralpainfullumpsscatteredoverthefourextremitiesandtrunkandfeverwereclinicalcluesofWCD.Anotherclinicalfeatureofpanniculitis inourcasewasthegoodresponsetomedical treatment,whichhasnotbeenobserved inuntreatedmalignancy.Fromthereviewof literature,variouscasereportssuggestedfavorableresponsetoglucocorticoid,azathioprine[8]andantimalarials[9].Inthiscase,thepatientdemonstratedsatisfactoryresponsetoprednisolone,colchicineandhydroxychloroquine.

WCDisaninfiltrativeinflammationoftheadiposetissueandoftenaccompaniesconstitutionalsymptoms.Theexactetiologyisstillamysterybutassociationwithconnective tissuediseases, lymphoproliferativediseasesandpancreaticdisordersshouldalwaysbeconsidered[10].Onthebasisofmicroscopicfindings,

Figure 2. Transverse sonogram of another breast lump. (A) Note several hyperechoic plaque-like lesions located in the subcutaneous layer (arrows) with gray-scale image of another left breast lump before treatment. Increased thickness with homogenously increased echogenecity in the overlying skin layer is shown (open arrowhead). (B) After 6 weeks’ therapy, sonogram of the corresponding region showed complete disappearance of the lesions.

Figure 3. Biopsy specimen of a subcutaneous nodule showed (A) panniculit is involving the fat lobules (hematoxylin-eosin stain, ×20) and (B) inflammatory cell infiltration, mainly mononuclear and foamy cells (hematoxylin-eosin stain, ×200).

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Sonographic findings of Weber-Christian disease

theinvolvedareaofpanniculitiscouldbeinthesepta(predominant involvementof the interlobularsepta),lobules (inflammationoccurring toagreaterextentin thefat lobules)orboth,butnostrongcorrelationbetweenhistologicalfindingsandclinicaldiagnosishasbeenestablished[11].InWCDpatients,panniculitisarisesmainlyfromfatlobulesalthoughbothlobularandseptalinvolvementhadbeenreported.Inourpatient,thehistopathologicexamshowedpanniculitisinvolvingfatlobules,whichwasconsistentwithpreviousreports.Theplaque-likelesionsinthesubcutaneoustissueshowningray-scaleUS images reflect inflammatorycellsinfiltrationinfat lobules.However, theechotexturalfindingsingray-scaleUSimagesarenon-specific.WealsoobservedfewDopplersignalswithinthelesionswithpowerDopplerimage,depictingahypovascularpatternthathelpstodifferentiatefromotherdiseaseswithhypervascularity, such as cellulitis [12] andsubcutaneouspanniculitis-likeTcell lymphoma[13].Asamatteroffact,breastnodulesinpatientsofWCDcouldalsobemistaken formalignancyonclinicalpresentationand imagestudies [14].Hoetal. alsoreportedthesonographicappearanceinacaseofWCDthatwassimilarwithourfindings[15].However,theyfoundsomeof theplaque-likeechogenic lesionsofsonographyseemedbelocateddeeptothesubcutaneouslayer.AlthoughHoetal.didnotmentionthediseasedurationoftheirpatients,maybethedifferenceisrelatedtodifferencestageofdisease.

Inconclusion,thesonographicappearanceofWCDcanaidtoearlyconfirmationofthediagnosis,exceptdetailedclinicalhistory,radiographicstudy,laboratoryinvestigationandbiopsy.

References1. PfeiferV.Uber einenFall vonHerdweiserAtrophie

de subcutanen Fettgewebes. DtschArchKlinMed1892;50:438-49.

2. WeberEP.Acaseof relapsingnon-suppurativenodularpanniculitis.BrJDermatol1925;37:301.

3. ChristianHA.Relapsingfebrilenodularnonsuppurativepanniculitis.ArchInternMed1928;41:338.

4. McNuttNS,MorenoA,ContrerasF.Inflammatorydiseaseofthesubcutaneousfat.In:DEEldev,etal(Eds.),Lever’sHistopathologyoftheskin,8thed.Philadelphia:Lippincott-Raven,1997;429-55.

5. HollandNW,McKnightK,ChallaVR, et al. Lupuspanniculitis(profundus)involvingthebreast:reportof2casesandreviewoftheliterature.JRheumatol1995;22:344-6.

6. PrendergastM,HopkinsonN.Breastcalcinosis,panniculitis

and fat hypertrophy in a 35-year-oldwomanwithdermatomyositis.Rheumatology(Oxford)2007;46:1378-9.

