대한류마티스학회지 Vol. 14, No. 3, September, 2007 원저 한국인조기류마티스관절염에서항 CCP 항체의진단적의의 대구가톨릭대학교의과대학내과학교실, 진단검사의학교실 *, 의학통계학교실 ** 박성훈ㆍ김지영ㆍ김성규ㆍ최정윤ㆍ김상경 * ㆍ신임희 ** =Abstract= Diagnostic Significance of Anti-CCP Antibody in Korean Early Rheumatoid Arthritis Sung-Hoon Park, Ji-Young Kim, Seong-Kyu Kim, Jung-Yoon Choe, Sang Kyung Kim*, Im-Hee Shin** Departments of Internal Medicine, Laboratory Diagnostics*, and Medical Statistics**, School of Medicine, The Catholic University of Daegu, Daegu, Korea Objective: To identify the sensitivity and specificity of the anti-cyclic citrullinated peptide antibody (anti-ccp) and rheumatoid factor (RF) in a diagnosis of Korean early rheumatoid arthritis (RA). Methods: Two hundred and sixty two patients diagnosed with RA were examined retrospectively and classified by three groups. A group 1 had a disease duration<24 months, and group 2 had a duration>24 months, and the third was a group of total patients. The sensitivity and specificity of the RF and anti-ccp in each group of RA were identified. Patients of the connective tissue disease other than rheumatoid arthritis were tested with RF and anti-ccp. Results: The sensitivity/specificity of RF and the anti-ccp in early RA were 90.4%/68.0% and 87.5%/89.3%, 91.3%/68.0%, 81.7%/89.3% in each, and 90.4%/68.0% and 84.7%/89.3% in the total RA patients. The accurate diagnosis rate, which is defined as (number of true positives plus true negatives)/ the total number of patients), of the RF and anti-ccp was 79.2%/88.4% in the early RA group, and 79.4% and 89.0% in the total patients group. Conclusion: Anti-CCP is more specific than RF in diagnosing RA. Although it is not statistically significant, diagnositc sensitivity of anti-ccp in early RA group is higher than that of established RA group. Key Words: Rheumatoid arthritis, Rheumatoid factor, Anti-cyclic citrullinated peptide antibody <접수일 :2007년 5월 22일, 심사통과일 :2007년 6월 25일> 통신저자 : 최정윤대구광역시남구대명 4동 3056-6 대구가톨릭대학교의과대학내과학교실 Tel:053) 650-4577, Fax:053) 629-8248, E-mail:jychoe@cu.ac.kr 227
대한류마티스학회지제 14 권제 3 호 2007 서 론 대상및방법 류마티스관절염은관절의만성적염증을유발하는자가면역질환으로전인구의약 0.5 1% 정도를이환하며 (1), 활막의만성적염증으로연골의파괴와골미란을초래하여영구적인장애를유발할수있다. 따라서류마티스관절염의치료목표는가능한한발병초기에진단을확립하고치료적개입을시작하여관절의파괴와변형을막고기능을보존하는데있다. 류마티스관절염의진단은 1987년미국류마티스학회 (American College of Rheumatology, ACR) 에서개정된분류기준을따르고있다 (2). 이기준은기본적으로임상적인증상들을위주로구성되어있으며이런증상들은흔히질환이이환된지상당기간이경과한후에야명확히드러나진단이확립될시기에는이미관절파괴가진행되기시작한경우가많다. 따라서이런분류기준은관절염의조기진단에는적합하지않을수있다 (3). 분류기준에포함된유일한혈청학적검사인류마티스인자는면역글로불린 G 분자의 Fc 부분에대한자가항체이며, 낮은민감도 (50 80%) 와중등도의특이도 (70 80%) 를가진다. 