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1 대한내과학회지 : 제 87 권제 4 호 특집 (Special Review) - 류마티스질환의새로운진단기준 전신경화증의새로운분류기준 순천향대학교의과대학순천향대학교서울병원류마티스내과 김현숙 Updated Classification Criteria for Systemic Sclerosis: the Concept of Early Diagnosis Hyun-Sook Kim Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea Systemic sclerosis (SSc) is a connective tissue disease of unknown origin, which is characterized by fibrosis of the skin and internal organs, and endothelial and immunologic dysfunction. The presence of a wide range of symptoms renders disease classification difficult. Although recent studies have contributed to our understanding of this debilitating illness, well-validated classification criteria are required for accurate comparison between registries and clinical trials, to assess response to treatment, morbidity and prognosis. Given the emphasis placed upon early and aggressive treatment, the 1980 American College of Rheumatology (ACR) classification criteria are of limited utility with respect to early diagnosis of SSc and limited cutaneous SSc. Recently, the 2013 ACR/European League Against Rheumatism classification criteria for SSc were published for research and clinical practice purposes. These criteria include skin thickening, fingertip lesions, telangiectasia, abnormal nailfold capillaries, Raynaud s phenomenon, SSc-specific autoantibodies and pulmonary complications pertaining to vasculopathy, autoimmunity and fibrosis. These updated criteria should allow a greater number of patients to receive an early diagnosis of SSc. (Korean J Med 2014;87: ) Keywords: Systemic sclerosis; 2013 ACR/EULAR classification criteria; Diagnosis 서론전신경화증 (Systemic sclerosis; SSc) 은섬유화, 내피세포기능이상의혈관병증을특징으로하는결체조직질환으로침범장기에따라만성적이고다양한임상경과를보인다 [1]. 지난수십년간매우드문질환이라고여겨졌던 SSc의병리 생태적이해는조직의광범위한섬유화이전에자가면역성, 내피세포기능이상으로인한소혈관손상 (microvascular injury) 이유기적으로진행한다는것이다 [2]. 최근에조기진단이강조되는이유는피부경화와다양한내부장기, 특히폐, 위장관, 심장, 신장의섬유화및기능이상을보이기전인염증기에치료를하는것이임상적으로병의경과를 Correspondence to Hyun-Sook Kim, M.D., Ph.D. Division of Rheumatology, Department of Internal Medicine, The Soonchunhyang University Seoul Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul , Korea Tel: , Fax: , healthyra@schmc.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 87, No. 4, 되돌리는중요한전환점이라는인식이확산되고있기때문이다 [2,3]. 그러나최근까지임상진료및연구에서사용하는 1980년미국류마티스학회 (American College of Rheumatology, ACR) 예비분류기준 (preliminary classification criteria) 은피부경화, 수지궤양 (digital ulcer, DU), 폐섬유화같은임상기준만을사용하고있어조기진단에는제약이많았다. 1988년과 2001년 LeRoy 등에의하여조기 SSc에대한개념의분류기준이발표되고많은보정과정을거쳐 2013년 ACR/ 유럽류마티스학회 (European League Against Rheumatism, EULAR) 분류기준이개정발표되었다. 이는 1980년예비분류기준의항목을기본으로레이노현상 (Raynaud s phenomenon, RP), 손톱모세혈관검사 (capillaroscopy), SSc 특이자가항체의양성, 모세혈관확장증 (Telangiectasia) 등을추가하여민감도와특이도를높히면서임상에서보다용이하게사용하도록하였다. 이런진단사항이임상에서중요한이유는어떤증후나이상소견이조기에보일때표적장기섬유화로진행하는 SSc로이행할것인지에대한예측을함으로써보다신속히류마티스전문의와상의하여적극적인치료를할수있다는것이다. 그러나아직까지 2013년 ACR/EULAR 분류기준은제한 (limited cutaneous, lc) SSc와광범위 (diffused cutaneous, dc) SSc 로는분류되기어려운특성을가지고있는 CREST증후군 ( 피부석회화증 [calcinosis cutis], RP, 식도운동능장애 [esophageal dysmotility], 가락피부경화증 [sclerodactyly], 모세혈관확장증 ) 이나피부경화증이없는전신경화증 (SSc sine scleroderma) 의진단에대한보완점이필요하다. 분류기준의변화 1980 년미국류마티스학회예비분류기준지난수십년간교과서를비롯하여관찰연구, 임상연구에는 1980년 ACR 예비분류기준을사용하였다. 이기준은동일한기준으로여러의료기관의환자를비교연구하려는목적으로 Alfonse T. Masi 가소속된연구모임에서 3차병원의류마티스내과를내원한 SSc, 전신홍반루푸스, 피부근염, 다발근염, RP가있는 797명의환자들의의무기록을분석하여 SSc의특징을 1개의주기준과 3개의부기준으로정의하였다 (Table 1). 