7. GosselinP,DelaporteE,CatteauB, et al. Sclerosinglipogranuloma in amale.AnnDermatolVenereol1995;122:682-5.

8. HottaT,WakamatsuY,MatsumuraN,etal.Azathioprine-inducedremissioninWeber-Christiandisease.SouthMedJ1981;74:234-7.

9. SorensenRU,AbramowskyC,SternRC.Corticosteroid-sparingeffectofhydroxychloroquineinapatientwithearly-onsetWeber-Christiansyndrome. JAmAcadDermatol1990;23:1172-4.

10.TerPoortenMC,ThiersBH.Panniculitis.DermatolClin2002;20:421-33.

11. PanushRS,YonkerRA,DleskA,etal.Weber-Christiandisease.Analysisof15casesandreviewoftheliterature.Medicine(Baltimore)1985;64:181-91.

12.RobbenSG.Ultrasonographyofmusculoskeletalinfectionsinchildren.EurRadiol2004;14Suppl4:L65-77.

13.KangBS,ChoiSH,ChanHJ,etal.Subcutaneouspanniculitis-likeTcelllymphoma:USandCTfindingsinthreepatients.SkeletalRadiol2007;36Suppl1:S67-71.

14.LeiboviciV,GileadL,GimmonZ, et al.Mammarycalcifications inWeber-Christiandisease.Eur JRadiol1994;18:70-1.

15.HoWT,LamPW. Sonographic appearance of acutepanniculitis involving the breasts. JUltrasoundMed2002;21:581-3.

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韋伯-克里斯欽疾病侵犯乳房之超音波發現：病例報告

黃光永� 陳一銘2,� 陳得源2,�,4 陳信華2,�,4

�大林慈濟醫院 過敏免疫風濕科

2台中榮民總醫院 過敏免疫風濕科

�國立陽明大學醫學院

4國立中興大學 生物科技研究所

韋伯-克里斯欽疾病屬於脂層炎的一種類型，為一罕見不明原因造成脂肪組織發炎合併發燒的疾

病。大部分的病人其脂層炎發生於四肢及軀幹的皮下脂肪組織層炎。在此我們報告一例韋伯-克里

斯欽疾病侵犯乳房之皮下脂肪組織及其治療前後之超音波影像。

關鍵詞：韋伯-克里斯欽疾病、超音波、乳房、脂層炎

88

Case report

Introduction

Systemiclupuserythematosus(SLE)isachronicautoimmuneinflammatorydiseasethatcanaffecttheskin, joints,kidneys, lungs,nervoussystem,serousmembranes, andotherorgans.Chylothorax is theaccumulationofchyle(lymphandfats)inthepleuralcavity.RarecaseshadbeenreportedofSLErelatedchylothorax[1,2].Here,wedescribeanSLEpatientwhodevelopedbilateralpleuraleffusionintheformofchylothorax.

Case report

A21year-oldwomanwithasix-yearhistoryofSLEinitiallytestedpositiveforantinuclearantibodies(ANA), extractablenuclear antigens (ENA), anti-dsDNAantibody, leukopenia,hypocomplementemia,livedoreticularis,Raynaud'sphenomenon,malarrash,andpolyarthritis.Forthepastfouryears,herdiseaseactivitywascontrolledbyazathioprine(75mgqod),hydroxychloroquine(100mgqd),andprednisolone(5mgqd).

Wedetectedbilateralpleuraleffusioninaroutinemedicalcheckup(Fig.1).Thepatientdeniedshortnessofbreath,fever,cough,poorappetite,orweightloss.Onphysicalexamination,wenoteddiminishedbreathingsoundsoverthebilaterallungfieldsandamalarrash.Chestradiographyrevealedbilateralmassivepleuraleffusion.Weperformedthoracocentesisandaspiratedoneliterofmilkyfluidfromeachside.Thesefluidscontainedpredominantlymaturelymphocytes(93%for

Refractory chylothorax in a patient with systemic lupus erythematosus: case report Bao-Bao Hsu1, Chien-Hsueh Tung1, Ming-Chi Lu1, Kuang-Yung Huang1, Ning-Sheng Lai1,2

1Department of Allergy, Immunology, and Rheumatology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan2Buddhist Tzu Chi University, Hualien, Taiwan

Correspondingauthor:Ning-ShengLai,M.D.,Ph.D.BuddhistDalinTzuChiGeneralHospital.No2,Ming-ShengRoad,DalinTown,Chia-YiCounty,Taiwan.Tel:+886-5-2648000ext501,Fax:+886-5-2648555E-mail:nslai@airpa.org.twReceived: March 20, 2010Revised: October 15, 2010Accepted: October 22, 2010

