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1 대한내과학회지 : 제 71 권제 6 호 2006 종 설 류마티스관절염에서항 CCP 항체의임상적의의 고려대학교의과대학내과학교실 노영희 송관규 The clinical significance of anti-ccp antibodies in rheumatoid arthritis Young Hee Rho, M.D., Ph.D. and Gwan Gyu Song, M.D., Ph.D. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea 서론류마티스관절염 (RA) 은원인불명의만성적인자가면역질환으로관절통, 골미란및관절파괴를일으켜생활에지장을초래한다 1). 골미란및관절파괴를최소화하기위해진단초기에항류마티스약물 (DMARD) 의사용이중요하며이질병초기를흔히 window of opportunity라고부른다 2). 이 window of opportunity의시기가수개월에서 1년정도로짧다는것이알려지면서 3) 류마티스관절염의조기진단이요구되어왔으나아직까지조기류마티스관절염의진단법은확실한것이없다 4). 류마티스관절염의진단은흔히 1987년에미국류마티스학회 (ACR) 에서제안된류마티스관절염의분류기준 5) 에의해내려지게되나이기준은조기류마티스관절염의발견에는유용하지않아 6) 질병초기에골미란및관절파괴를예방하는데제한점이있었다. 이분류기준에검사실소견으로혈청류마티스인자 (RF) 의측정이있으며실제로약 70% 의류마티스관절염환자에서류마티스인자가발견되며류마티스인자양성인류마티스관절염환자는음성인환자에비해골미란이나관절파괴등임상적인양상이심하여진단및예후예측에서가치를보인다 1). 그러나민감도가 60%, 특이도가 80% 로높지않으며 7) 특히정상인에서도발견이가능하며다른만성적인질환에서도발견이되는등류마티스관절염의진단에비특이적이여서어려움이많았다. 그러나최근에류마티스관절염에비교적민감하게검 출이되면서매우높은특이도를지니며질병초기에도발견되는항 CCP (Cyclic Citrullinated Peptide) 항체검사법이개발되면서류마티스관절염의진단및조기류마티스관절염의발견에많은도움을줄것으로기대되고있다. 이에류마티스관절염에서항 CCP 항체가차지하는임상적인의의를진단, 예후, 치료적인측면에서살펴보고항 CCP 항체가류마티스관절염의병태생리에도직접적인기여를하는지고찰하고자한다. APF 및 AKA : 항시트룰린항체군의시초전술한바와같이류마티스인자는그비특이성으로인해검사의해석에문제가발생하면서보다류마티스관절염에특이한혈청검사를개발하고자하는노력이오래전부터활발했다. 1964년도에 Neinhuis 및 Mandema가류마티스관절염환자의혈청에서매우특이한항핵주변인자 (anti perinuclear factor, APF) 을발견하였으며 8) 1979년도에 Young 등이역시높은특이도를보이는항케라틴항체 (anti keratin antibody, AKA) 를발견하여 9) 류마티스관절염의진단에도움이될것으로믿었다. 그러나 APF은검사에인간의구강상피세포가필요하며 AKA는동결된쥐의식도조직이필요하여준비가까다롭고두검사모두간접면역형광법 (IIF) 을이용하여진단하였기때문에정확한진단을위해숙련된인력이필요하여널리사용되지못했다. 이두자가항체가같은항원인 filaggrin에대한항원임을밝혀지고 10) 특히 filaggrin내에시트룰린이존재할때만항원을인식

2 -The Korean Journal of Medicine : Vol. 71, No. 6, Figure 1. Citrullinization of arginine under the presence of calcium ions and PAD. 함이알려지면서현재에이르러서는 APF와 AKA는통틀어항시트룰린항체 (ACPA) 로불리우게되었다 11). 시트룰린은일종의아미노산으로아르기닌이 PAD (Peptidylarginine deiminase) 이라는효소에의해탈이민화 (deimination) 되면서만들어지며 12) ( 그림 1) 그생리적인역할은확실히알려진바는없으나 protein unfolding이나세포사멸 (apoptosis) 과연관이있을것으로추정되고있다 13, 14). Filaggrin은 PAD에의해아르기닌기가시트룰린화되며이후에야 APF나 AKA 등에의해항원으로인식되는것으로알려져있다 15, 16). PAD는현재까지다섯가지아형이밝혀졌으며이중 PAD2와 PAD4가주로호중구나단핵구, 탐식세포등면역세포에존재하여항시트룰린항체의생성과연관이있을것으로생각되고있다 12). 항 CCP 항체검사의개발 항시트룰린항체들이비록특이도는높으나검사법이까다로와보다더용이한검사법을개발하려는노력이계속되었는데 van Venrooij 등에의해항 CCP 항체가개발되면서 17) 새로운전기를맞게되었다. 이들은여러가지 filaggrin 제재에류마티스관절염환자의혈청의반응이다르며시트룰린이포함된분자입체구조 (conformation) 의차이에의해반응률의차이가나는것 이라고생각했다 15, 18). 