또한류마티스인자는다른결체조직질환이나고령의정상인에서도나타날수있다. 항Cyclic Ctrullinated Peptide (CCP) 항체는 citrulline residue를포함하는항원결정기에반응하는자가항체로항fillagrin 항체의한종류이다. 최근류마티스인자와비슷한민감도를보이면서더우수한특이도 (81 100%) 를가진 2세대항CCP항체가개발되어연구에이용되고있다 (4). 항CCP항체는높은진단특이도와더불어환자들의기능적상태와도관련이있으며 (5), 조기류마티스관절염환자에서관절손상과도관계가있는것으로알려지고있다 (6-10). 저자들은본연구에서조기류마티스관절염환자들에있어항CCP항체의민감도와특이도를류마티스인자와비교하여임상적의의를찾아보고자한다. 1. 연구대상 2005년 10월부터 2006년 9월까지본원에서 1987년미국류마티스학회에서개정된분류기준에의해류마티스관절염으로진단된환자 262명을후향적으로조사하였다. 진료기록부검토를통해류마티스관절염환자군을발병 24개월이내의조기환자군과그이상환자군, 그리고전체환자군의 3군으로분류하였다. 류마티스관절염이외의결체조직질환으로진단된 122명의검사결과를비교하였다. 2. 연구방법류마티스관절염환자군과비환자군의진단당시의류마티스인자, 적혈구침강속도, C-반응단백, 항 CCP항체를조사하였다. 대조군의검체는 80 o C에서보관후류마티스인자및항CCP항체를검사하였다. 류마티스인자는면역혼탁도측정법 (immunoturbidometry) 에의해 Cobas integra RFII (Roche Diagnostics GmbH, Germany) 로검사하였고, 항CCP 항체는 DIASTAT TM (Axis-Shield Diagnostics, United Kingdom) 을사용하였으며 ELISA 법으로검사하였다. 류마티스인자와항CCP항체검사의결과는제조사의권고에따라각각 10 IU/mL, 5 U/mL 이상을양성으로판정하였다. 환자군의진단에있어류마티스인자와항CCP항체의민감도와특이도, 진단의정확도 (11) 를알아보고이환기간에따라조기관절염의진단에있어류마티스인자와항CCP항체의민감도와특이도의차이를비교해보았다. 3. 통계분석각그룹의일반적인특성및검사실적소견에대해서는도수 ( 백분율 ) 및평균 ( 표준편차 ) 을제시하였고, 독립 t-test 및 Chi-square test로비교하였다. 각그룹간의검사실적소견의비교를위해서는두표본 t-test 및 Chi-square test를이용하여분석하였다. 또한각그룹에서, RF와 anti-ccp에대한민감도 (sensitivity) 와특이도 (specificity) 를구하고, receiver operating characteristics 곡선 (ROC curve) 과더불어곡선하면적을제시, 비교하였다. 모든분석에이용된통계패 228
박성훈외 : Anti-cyclic Citrullinated Peptide Antibody in Early RA Table 1. Baseline characterisrics of studied patients Group Total Male Female Male (age) Female (age) Total (age) n n (%) n (%) mean (SD) mean (SD) mean (SD) p value* 1. RA 24 Mo 136 32 (23.5) 104 (76.5) 50.78 (12.57) 48.19 (13.65) 48.80 (13.41) 0.341 2. RA>24 Mo 126 18 (14.3) 108 (85.7) 54.28 (12.54) 51.31 (11.74) 51.73 (11.85) 0.326 3. Other connective tissue disease 122 32 (26.2) 90 (73.8) 42.31 (12.12) 45.41 (12.87) 44.60 (12.70) 0.237 *Two sample t-test between male and female age Other connective tissue disease : 3 Adult onset Still s disease, 8 Behçet s disease, 26 Fibromyalgia syndrome, 9 Gout, 4 Juvenile rheumatoid arthritis, 4 Mixed connective tissue disease, 2 Polymyalgia rheumatica, 51 Palindromic rheumatism, 3 Psoriatic arthritis, 3 Systemic lupus erythematosus, 1 Systemic sclerosis, 8 Undifferentiated connective tissue Disease Table 2. Comparison of laboratory parameters in each group of patients Group RF (IU/mL) Positive Anti CCP (U/mL) Positive CRP (mg/l) ESR (mm) mean (SD) rate (%) mean (SD) rate (%) mean (SD) mean (SD) 1. RA 24 Mo 148.77 (172.65) 90.44 62.35 (41.29) 87.50 13.81 (23.69) 37.34 (27.87) 2. RA>24 Mo 150.50 (220.08) 91.27 64.30 (42.43) 81.75 14.77 (21.43) 36.94 (29.78) 3. Total RA 149.60 (196.51) 92.36 63.29 (41.77) 84.73 14.27 (22.59) 37.15 (28.57) 4. Other connective tissue disease (CTD) 35.64 (176.27) 30.33 4.39 (13.75) 9.02 11.86 (49.36) 15.80 (16.39) AOSD* 18.00 (16.94) 66.67 8.44 (10.62) 33.33 0.30 (0.17) 23.00 (14.80) BD 6.71 (1.26) 0 0.80 (0.58) 0 1.71 (2.34) 9.13 (7.83) FMS 16.49 (24.89) 30.77 3.64 (8.17) 11.54 3.82 (7.63) 19.31 (20.00) Gout 5.96 (1.95) 0 1.78 (1.27) 0 3.66 (7.06) 16.22 (18.35) JRA* 8.27 (2.71) 25 1.33 (0.53) 0 1.36 (1.57) 3.50 (1.73) PMR 5.90 (0.57) 0 3.09 (1.75) 0 2.35 (1.34) 13.50 (4.95) PR* 56.137 (264.99) 35.29 4.68 (15.11) 7.84 20.43 (73.87) 13.86 (12.91) PsA 8.03 (2.29) 33.33 0.97 (1.04) 0 48.67 (57.09) 50.67 (42.16) SLE* 14.70 (6.78) 100 3.67 (2.37) 33.33 9.00 (9.42) 16.67 (9.29) SSc 11.90 ( ) 100 7.80 ( ) 100 7.60 ( ) 30.00 ( ) MCTD* 122.25 (212.58) 50 26.13 (49.25) 25 10.90 (13.54) 13.50 (17.00) UCTD* 22.38 (27.59) 37.50 2.34 (1.46) 12.5 2.95 (5.61) 13.00 (7.48) *Diseases that can show RF positivity AOSD: Adult onset Still s disease, BD: Behçet s disease, FMS: Fibromyalgia syndrome, JRA: Juvenile rheumatoid arthritis, PMR: Polymyalgia rheumatica, PR: Palindromic rheumatism, PsA: Psoriatic arthritis, SLE: Systemic lupus erythematosus, SSc: Systemic sclerosis, MCTD: Mixed connective tissue disease, UCTD: Undifferentiated connective tissue Disease 키지는 SPSS Win. Ver. 12.0이었으며, 통계적유의성을위하여설정된유의수준은 0.05였다. 결과연구에포함류마티스관절염환자군과기타결체조직질환환자의남녀비와연령은표 1과같으며 각군에서남녀비나연령분포에있어통계적인차이는없었다 (p=0.34, 0.33). 이환기간에따른류마티스관절염군과기타결체조직질환군의검사실소견과나이의비교는표 2, 3과같으며류마티스관절염환자군에서이환기간을제외하고는 (p<0.05) 통계적으로유의한차이가없었다. 기타결체조직질환으로진단된 122명은성인형 229
대한류마티스학회지제 14 권제 3 호 2007 Table 3. Comparison of laboratory parameters in each group of RA patients RA total RA 24 Mo RA>24 Mo p-value* mean (S.D) mean (SD) mean (SD) RF 149.90 148.77 150.50 0.943 (IU/mL) (196.51) (172.65) (220.08) CRP 14.27 13.81 14.77 0.732 (mg/l) (22.59) (23.69) (21.43) ESR 37.15 37.34 36.94 0.912 (mm) (28.57) (27.87) (29.78) Anti CCP 63.29 62.35 64.30 0.706 (U/mL) (41.77) (41.29) (42.43) Age 50.21 48.80 51.73 0.063 (12.74) (13.41) (11.85) *Two sample t test between RA 24 Mo and RA>24 Mo. RF: Rheuamtoid factor, CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, Anti-CCP: Anti- cyclic citrullinated peptide Table 5. Sensitivities, specificities and accurate diagnosis rate of RF and CCP Ab in each group of RA patients Sensitivity Specificity ADR (%) (%) (%) RA 24 Mo RF 90.0 68.0 79.2 Anti-CCP 87.5 89.3 88.4 RF or Anti-CCP 92.6 65.6 79.1 RA>24 Mo RF 91.3 68 79.7 