WedescribeararecaseofSLE-relatedchylothorax.A21year-oldwomanwithasix-yearhistoryofSLEsufferedasilentbilateralpleuraleffusion.Onphysicalexamination,diminishedbreathingsoundsoverthebilaterallungfieldsandamalarrashwerenoted.Chestradiographyrevealedbilateralmassivepleuraleffusion.Thoracocentesiswasperformedandanodorlessmilkyfluidfromeachsidewasaspirated.Thesefluidscontainedpredominantlymaturelymphocytes(93%fortheleftpleuralcavity,81%fortherightpleuralcavity)andnoevidenceofmalignancy.Themajorcompositionsoftheleftandrightpleuralfluid(respectively)werecholesterol,triglycerides,andtotalprotein.PleuralfluidtestedpositiveforANAs.Therewasnoevidenceofmicroorganismsormycobacteria.Apleuralbiopsywasnegativeformalignancyortuberculosis.Bipedallymphangiographyshowednoevidenceoflymphaticleakinthethoracicorperitonealcavities.Thispresentationismostcompatiblewithadiagnosisoflupus-relatedchylouspleuraleffusion.Ourcasewasresistanttohydrocortisoneandcyclophosphamidetreatment.Thechylothoraxdidnotresolve12monthslaterafterinitialpresentation.

Key words:chylothorax,systemiclupuserythematosus

Formosan Journal of Rheumatology 20�0;24:88-9�

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theleftpleuralcavity,81%fortherightpleuralcavity)andnoevidenceofmalignancy.Thecompositionsoftheleftandrightpleuralfluid(respectively)were51,82mg/dLofcholesterol;333,1592mg/dLoftriglycerides;and3.1, 3.3 g/dLof total protein.Wediagnosedchylothorax.Pleural fluid testedpositiveforANAs.Therewasnoevidenceofconventionalmicroorganismsormycobacteria.Apleuralbiopsywasnegative formalignancyortuberculosis.Bipedallymphangiographyshowednoevidenceoflymphaticleakinthethoracicorperitonealcavities.Acomputedtomographic(CT)scanofchest indicatedalargeamountofbilateralpleuraleffusion,butnoevidenceofpulmonaryparenchymallesionormediastinallymphadenopathy.Therewasnohistoryofantecedentchesttraumaorthoracicsurgery.Laboratorytestsfromhemograms,biochemistrytests,erythrocytesedimentationrate,C-reactiveprotein,andurinalysiswerenormal.Immunologicalstudiesoftheserumshowedasfollow:ANA1:80withdiffusepattern;negativeanti-cardiolipinantibody;complementC3:65mg/dL(normalrange:90-180mg/dL);complementC4:12mg/dL(normalrange:10-40mg/dL);CIC:69µg/mL(normalrange:0-45µg/mL);andanti-dsDNAantibody:37.4IU/mL(normalrange:0-15IU/mL).

Thispresentationismostcompatiblewithadiagnosisoflupus-inducedchylouspleuraleffusion.Thepatientwastreatedwithhydrocortisone(200mgq6h)foronemonth followedbyabolusof intravenousmonthlycyclophosphamide(400mg/m2)for2months.Despite

severalsessionsofpleuraldrainageandalowfatdiet,thepatientre-accumulatedpleuralfluidsafterremovalofthechesttube.Onemonthafterinitiationoftreatment,thedrainagereducedtoabout200-300ccperday,butthoracicfluidscontinuedtoaccumulateuntildischarge.

Discussion

Chylothoraxis theaccumulationofchyle(lymphandlipids) inthepleuralcavityfollowingdisruptionorocclusionofthethoracicductoritstributaries.Thediagnosisismadebypresenceoffatwithinthepleuralfluid.Triglyceridelevelsgreater than110mg/dLarehighlysuggestiveofchylouseffusion[3].Inourpatient,thehightriglyceridecontentinbilateralpleuralfluids(333mg/dLintheleft,1592mg/dLintheright)supportsthediagnosisofchylothorax.