결국인공적으로만든환형의분자구조를지닌시트룰린기가있는펩타이드 ( 그림 2) 에만족할만한수준의민감도및기존의항시트룰린항체들이보인높은특이도를유지하는항 CCP 항체검사법을개발하게되었으며이후여러종류의 peptide library 를조사하여민감도를더높인항 CCP2 항체검사법을개발하게되어 19) 현재널리쓰이고있다. 항 CCP 항체검사법은인체내에존재하는항원을검출하는것이아니라기존의 APF이나 AKA 보다잘반응하는인공적인펩타이드를만들어검출률을높인검사라고볼수있다. 인공적인펩타이드는생성이용이하며천연항원보다불순물이들어갈소지가적게되며 ELISA 법으로검출이가능하여보다더정확한검사가가능하다는이점이있다. 류마티스관절염에서항 CCP 항체의진단적가치 Schellekens 등이최초로류마티스환자대조군실험을통하여항 CCP 항체의진단적가치를조사하였으며 17) 이연구에서 288명의류마티스관절염환자와 480명의대조군에서항 CCP 항체가류마티스관절염환자의진단에 68% 의민감도, 98% 의특이도를보였다. 이후여러연구를통하여항 CCP 항체의민감도는 47~88%, 특이도 89~98% 로보고되었다 20). 최근에항 CCP 항체의진단적인가치에대해 Avouac 등이메타분석한연구에의하면 7) 항 CCP1 항체에서는류마티스관절염의진단민감도는 53%, 특이도는 95% 으로분석되었다. 개량된항 CCP2 항체에서는민감도가 68%, 특이도는 95% 로민감도가개선되었으며기존의류마티스인자의민감도 60%, 특이도 79% 에비해상당한수준으로특이도가높은검사라는결과를보여주었다. 평균적으로항 CCP 항체는류마티스관절염환자의약 60~70% 에서발견된다고한다 11). 이러한결과를볼때항 CCP 항체는류마티스관절염에상당히특이한항체임을알수가있다. Figure 2. The (cyclic) citrullinated peptides used for the detection of anti-ccp antibodies 17). The cysteine residues bind to make a cyclic structure (X=citrulline). Peptide cfc1 cfc1-cyc Amino Acid Sequence SHQESTXGRSRGRSGRSGS HQCHQESTXGRSRGRCGRSGS

3 -Young Hee Rho, et al : The clinical significance of anti-ccp antibodies in rheumatoid arthritis - 조기류마티스관절염의진단에서항 CCP 항체의가치항 CCP 항체가류마티스관절염에특이한항체임이알려지면서조기류마티스관절염의예측인자로서가치가있을것인가에대한연구도이루어졌다. 위에서언급한 Schellekens 등의연구에서조기관절염클리닉에방문한환자를대상으로조사한결과류마티스관절염으로판명된 149명의환자에서항 CCP 항체가 48% 의민감도및 96% 의특이도를보였다 17). 이는같이측정한류마티스인자의민감도 54% 및특이도 91% 에비해좀더특이한검사임을밝혔다. 또, 관절염이없는정상인구를대상으로한 Rantapaa-Dahlqvist 등의코호트연구에의하면 21) 결국류마티스관절염으로이행한 83명의혈액공여자의과거혈액에서민감도가증상발생 1.5년이전에채취한혈액의경우 25% 인데비해 1.5년이내의혈액의경우는 52% 로증가하였으며특이도는똑같이 98% 이라는주목할만한연구결과를발표하기도하였다. 이는항 CCP 항체가류마티스관절염이발생하기전에이미존재한다는사실을입증한연구로서의미가있다. Avouac 의메타분석에의하면조기미분화성관절염이류마티스관절염으로이행하는데있어항 CCP1 항체의존재는 20의오즈비 (OR) 를항 CCP2 항체는 25의오즈비를나타내 7) 항 CCP 항체가조기류마티스관절염의진단및예측에있어서유용한검사임을밝혔다. 예후예측인자로서항 CCP 항체의가치류마티스인자의존재가류마티스관절염의나쁜예후인자로알려져있는만큼항 CCP 항체도그렇지않을까라는예상을할수가있다. Kroot 등의연구에서는 22) 273명의류마티스관절염을대상으로 6년간추적한결과항 CCP 항체가존재하는환자가존재하지않는환자에비해방사선학적인골손상이더심함을입증한연구결과를발표하여항 CCP 항체가류마티스관절염의불량한예후인자로작용할수있음을주장했다. 이외에 van der Helm-van Mil 등에의하면 23) 항 CCP 항체를가진류마티스관절염환자는그렇지않은환자에비해임상양상은비슷하나시간이지나면서항 CCP 항체를지닌환자가그렇지않은환자에비해골미란이나관절종창이심하다는결과를발표하기도하였다. 특히, van Gaalen 등 24) 과 Kaltenhauser 등 25) 은류마티스관절염과 깊은연관이있는 shared epitope 이라고말하는 HLA- DRB1 계열의유전형을지닌류마티스환자가항 CCP 항체가발생할확률이더크며이런경우더심한질환경과를보인다고발표하여항 CCP 항체가류마티스관절염의발생에있어유전적인연관과함께예후를예측할수있는지표로서의미를지님을주장하였다. 이러한연구결과를종합하면항 CCP 항체는류마티스인자와함께불량한예후의예측인자가될수있으며유전적인배경도있음을알수가있다. 