Anti-CCP 81.7 89.3 85.5 RF or Anti-CCP 93.7 65.6 79.6 RA total RF 90.8 68 79.4 Anti-CCP 84.7 89.3 87.0 RF or Anti-CCP 93.1 65.6 79.3 RF: Rheuamtoid factor, Anti-CCP: Anti-cyclic citrullinated peptide, ADR: Acurate diagnosis rate Table 4. Positive rate of RF and anti CCP antibody in each group of RA patients RA 24 Mo RA>24 Mo RA total n (%) n (%) n (%) Anti-CCP ( ) RF ( ) 10 (7.4) 8 (6.3) 18 (6.9) RF (+) 7 (5.1) 15 (11.9) 22 (8.4) Anti-CCP (+) RF ( ) 3 (2.2) 3 (2.4) 6 (2.3) RF (+) 116 (85.3) 100 (79.4) 216 (82.4) Total 136 (100.0) 126 (100.0) 262 (100.0) Anti-CCP: Anti-cyclic citrullinated peptide, RF: Rheuamtoid factor 스틸병 (adult onset still's disease, AOSD) 3명, 베체트병 (Behcet's disease, BD) 8명, 섬유조직염 (fibromyalgia syndrome, FMS) 26명, 통풍 (gout) 9명, 소아기류마티스관절염 (juvenile rheumatoid arthritis, JRA) 4 명, 혼합결체조직질환 (mixed connective tissue disease, MCTD) 4명, 류마티스성다발성근육통 (polymyalgia rheumatica, PMR) 2명, 재발성류마티즘 (palindromic rheumatism, PR) 51명, 건선성관절염 (psoriatic arthritis, PsA) 3명, 전신홍반루푸스 (systemic lupus erythematosus, SLE) 3명, 전신성경화증 (systemic sclerosis, SSc) 1명, 미분화결체조직질환 (undifferentiated connective tissue disease, UCTD) 8명이었다. 항CCP항체음성인환자군에서류마티스인자는 24개월이하류마티스관절염환자군에서 5.1%, 24개월초과환자군에서 11.9% 가양성으로나타나이환기간이긴군에서류마티스인자의양성율이더높은것으로나타났고 ( 표 4), 이에비해류마티스인자음성인환자군에서항 CCP항체의양성율은이환기간에따라각각 2.2%, 2.4% 로차이가없었다, 이환기간 24개월이하의조기류마티스관절염환자군에서류마티스인자와항CCP항체의민감도 / 특이도는각각 90.4%/68.0%, 87.5%/89.3% 이었고, 전체류마티스관절염군에서의민감도 / 특이도는각각 90.8%/ 68.0%, 84.7%/89.3% 로나타났다 ( 표 5). 각검사법의진단의정확도 (acurate diagnosis rate, 전체환자에대한진양성과진음성환자합의비 ) 는각군에서류마티스인자 / 항CCP항체가 79.2%/88.4%, 79.7%/89.5%, 79.4%/87.0% 로항CCP항체가류마티스인자보다더높은것으로나타났다 ( 표 5). 각검사결과의 ROC 곡선은그림 1과같으며각각의곡선하면적은그림 1에표시된바와같다. 각곡선하면적은 0.5 이상 (p<0.05) 값을나타내어통계적으로유의한 ROC 곡선의형태를보였다. 230
박성훈외 : Anti-cyclic Citrullinated Peptide Antibody in Early RA Fig 1. Receiver operator characteristics (ROC) curves of RF and anti-ccp. (A) RA 24 Mo, (B) RA>24 Mo, (C) RA total. 고찰류마티스관절염은이환이후환자들마다매우다양한임상양상을가진다. 상당수의환자에서피로감, 비특이적인근육통및, 관절증상등의전구증상이서서히진행하여이단계에는조기진단이어려울수있다. 일부의환자에서는증상이급성으로나타날수있고, 일부에서는수년간재발성류마티즘의양상으로발현한뒤류마티스관절염으로발전하기도한다. 발병기전은아직정확하게알려져있지않으나유전적인요인과감염, 흡연과같은환경적인요인이같이작용하는것으로생각되어지고있다 (12). 관절염의진행으로인한관절파괴로환자의삶의질과사회경제적비용이증가함에따라가능한한발병초기에진단을확립하여항류마티스약물을비롯한치료를시작함으로써질병활성도를조절하고 관절손상을막는것이효과적인것으로알려지고있다 (13,14). 그러나현재까지는혈청학적진단요소로류마티스인자가유일하게이용되어질수있어조기진단에어려움이있다. 최근류마티스관절염의치료에대한개념의변화로가능한한빨리항류마티스약물을비롯한치료를시작하는것이기능적장애의진행을늦추는것으로알려지고있다 (15-18). 그러기위해서는염증성관절염의이환초기에신뢰성있는감별진단을할수있어야하지만발병초기에는특징적인임상양상을나타내지않는경우가많다. 이럴경우상당한시간이경과하여관절손상이나타나기시작해서야임상양상들을중심으로구성된분류기준을만족하여치료가시작되는경우가많다. 그럼에도불구하고류마티스인자는그역가가높아짐에따라관절손상이나장애와같은나쁜예후와관련이있고쉽게이 231