Chylothoraxcanhaveanontraumaticortraumaticetiology.Surgicalproceduresandchesttraumaaccountformosttraumaticcasesofchylothorax.Ifthereisnohistoryof traumaorsurgery,malignancyis themostfrequentcause[4,5].Besidesmalignancy,nontraumaticchylouseffusionmybecausedbyvenousthrombosis,thoracic irradiation, superiorvenacavasyndrome,livercirrhosis,heartfailure,Kaposisarcoma,lymphangioleiomyomatosis,regionalileitis,tuberculosis,andfilariasis.Someconnectivetissuediseaseshavealsobeenassociatedwithchylothorax, includingBehcet'sdisease [6], sarcoidosis [7],andSLE[1,2,8].TherehaveonlybeenfourreportedcasesofchylothoraxinSLEpatients.CasereportsfromStrausseretal.andLinetal.[1,8]describedchylothoraxascomplicationofestablishedSLE.Leeetal.[2]reportedtwocaseswithpreviouslyundiagnosedSLEwhopresentedwithbilateralchylothorax,chylousascites,andprotein-losingenteropathy.

Inourcase,weconductedavigoroussearchforunderlyingmalignancies and infection.Repeatedcytologicexamination,Gramstaining,stainingforacidfastnessofpleuralfluids,biopsyofpleura,andCTscanofthechestwereallunremarkable.Becausesuchcasesarerare, themechanismofSLE-inducedchylothoraxisnotwellunderstood. Inflammation, increaseoflymphaticvesselpermeabilityandpleuramembranefibrosiswereallpossiblecausesbutnotheoriesaboutitspathogenesiswasconfirmed.Previouscasereportsindicatedthatpatientswereresponsivetocorticosteroidwithorwithoutcyclophosphamide.Ourcasedidnotsignificantly improvewith those treatmentsandwefoundpersistentbilateralpleuraleffusionsinfollow-up

Figure 1. Bilateral pleural effusion in the absence of cardiopulmonary distress signs.

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Chylothorax in SLE

chestradiography.Thepatientremainedasymptomaticwhenseenather followup12monthsafter initialdiagnosisofchylothorax.

Conclusion Pulmonary involvement inSLE iscommon,but

chylothorax is a raremanifestationofSLE.Afterexclusionofcommonunderlyingdiseases,chylothoraxcanbeacomplicationofSLE.

References1. LinYJ,ChenDY,LanJL,HsiehTY.Chylothoraxasthe

initialpresentationofsystemiclupuserythematosus.ClinRheumatol2007:26:1373-4.

2. LeeCK,HanJM,LeeKNetal.Concurrentoccurrenceof chylothorax, chylous ascites, and protein-losingenteropathyinsystemiclupuserythematosus.JRheumatol2002;29:1330-3.

3. StaatsBA,EllefsonRD,BudahnLL,DinesDE,PrakashUBS,OffordK.The lipoproteinprofileofchylousandnonchylouspleuraleffusion.MayoClinProc1980;55:700-4.