치료반응의척도로서항 CCP 항체의가치류마티스관절염의치료에있어서유용하게쓰일수있는혈액검사소견이그리많지않다. 적혈구침강속도 (ESR) 나 C-반응단백 (CRP) 은류마티스관절염에특이적이지않으며류마티스인자는류마티스관절염의활성에좋은평가기준이되지못하였다. 항 CCP 항체의혈청수준이류마티스관절염의활성및치료반응의평가척도로쓰일수있을까에대한여러연구가있었으며주로생물학적제재 (Biologic agent) 의사용과연결지어발표가되었다. Alessandri 등 26) 은 43명의난치성류마티스관절염환자를항종양괴사인자억제제 (anti- TNF-α) 인 infliximab으로치료하면서항 CCP 항체의혈청농도를측정하였는데치료 6개월후에치료반응이있는환자에서만유의한수준으로농도가감소한다는결과를발표하였다. 이외에도다른항종양괴사억제제인 adalimumab이나 27) etanercept에서도 28) 비슷한결과를보인연구가있다. 그러나반면에 Mikuls 등 29) 은과거류마티스임상시험에서치료전후의혈액이보관되어있는 66명의류마티스관절염환자를대상으로류마티스인자와항 CCP 항체의농도를측정한결과치료반응은류마티스인자와는연관이있었으나항 CCP 항체와는연관이없었다는결과를발표하였다. 류마티스관절염의치료반응과비례하여항 CCP 항체의농도가반드시감소하지않는다는연구는이외에도있어 18) 아직까지는항 CCP 항체가류마티스관절염의치료에있어활성지표로확립되기까지는더많은연구가필요할것으로생각된다. 한국의항 CCP 항체에대한연구한국인을대상으로한항 CCP 항체의연구가몇가지가있으며주로진단적유용성과관련된것이많다

4 - 대한내과학회지 : 제 71 권제 6 호통권제 556 호 강등 30) 은 134명의류마티스관절염환자와 86명의대조군을대상으로항 CCP 항체와류마티스인자의민감도와특이도를측정한결과항 CCP 항체와류마티스인자각각민감도는 76.1% vs. 67.2%, 특이도는 94.2% vs. 74.4% 였으며특히류마티스인자가음성인류마티스환자의 47.4% 에서항 CCP 항체가양성이라는결과를보고하였다. 또한김등 31) 은 114명의류마티스관절염환자와 202명의대조군을대상으로조사하여항 CCP 항체와류마티스인자각각의민감도가 68.4% vs. 66.7%, 특이도가 96% vs. 84.6% 이라는결과를발표하였으며최등 32) 은 324명의류마티스관절염환자와 251명의대조군을대상으로연구한결과항 CCP 항체가민감도 72.8%, 특이도 92.0% 로서항필라그린항체 (AFA) 의민감도 70.3%, 특이도 70.5% 및류마티스인자의민감도 80.6%, 특이도 78.5% 에비해우수한특이도를보여주는등한국의연구도외국의예와비슷한결과를보여주었다. 이외에기능적인상태와의연관성을연구한김등 33) 은항 CCP 항체의존재가류마티스관절염의기능적인상태에나쁜영향을미친다는결과를발표하기도하여, 한국인에서항 CCP 항체는류마티스관절염에서나쁜경과를예측하는인자임을주장하였다. 그러나아직기존의외국연구와비교할때한국인을대상으로정상인에서항 CCP 항체가미래의류마티스관절염의발생을예측할수있는지와치료반응의지표로서사용될수있는지에대한연구가없어좀더많은연구가필요한실정이다. 류마티스관절염의병태생리에서항 CCP 항체의역할항 CCP 항체가위에서언급한것처럼진단과예후의중요한예측인자로대두가되면서, 특히항 CCP 항체가류마티스관절염에매우높은특이도를보이면서자연스럽게항 CCP 항체가류마티스관절염의발병기전에어떤역할을하지않을까라는생각을할수가있다. 단백질의시트룰린화는단백질합성후에일어나는변화 (post-translational modification) 로서위에서언급한것처럼그기능은세포사멸과정중에세포내단백질의분해를위한절차로생각되고있다. 시트룰린화과정에관여하는 PAD 효소는칼슘의존재하에서활성을보이는데세포내에서는칼슘의농도가역치보다낮아반응 이일어나지않는다 34). 그러나세포가죽으면서세포내에저장된칼슘이방출이되면 PAD 가활성을보일수있는농도가될수있는것으로생각되고있다 11). 관절내에여러종류의염증반응이일어나면 PAD를가진염증세포가조직내에침윤하게되며조직내에세포사멸과세포괴사 (necrosis) 가혼재된상태가일어나면세포외로유리된각종세포내단백질이 PAD의표적이되어단백질의시트룰린화가일어나며이시트룰린화된단백질들이분해의대상이되어면역반응이일어나게되며이과정에서항 CCP 항체가발생하게된다는것이시트룰린면역이류마티스관절염의발생에기여한다는가설의주요내용이다. 이과정에서시트룰린화가될가능성이큰단백질로는 fibrin, vimentin, histone 등이있다고생각되고있다 34). 염증반응에대해불완전한세포사멸이발생되는것이나, 염증반응을유발시키는기저상태, 그리고 PAD가단백질을시트룰린화시키는정도는환경적, 유전적인요소가작용한다고여겨지고있다. 이에대한유전적인증거로류마티스관절염의발생에 PAD4의유전적인다형성이연관이있다는보고가있으며 35) 특히앞에서도언급한것처럼류마티스관절염과깊은연관성을지닌, shared epitope 이라고불리는 HLA- DRB1 계열의유전형이항 CCP 항체의발생과강한연관이있다는연구들이주목을받고있다. 