대한류마티스학회지제 14 권제 3 호 2007 용될수있는혈청학적표지자가없어현재까지도분류기준에포함되어있다 (19). 류마티스관절염에서발견되어지는자가항체로인간구강점막상피세포의핵주위과립에대한 antiperinuclear factor와인간표피세포의 filagrin에대한항체인항keratin항체가이용될수있으며 (20,21), 류마티스관절염의진단에높은특이도를보이는것으로보고되었으나 (22) 검사방법상의문제등으로일반적으로이용하기에는어려움이있다. 최근 filaggrin의 arginine residues가 peptidylarginine deiminase (PADI) 에의해 citrulline residues로변화가일어나고이런 citrullinated residue을포함한기질에반응하는항체가밝혀지면서, 여기서변형된 cyclic citrullinated peptide에대한항체가류마티스관절염환자의진단에이용되고있다 (23). 국내에서최등은연구에서류마티스인자의민감도, 특이도가각각 80.6%, 78.5% 인데비해항CCP항체의민감도, 특이도는각각 72.8%, 92% 로보고하였고, 두가지검사를같이적용할경우각각 79.3%, 96.4% 로높아지는것으로보고하였다 (24). Avouac 등이최근까지발표된연구결과들을분석한바에따르면류마티스관절염의진단에있어항CCP항체의민감도는 39 94%, 특이도는 81 100% 까지보고되고있고, 미분화관절염으로부터류마티스관절염으로의변화와도유의하게관련되어있으며 (4) 건강대조군의류마티스관절염의발병의예측하는데도류마티스인자보다높은민감도를나타내는것으로보고되었다 (25). 이와같이높은특이도때문에항 CCP항체가류마티스관절염의병인과도관련이있을것으로추정되기도하는데, Suzuki 등은 PADI type4 의한일배체가정상인에서보다류마티스관절염환자에서더의미있게관찰되는것으로보아류마티스관절염환자에서단백질이더쉽게 citrulline화되고과도하게 citrulline화된단백질들이관절내에서비정상적인면역반응을유발시킬수있을가능성을시사하였다 (26). 본연구에서류마티스관절염의이환기간에따른류마티스인자와항CCP항체의검사결과에따르면진단적특이도가각각 68%, 89.3% 로항CCP항체가더높으며, 민감도에있어서는류마티스인자가이환기간에따라각각 90.5%, 91.3% 로항CCP항체에 비해높으나, 항CCP항체의경우, 이환 24개월이지난환자군에서의민감도가 81.7% 인것에비해조기환자군에서는 87.5% 로나타났다. 이환기간에따른각군에서항CCP항체는류마티스인자보다높은진단적특이도를가지며, 민감도에있어서는류마티스인자보다낮은수치를보이나조기환자군으로환자군을제한하여전체환자군보다통계적으로유의하지는않으나민감도가높게나타나는것으로보아조기환자군의진단에도움이될것으로생각된다. 전체류마티스환자군과비류마티스결체조직환자군에대한진양성과진음성의비 ( 진단의정확도, acurate diagnosis rate) 는모든군에서항 CCP항체나류마티스인자간에차이가없었다. 본연구에서미비한사항으로류마티스관절염환자군과기타결체조직질환군에서류마티스인자의양성률이기존에알려진결과보다높게측정된점을들수있다. 이는연구대상에포함된환자들중상당수가이전의료기관에서류마티스인자양성도를확인하고전원된환자들이기때문인것으로추측된다. 또한대조군을건강한정상인집단으로하지않고결체조직질환으로진단된환자를대상으로하여, 일부환자에서는류마티스인자가양성으로나타날수있고, 환자수가적어결과에영향을미칠수있을것 으로생각된다. 따라서향후에는더많은조기류마티스관절염환자군과대조군으로연구가행해져야할것으로생각되며, 진단에있어항CCP 항체의역가에따른류마티스인자와의비교나임상양상의정도와의연관성등도연구되어져야할것으로생각된다. 결 류마티스관절염의진단에있어항CCP항체는류마티스인자보다더진단적특이도와정확도가높다. 그리고조기질환군에서의항CCP항체는전체질환군에서의항CCP항체보다더높은민감도를가진다. 론 REFERENCES 1) Kvien TK. Epidemiology and burden of illness of rheumatoid arthritis. Pharmacoeconomics 2004;22:1-12. 232
박성훈외 : Anti-cyclic Citrullinated Peptide Antibody in Early RA 2) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24. 3) Visser H, le Cessie S, Vos K, Breedveld FC, Hazes JM. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum 2002;46:357-65. 4) 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 2006;65:845-51. 5) 김경희, 이성원, 정원태. Association of Anti-cyclic Citrullinated Peptide (CCP) Antibodies and Functional Status in Rheumatoid Arthritis. 대한류마티스학회지 2006; 13: 46-51. 6) Forslind K, Ahlmen M, Eberhardt K, Hafstrom I, Svensson B. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-ccp). Ann Rheum Dis 2004;63:1090-5. 7) Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis 2005;64:196-201. 8) Quinn MA, Gough AK, Green MJ, Devlin J, Hensor EM, Greenstein A, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford) 2006; 45:478-80. 9) Meyer O, Nicaise-Roland P, Santos MD, Labarre C, Dougados M, Goupille P, et al. Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis. Arthritis Res Ther 2006;8:R40. 10) Bongi SM, Manetti R, Melchiorre D, Turchini S, Boccaccini P, Vanni L, et al. Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis anti-ccp and bone damage in RA. Autoimmunity 2004;37:495-501. 11) Matsui T, Shimada K, Ozawa N, Hayakawa H, Hagiwara F, Nakayama H, et al. Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis. J Rheumatol 2006;33: 2390-7. 12) Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 2004;50:3085-92. 13) Emery P. The Roche Rheumatology Prize Lecture. The optimal management of early rheumatoid disease: the key to preventing disability. Br J Rheumatol 1994; 33:765-8. 14) van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with secondline antirheumatic drugs. A randomized, controlled trial. Ann Int Med 1996;124:699-707. 15) O'Dell JR. Therapeutic strategies for rheumatoid arthritis. New Engl J Med 2004;350:2591-602. 16) Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis 2005;64:1731-6. 17)van Aken J, Lard LR, le Cessie S, Hazes JM, Breedveld FC, Huizinga TW. Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis. Ann Rheum Dis 2004;63:274-9. 18) Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004;43:906-14. 19) Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108-11. 20) Nienhuis RL, Mandema E. A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis 1964;23:302-5. 21) Young BJ, Mallya RK, Leslie RD, Clark CJ, Hamblin TJ. Anti-keratin antibodies in rheumatoid arthritis. Br Med J 1979;2:97-9. 22) Vincent C, de Keyser F, Masson-Bessiere C, Sebbag M, Veys EM, Serre G. Anti-perinuclear factor compared with the so called "antikeratin" antibodies and antibodies to human epidermis filaggrin, in the diagnosis of arthritides. Ann Rheum Dis 1999; 58:42-8. 23) 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 233
대한류마티스학회지제 14 권제 3 호 2007 Clin Invest 1998;101:273-81. 24) 최석우, 임미경, 신동혁, 임춘화, 심승철. 류마티스관절염환자에서 Anti-cyclic citrullinated peptide antibodies 검사의진단적유용성. 대한진단검사의학회지 2003; 2: 132-8. 25) Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741-9. 26) Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nature Genetics 2003;34:395-402. 234