4. ValentineVG,RaffinTA.Themanagementofchylothorax.Chest1992;102:586-91.

5. PressOW, PressNO,Kaufman SD.Evaluation andmanagement of chylous ascites. Ann InternMed1982;96:358-64.

6. KonishiT,TakeuchiH,IwataJ,NakanoT.Behcet'sdiseasewithchylothorax-casereport.Angiology1988;39:68-71.

7. JarmanPR,WhyteMK,SabroeI,HughesJM.Sarcoidosispresentingwithchylothorax.Thorax1995;50:1324-5.

8. Strausser JL,FlyeMW.Managementofnontraumaticchylothorax.AnnThoracSurg1981;31:520-6.

9�

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紅斑性狼瘡併發頑固性乳糜胸－一病例報告

許寶寶� 童建學� 呂明錡� 黃光永� 賴寧生�,2

�佛教大林慈濟綜合醫院 內科部 過敏免疫風濕科

2花蓮慈濟大學醫學院

我們報告一位系統性紅斑狼瘡引起兩側乳糜胸少見案例。病人21歲女性罹患狼瘡已有六年一直控

制良好，此次在體檢中發現無症狀之兩側胸肋腔積水。物理檢查僅發現兩側呼吸音減少及輕微兩頰

紅斑。胸部X光呈現兩側肺肋積水，肋穿刺抽出牛乳狀液體。分析成分細胞主要為淋巴細胞（左邊

93%，右邊81%）、膽固醇、三酸甘油脂以及蛋白質。抽出液檢測ANA陽性，細菌暨抗酸菌陰性。

肋膜切片無癌細胞及結核菌。淋巴攝影檢查在胸腔及腹腔無淋巴漏液。最後診斷為系統性紅斑狼瘡

相關之乳糜胸。本案例以高劑量類固醇及賽得星治療皆無明顯效果，治療12月之後仍有明顯雙側乳

糜胸但無任何臨床症狀。

關鍵詞：乳靡胸、全身性紅斑狼瘡

92

Case report

Introduction

Multicentric reticulohistiocytosis (MRH) isone of destructive arthropathy and a rare non-Langerhanshistiocytosischaracterizedbyanextensivepapulonodularcutaneouseruptionaswellassevere,sometimesdestructive,arthropathy.Arthritisandjointdamageareusuallyprogressive[1].Itmaybeassociatedwithinternalmalignancyorconnectivetissuedisease.CaroandSenearfirstdescribedthisdisorderin1952asreticulohistiocyticgranuloma[2].GoltzandLaymonoriginally coined the termMRH in1954becauseof themulti-focaloriginandsystemicnatureof theprocess[3].Less than500caseshavebeenreportedin theworld literature todate.ThepathogenesisofMRHisunknown;however,aberrantproliferationof

thehistiocyticpopulationispostulatedinresponsetomonokines,cytokinesandothersecretoryproductsthatpromotemacrophageproliferationandphagocytosis[1].ThediagnosisofMRHisbasedonthecharacteristichistopathologicalfindings,presentingmultinucleatedgiantcellsofaforeign-bodytype,withirregularsizeandshapereaching50-100µmindiameter.Uptonownoconsistentlyeffectivetreatmenthasbeenidentified.

Case Report

A35-year-oldwomanwithapasthistoryofasthmapresentedwithtwo-monthhistoryofanseverepruriticeruptionconsistingofmultipleshinypink1-2mmpapulesarrangedingroupsontheforehead,upperback,scalp,auricleofearsalsograduallyspreadingtothedorsalhand,fingers,nailfoldmarginandanteriorknee(Fig.1).Shealsohadjointpaininvolvingherknees,metacarpophalangealandproximal interphalangealjointsandwristssinceonemonth.Therewasneitherhistoryofmorningstiffnessof jointsnordeformityof joints.Onexamination,patientwasafebrileandswellingofmetacarpophalangeal,proximalanddistalinterphalangeal joint,knees,andwristswerenoted.

Multicentric reticulohistiocytosis mimicking rheumatoid arthritis in a 35-year-old woman – case report Chyou-Shen Lee1,2,3, Mei-Eng Tu4, Tien-Ling Chen1

1Division of Rheumatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan2Mackay Medicine, Nursing and Management College, Taipei, Taiwan3Taipei Medical University, Taipei, Taiwan4Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan

Correspondingauthor:Chyou-ShenLee,M.D.TaipeiMedicalUniversity,MackayMedicine,NursingandManagementCollege.5F,No1,Alley8,Lane554,Bei-AnRoad,Taipei,Taiwan.Tel:+886-932011865,Fax:+886-2-85097765E-mail:amy@ms2.mmh.org.twReceived: December 1, 2010Accepted: December 1, 2010

A35-year-oldladyinitiallypresentedwithtwo-monthhistoryofseverepruriticshiningskinlesionscouplewithone-monthhistoryofpolyarthritisinvolvingthejointssimilartothepatternsofrheumatoidarthritis.However,thelaboratoryautoantibodies,complements,andtumormarkersinvestigationdisclosednon-significance.Thejointfluidstudyshowedmildincreasedcellcountswithlymphocytepredominant.Theskinbiopsyconfirmedtobeacaseofmulticentricreticulohistiocytosis.Non-steroidanti-inflammatorydrugs,hydroxychloroquine,sulfasalazineandmethotrexatewereadministeredfortwomonths,butwereineffective.Wereportthiscaseforitsrarity.

Key words:Multicentricreticulohistiocytosis,polyarthritis,skinlesions

Formosan Journal of Rheumatology 20�0;24:92-96

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Lee et al

Dermatological examination revealeddiscretebutgrouped, firm,pink,non-scaly,non-tenderpapulesrangingfrom1to2mmovertheheadanddigits.Restofthesystemicexaminationwaswithinnormallimits.Routinehaematological investigations,erythrocytesedimentationrate,C-reactiveprotein, lipidprofile,thyroidprofile,antinuclearfactor,rheumatoidfactor,anti-Sm,anti-RNP,anti-SSA,anti-SSB,anti-neutrophilcytoplasmicantibodiesandHLA-B27werenegative.Thelevelofanti-CCPwas0.74EliAU/mL(<7EliAU/mL).TumormarkerssuchasCA-153,CA-199,CA-125werewithinnormal limits.Electrocardiogram,chestX-ray,ultrasoundabdomen/pelviswasunremarkable.X-rayhandsshowedmildosteopeniawithouterosion.Arthrocentesisstudyofkneejointrevealedleukocytecount720/cm3withlymphocytepredominant.