이 shared epitope과항 CCP 항체의연관성에환경적인요인도작용하는것으로밝혀졌는데, 흡연을하는류마티스관절염환자에서항 CCP 항체가발생하는경우는 shared epitope 를지닌경우에만국한되다는주목할만한보고 36) 는그동안류마티스관절염의위험인자로서흡연의병태생리적인역할에대한설명을할수있게되었다. 또한 shared epitope 그자체가류마티스관절염의독립적인위험인자가아니고항 CCP 항체의발생을통하여류마티스관절염을발생시킨다는보고 37) 는항 CCP 항체의역할을강조하는하나의연구로볼수가있다. 위의연구결과에서볼수있듯이 shared epitope 과항 CCP 항체는연관이크며이두가지가모두존재하는경우증상이심하고예후가불량하여항 CCP 항체가있는류마티스환자와없는환자를별도의질환으로생각할수있는것이아니냐는의견도있으나 38) 확립되지못한상태이다. 다만이들결과에서류마티스관절염은매우 heterogenous 한질환임은알수있다

5 - 노영희외 1 인 : 류마티스관절염에서항 CCP 항체의임상적의의 - 미해결 영역 REFERENCES 항 CCP 항체검사의여러가지유용성에도불구하고아직류마티스관절염의진단에있어서여러가지한계점을지닌것도사실이다. 항 CCP 항체의높은특이도에도불구하고다른질병 ( 루푸스나강직성척추염등 ) 에서도항 CCP 항체가발견되고있다 7). 또한항 CCP 항체는기존의류마티스인자에비해민감도가매우우수한편은아니어서류마티스관절염의선별검사로서는아직부족한점이많다. 항 CCP 항체와류마티스관절염의병태생리와의관계를시사하는연구들에도불구하고연구를위한동물모델은확립되어있지못하다. 기존의콜라겐유발관절염 (CIA) 쥐모델에서항 CCP 항체가발견되었다는명확한증거가없으며 39, 40) 동물에항 CCP 항체를주입하는경우에도관절염이유발되는지는확인되지않고있다. 다만, 최근의연구에의하면시트룰린에면역관용 (tolerance) 을일으킨쥐에서콜라겐유발관절염이유의하게감소한다는연구 41) 는주목할만하다. CCP 자체가인공적인단백질이며따라서아직시트룰린면역자체가관절내의어떤항원을겨냥하고있는지에대해서도모르고있는실정이다. 이러한사실들은항 CCP 항체가류마티스관절염의발병에기여하는정도를평가하는데어려움을주고있다. 결론항 CCP 항체는기존의류마티스인자가류마티스관절염의진단에있어서가진제한점을개선시킨, 보다특이도가높은진단검사이다. 뿐만아니라류마티스관절염의조기진단및예후평가에있어서도유용한검사이며치료반응의평가척도가될수있는가능성도지니고있다. 향후항 CCP 항체가과연얼마나류마티스관절염의발생에기여하는지에대한연구가시행되어야할것으로생각된다. Key Words : Anti-CCP antibody, Rheumatoid arthritis, Diagnosis, Prognosis 중심단어 : 항 CCP 항체, 류마티스관절염, 진단, 예후 1) Lipsky PE. Rheumatoid Arthritis. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds. Harrison's Principles of Internal Medicine. 16th ed. p , New York, McGraw- Hill, ) Huizinga TW, Landewe RB. Early aggressive therapy in rheumatoid arthritis: a 'window of opportunity'? Nat Clin Pract Rheumatol 1:2-3, ) Quinn MA, Cox S. The evidence for early intervention. Rheum Dis Clin North Am 31: , ) Smolen JS, Aletaha D, Machold KP. Therapeutic strategies in early rheumatoid arthritis. Best Pract Res Clin Rheumatol 19: , ) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31: , ) Harrison BJ, Symmons DP, Barrett EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. American Rheumatism Association. J Rheumatol 25: , ) Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 65: , ) Nienhuis RL, Mandema E. A New Serum Factor in Patients with Rheumatoid Arthritis; the Antiperinuclear Factor. Ann Rheum Dis 23: , ) Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ. Anti-keratin antibodies in rheumatoid arthritis. Br Med J 2:97-99, ) Sebbag M, Simon M, Vincent C, Masson-Bessiere C, Girbal E, Durieux JJ, Serre G. The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J Clin Invest 95: , ) van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol 175: , ) Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays

6 -The Korean Journal of Medicine : Vol. 71, No. 6, : , ) Tarcsa E, Marekov LN, Mei G, Melino G, Lee SC, Steinert PM. Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 271: , ) Asaga H, Yamada M, Senshu T. Selective deimination of vimentin in calcium ionophoreinduced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243: , ) Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101: , ) Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, Simon M, Senshu T, Masson-Bessiere C, Jolivet-Reynaud C, Jolivet M, Serre G. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 162: , ) Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, van Venrooij WJ. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43: , ) Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-ccp autoantibodies in rheumatoid arthritis. Rheumatology (Oxford) 45:20-25, ) van Venrooij WJ, Vossenaar ER, Zendman AJ. Anti-CCP antibodies: the new rheumatoid factor in the serology of rheumatoid arthritis. Autoimmun Rev 3 Suppl 1:S17-19, ) Herold M, Boeser V, Russe E, Klotz W. Anti-CCP: history and its usefulness. Clin Dev Immunol 12: , ) Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, van Venrooij WJ. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48: , ) Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't Hof M, van de Putte LB, van Rijswijk MH, van Venrooij WJ, van Riel PL. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 43: , ) van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Toes RE, Huizinga TW. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther 7:R , ) van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM, Breedveld FC, Zanelli E, van Venrooij WJ, Verweij CL, Toes RE, de Vries RR. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum 50: , ) Kaltenhauser S, Pierer M, Arnold S, Kamprad M, Baerwald C, Hantzschel H, Wagner U. Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology (Oxford), ) Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, Valesini G. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-tnf alpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 63: , ) Atzeni F, Sarzi-Puttini P, Dell' Acqua D, de Portu S, Cecchini G, Cruini C, Carrabba M, Meroni PL. Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study. Arthritis Res Ther 8:R3, ) Chen HA, Lin KC, Chen CH, Liao HT, Wang HP, Chang HN, Tsai CY, Chou CT. The effect of etanercept on anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann Rheum Dis 65:35-39, ) Mikuls TR, O'Dell JR, Stoner JA, Parrish LA, Arend WP, Norris JM, Holers VM. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody. Arthritis Rheum 50: , ) 강희정, 서영일, 이영경, 조현찬. 류마티스관절염에서항 Cyclic Citrullinated Peptide 항체의진단적유용성. 대한류마티스학회지 10: , ) 김경희. Anti-Cyclic Citrullinated Peptide Antibody 검사의임상적유용성. 대한진단검사의학회지 23: , ) Choi SW, Lim MK, Shin DH, Park JJ, Shim SC. Diagnostic performances of anti-cyclic citrullinated peptides antibody and antifilaggrin antibody in Korean patients with rheumatoid arthritis. J Korean

7 -Young Hee Rho, et al : The clinical significance of anti-ccp antibodies in rheumatoid arthritis - Med Sci 20: , ) 김경희, 이성원, 정원태. 류마티스관절염에서항 -CCP 항체와기능적상태와의상관성. 대한류마티스학회지 13:46-51, ) Vossenaar ER, van Venrooij WJ. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 6: , ) Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34: , ) Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA, Kloppenburg M, de Vries RR, le Cessie S, Breedveld FC, Toes RE, Huizinga TW. Smoking is a risk factor for anti-ccp antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis 65: , ) van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 54: , ) de Vries RR, Huizinga TW, Toes RE. Redefining the HLA and RA association: to be or not to be anti- CCP positive. J Autoimmun 25 Suppl:21-25, ) Vossenaar ER, Nijenhuis S, Helsen MM, van der Heijden A, Senshu T, van den Berg WB, van Venrooij WJ, Joosten LA. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48: , ) Vossenaar ER, van Boekel MA, van Venrooij WJ, Lopez-Hoyoz M, Merino J, Merino R, Joosten LA. Absence of citrulline-specific autoantibodies in animal models of autoimmunity. Arthritis Rheum 50: , ) Kuhn KA, Kulik L, Tomooka B, Braschler KJ, Arend WP, Robinson WH, Holers VM. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116: ,

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<31332EB1E8C1F6BFB52E687770> 대한내과학회지 : 제 76 권제 2 호 2009 재발성류마티즘의예후인자로서의항 CCP 항체의유용성 대구가톨릭대학교의과대학 1 내과학교실, 2 진단검사의학교실, 3 의학통계학교실 김지영 1 박성훈 1 김성규 1 김상경 2 신임희 3 최정윤 1 Anti-CCP antibodies predict progression of palindromic rheumatism