Histopathologicalexaminationofoneof theskinlesionsshowedadiffuse,dense, superficialdermalinfiltratecomprisinglargemultinucleatedmacrophageswithabundanteosinophilicgroundglasscytoplasm(Fig.2A).HistoimmunostainsofthelesionrevealedthatcellswerepositiveforCD68(Fig.2B),andnegativeforS100

protein(Fig.2C).Thesefindings,alongwiththeclinicalpresentation,confirmedthediagnosisofMRH.

The patientwas started on non-steroid anti-inflammatory drugs, hydroxychloroquine andsulfasalazine.Simultaneouslymethotrexatewasstartedat adoseof15mg/week for twomonth,but jointswellingandlimitedjointmotionwereexaggerated.Anti-tumornecrosisfactoragentwassuggested.Butshewaslostoffollowup.

Discussion

From the clinical features of dermatologicallesions,we should consider the case to be non-infectious,non-inflammatory,noepidermalchange,mainlydermisinvolved,dermaldepositionanddermalcellularinfiltrateddiseases.Astothedermalcellularinfiltrateddiseases,thedifferentialdiagnosisincludesdisseminatedLangerhanscellhistiocytosis, tuberousxanthomas,xanthogranuloma,reticulohistiocytosis,andgranulomasannulare[4].Alsoourpatientexperiencedthepolyarthritissimilar to thepatternofrheumatoid

Figure 1. Skin signs: (A) pink papules on the forehead, (B) firm shining erythematous papules on the ears, (C) firm shining erythematous papules on the finger nail fold margin,with telangiectasia on the finger nail fold.

Figure 2. Histopathological findings: (A) Hematoxylin and eosin stains at high power of a biopsy from the left hand shows a diffuse dermal infiltrate of macrophages containing eosinophilic ground glass cytoplasm. (B) Immunohistochemical stains show lesional macrophages are CD68 positive. (C) Immunohistochemical stains show lesional macrophages are S�00 negative.

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arthritis,weshoulddifferentiatebetweenrheumatoidnodules,Gottron'spapules,gouty tophi,sarcoidosis,andpsoriaticarthritis.Diagnosisisbasedonacarefulhistoryandphysicalexamination,confirmedbyclassichistopathologicfindingsoftheproliferatinghistiocytes.Dermalinfiltrationofmultinucleatedgiantcellswitheosinophilicgroundglasscytoplasmischaracteristicfeature. Immunohistologically theyarepositive forCD68(histiocyticcells)[5],lysozyme,periodicacid-SchiffandSudanblack, indicating thepresenceofglycolipidsand/orglycoproteinsandneutralfat,whereasnegativeforS100protein,CD1a,factorXIIIa(non-Langerhanscell),monocyte-macrophageorigin [6].Histologicalfindingofourpatientwasconsistentwithreportedliteratures.

MRHalsoknownas lipoiddermatoarthritishasaworldwidedistribution. Itmostcommonlyaffectsmiddle-aged,whitewomen(60-75%),with isolatedpolyarthritis(50%),cutaneouslesions(25%)orbothconcurrently(25%)[3].Ourpatientpresentedwithbothskin lesionand joint involvement .Thepolyarthritisisusuallysymmetric,progressive,anddestructive,potentially progress to arthritismutilans,with apredilectionfordistal interphalangeal joints[7].Butthedisablingarthriticprocessprogressesrapidlyintheearlystageandthendecreasesinintensitytobecomelessactiveovertheensuing8-10years[1].Themainradiologicfeatureismildtomoderateosteopeniaanddisproportionatebonydestructioncomparedtoarticularcartilageloss.Resorptionofsubchondralbonecanleadtoformationoferosionsspreadingfrommargintojointsurface[5].

Characteristicandveryimportantcutaneouslesionsaresmalltumefactionsaroundnailfoldstermed‘coralbeads' sign, tobe reallypathognomonicofMRH,andhavebeennotedinapproximately40%ofcases.Vermicular lesionsbordering thenostrils areverysuggestiveofMRH.Eyelidlesionsinthosecasessimilartoxanthelasmasfromtheclinicalfeatures,seemtobe,in fact,MRHlesions.Theface(noseandparanasalareas)andhands(dorsumandlateralaspectsoffingersandnailfolds)aremostcommonlyaffected.Theears,forearms,elbows,scalp,andmucosalsurfacescanbeaffectedaswell.MRHclassicallypresentswith1to2mmtoseveralcentimetersindiameterpinknodulesandpapulesdistributedacrally.Theskinlesionstendtowaxandwaneindependentofarthritis[3].

Althoughjointsandskinarecommonlyinvolved,an estimated 50% of patients withMRH alsodeveloppapulesandnodulesoftheoropharyngealornasopharyngealmucosa;thatmayoccasionallyprogress

tohistiocytomas.Rarely,patientsdevelopvisceralinvolvementresultinginserositis,gastriculceration,andprogressiveheartfailure[8].

LaboratoryresultsrevealelevatedESRandanemiain50%ofpatients,andhypercholesterolemiain30%.Thepresenceofcryoglobulinemiaandcoldagglutinins,butnotrheumatoidfactor,isoccasionallyseen.

Inupto25%ofcases,MRHhasbeenfoundtooccurinassociationwithawiderangeofunderlyinginternalmalignancies,suggestingthatthediseasemayrepresentaparaneoplasticconditioncausedbyreactiveproliferativehistiocytes[9].WhileMRdoesnotfulfillthecriteriaforaparaneoplasticdisease,patientspresentingwithMRHshouldbeinvestigatedforanoccultneoplasticdisease.TreatmentoftheunderlyingmalignancyoftenparallelsregressionofMRH,butJanssenetalreportedthatMRdoesnotrunacourseparalleltoneoplasm[10].

TheetiologyofMRHisunknown.Thecharacteristicextensivepapulonodularcutaneouseruptionandseveredestructivepolyarthritisresultfromtissueinfiltrationofactivatedproliferativehistiocytesandmultinucleargiantcells,releasinginterleukin(IL)-12,IL-1,IL-6,andTNF[11],proteaseandurokinasethatmayplayamajorpartintheextracellularmatrixdegradation.Recentreportdemonstrated that thedevastatingosteolyticprocessbyMRHmayberelatedtotheunfavorablebiologicalexpressionofCD10inground-glass-likegiantcells[12].

To date, no treatment has been shown to beuniversallysuccessful; the tendency tousemultiplediseasemodifyinganti-rheumaticdrugsaswellasthenaturalrelapsingandremittingnatureoftheconditionmakesinterpretationoftherapeuticresponsedifficult.Studieshavedemonstratedincreasedlevelsof tumornecrosisfactor(TNF)-αinthesynoviumandsynovialfluid inMRH.Severalreportswithanti-TNFagentshaveshowninconsistentlysymptomaticimprovement[13].ResponsesofMRHtointravenousbisphosphonatetreatmenthaveshownimprovementof jointand, insomecases,skinmanifestations[14].Bisphosphonatesarepotentinhibitorsofosteoclastactivity.Theyhavebeenshownnotonlytodecreasemonocyte/macrophage-osteoclastdifferentiationbutalsotopromoteosteoclasticapoptosis,aswellasinhibitingosteoclasticresorptiveactivity,allofwhichcouldinhibitboneresorptionanderosivedisease[15].

References1.TajirianAL,MalikMK,Robinson-BostomL,Lally

EV.Multicentric reticulohistiocytosis.ClinDermatol2006;24:486-92.

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2.CaroMR,SenearFE.Reticulohistiocytomaoftheskin.AMAArchDermSyphilol1952;65:701-13.

3.RezaieyazdiZ,SandooghiM,TorghabeHM,DerhamiA.Multicentricreticulohistiocytosis:Acasereport.ActaMedIran2005;43:372-6.

4.CareyRN,BlotzerJW,WolfeID,GlusmanSM,AmettFC.MulticentricreticulohistiocytosisandSjögren'ssyndrome.JRheumatol1985;12:1193-5.

5.GotoH, InabaM,KobayashiK, ImanishiY,KumedaY, InuiK, et al. Successful treatment ofmulticentricreticulohistiocytosiswithalendronate:Evidenceforadirecteffectofbisphosphonateonhistiocytes.ArthritisRheum2003;48:3538-41.

6.RapiniRP.Multicentricreticulohistiocytosis.ClinDermatol1993;11:107-11.

7.LiangGC,GranstonAS.Completeremissionofmulticentricreticulohistiocytosiswithcombinationtherapyofsteroid,cyclophosphamide,andlow-dosepulsemethotrexate:Casereport,reviewoftheliterature,andproposalfortreatment.ArthritisRheum1996;39:171-4.

8.GelmettiC,CaputoR.Non-Langerhanscellhistiocytosis.In:FreedburgIM,EisenAZ,WolffK,etal,eds.Fitzpatrick'sDermatology inGeneralMedicine.5thed.NewYork:McGraw-Hill,1999;1892-900.

9.LuzFB,GasparTAP,Kalil-GasparN,Ramos-e-SilvaM.Multicentric reticulohistiocytosis. JEurAcadDermatolVenereol2001;15:524-31.

10. JanssenBA,Kencian J,BrooksPM.Close temporaland anatomic re la t ionship between mul t icentr icreticulohistiocytosisandcarcinomaofthebreast.JRheumatol1992;19:322-4.

11.Trotta F, CastellinoG, LoMonacoA.Multicentricreticulohistiocytosis.Best PractResClinRheumatol2004;18:759-72.

12.TashiroA,TakeuchiS,NakaharaT,ObaJ,TsujitaJ,FukushiJ,etal.AberrantexpressionofCD10inground-glass-likemultinucleatedgiantcellsofmulticentricreticulohistiocytosis.JDermatol2010;37:995-7.

13.KovachBT,CalamiaKT,WalshJS,GinsburgWW.Treatmentofmulticentricreticulohistiocytosiswithetanercept.ArchDermatol2004;140:919-21.

14.CodrianskyKA,RungerTM,BhawanJ,KantarciA,KissinEY.Multicentricreticulohistiocytosis:asystemicosteoclasticdisease?ArthritisRheum2008;59:444-8.

15.AdamopoulosIE,WordsworthPB,EdwardsJR,FergusonDJ,AthanasouNA.Osteoclastdifferentiationandboneresorptioninmulticentricreticulohistiocytosis.HumPathol2006;37:1176-85.

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類似類風濕性關節炎之多中心性網狀組織細胞增多症-病例報告

李修身� 涂玫音2 陳天令�

台北馬偕紀念醫院 �過敏免疫風濕科

2皮膚科

一位35歲女性主訴兩個月嚴重搔癢之閃亮皮疹合併一個月類似類風濕性關節炎多之發性關節炎。但

是所有實驗室自體免疫抗體，補體檢查以及腫瘤標記篩選都是正常。關節液抽取檢查顯示白血球略

為增加，其中多數為淋巴球。而皮膚切片病理報告證實為多中心性網狀組織細胞增多症。該病患接

受兩個月之非類固醇消炎藥，奎寧，salfasalazine，methotrexate治療，對皮膚病變以及關節症狀效

果不佳。本篇論文報告此例少見病例。

關鍵詞：多中心性網狀組織細胞增多症、多發性關節炎、皮膚病變

97

Formosan Journal of Rheumatology 20�0;24:97

Clinical Image

“Hide-bound” bowel sign in a patient with progressive systemic sclerosis and chronic intestinal pseudo-obstruction Pei-Chen HsuDepartment of Internal Medicine, Da-Chien General Hospital, Miao-Li, TaiwanDepartment of Life Sciences, National Chung-Hsing University, Taichung, Taiwan

A69-year-oldwomanpresentedwithsevereabdominalpainanddistensionfor2days.Sheisapatientwithlimitedtypeprogressivesystemicsclerosis.Shehadexperiencedthesameepisodesinthepastfewmonths.PhysicalexaminationdemonstratedRaynaud’sphenomenon,sclerodactyly,skintightnessonface,handsandforearms,polygonaltelangiectasisonfaceandhands,softanddistendedabdomenwithdiffusetenderness,decreasedbowelsoundsandtympanytopercussion.Therewerenosignsofmechanicalintestinalobstructionorperitonitis.Theplainfilmoftheabdomendemonstratedseveredilatedloopsofsmallbowel,termedthe“hide-bound”bowelsign.Thissigndelineatesnarrowseparationandnormalthicknessofvalvulaeconniventes,relativetodilatationofthebowellumen.Itwasthoughttobecausedbymoreseveresmoothmuscleatrophyandfibrosisoftheinnercircularlayerofthetunicamuscularis,thantheouterlongitudinallayer[1].Shewasdiagnosedwithchronicintestinalpseudo-obstructionbasedonclinicalcourse,physicalexaminationandradiographicfindings,andtreatedconservativelywithparenteralnutrition,cisaprideandantibiotics.

Reference:1. PickhardtPJ.The“hide-bound”bowelsign.Radiology1999;213:837–8.

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