이기준은임상증상과단순흉부방사선검사 (X-ray) 에만준하여주기준인근위부피부경화를만족하거나부기준가락피부경화증, 수지함요반흔이나 DU 그리고양 측폐하부의특징적폐섬유화세가지중두개이상을만족하면 SSc이라분류하였다 [4]. 그러나 lc SSc 중 10-20% 에서분류가불충분한데, 예로전형적인함요반흔이나 DU, RP만있거나가락피부경화증과혈관확장증만있는경우는 SSc에의한증상으로여겨져도분류기준에맞지않는다. 이러한선택편견은주로 RP가있으면서 X-ray에서는정상이나고해상컴퓨터단층촬영 (high-resolution computed tomography, HRCT) 에서간질성폐섬유화의조기변화가보이고, 특징적인위식도병증그리고가락피부경화증만있는경우에서누락을보여진단및분류에혼선을주었다. 보통분류기준은진단기준과는차이가있는데, 질환을진단하는데민감도나특이도가 100% 라면분류기준이진단기준과동일하게사용가능하나이는거의불가능하다. 대신분류기준은진단보다는여러각기다른기관에서동일하게코호트를포함한임상연구를진행할수있는균질성에초점을두기때문에진단기준이민감도에중점을두는것에비하여특이도를극대화하는것을중요시한다 [5]. 이에피부경화가뚜렷이생기기전인질환초기부터보이는 RP나 SSc 특이자가항체가있는 lcssc 의일부경우를어떻게정의하고분류할지에대한필요성이제기되었다. 전신경화증의초기임상증상의중요성 RP는 1980년 SSc ACR 예비분류기준에충족되지않는환자뿐아니라기타다른결체조직질환에서도나타나는증상이며 SSc의거의대부분에서피부경화가나타나기수주에서수년전부터발생한다. 그러므로 RP가있는환자중에서어떤경우가 SSc로진행할지여부에대한예측이필요하다. 이에대한몇몇연구에서손톱모세혈관검사의전형적인소견 ( 거대혈관, 무혈관지점 ) 과자가항체중항centromere, Table Preliminary American College of Rheumatology classification criteria for systemic sclerosis [4] Major criteria Cutaneous scleroderma proximal to MCP/MTP joints Minor criteria Sclerodactly Digital pitting scar or ulcers Bibasilar pulmonary fibrosis in X-ray A patient satisfies the criteria if she/he fulfills the major criteria or at least 2 of the 3 minor criteria. MCP, metacarpophalangeal; MTP, metatarsophalangeal

3 - Hyun-Sook Kim. Classification Criteria for Systemic Sclerosis - 항topoisomerase I, 그리고항RNA-polymerase III 항체가 SSc 로의이행을강하게예측한다는것을보여주었다 [6,7]. 이에 1988년임상경험이많은국제전문가위원회에서좀더실제적인세분류가필요함에합의를하였고 SSc 특이자가항체, 손톱모세혈관검사및임상양상을구분하여피부경화침 Table 2. Criteria proposed by LeRoy and Medsger for the diagnosis and classification of early systemic sclerosis [9] Raynaud s phenomenon plus Systemic sclerosis (SSc) type capillaroscopic pattern (megacapillaries, avascular area: early/active/late pattern) And/or SSc specific autoantibodies (Ab) (anticentromere Ab, anti-topoisomerase-i (Scl70) Ab, anti RNA polymerase III Ab, anti U3 RNP Ab, anti PmScl Ab, anti ThTo Ab) 범범위에따라 dc SSc와 lc SSc로나누며 CREST증후군은 lc SSc에보다근접하다고하였다. 그러나일련의관찰연구들에서상당수의 SSc 환자들이질병의경과를되돌릴수없는섬유화나위축, 혈관폐색이진행되기전분류기준에충족되지않아조기진단이어려워주요장기의섬유화로진행하는아쉬움을남겼다 [8]. LeRoy 와 Medsger 의조기전신경화증분류및손톱모세혈관검사의중요성조기류마티스관절염은증상발현 6개월이내로항류마티스약제에가장효과적인치료경과를보일수있음으로정의하나, 조기 SSc는 SSc로완전히이행되기전인전임상기와혼용되기도한다. 통상적으로, 조기 SSc란 Medsger 등 [9] 이제시한바와같이 dc SSc는 3년이내, lc SSc는 5년이 A B C D Figure 1. Example nailfold capillaroscopic results for systemic sclerosis (SSc; 400x): (A) Capillary dilatation in early-phase SSc. (B) Typically, several giant capillaries and microhemorrhages are observable during the active phase of SSc. (C)(D) During late-phase SSc, ramified capillaries and avascular areas are also observed, along with bushy capillaries

4 - 대한내과학회지 : 제 87 권제 4 호통권제 650 호 Table American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis [14] Item Sub-item(s) Weight/score Skin thickening of the fingers of both hands 9 extending proximal to the MCP joints (sufficient criterion) Skin thickening of the fingers Puffy fingers 2 (only count the higher score) Sclerodactyly of the fingers (distal to the MCP joints but proximal to the PIP joints) 4 Fingertip lesions Digital tip ulcers 2 (only count the higher score) Fingertip pitting scars 3 Telangiectasia 2 Abnormal nailfold capillaries 2 PAH and/or interstitial lung disease Pulmonary arterial hypertension 2 (maximum score is 2) Interstitial lung disease 2 Raynaud s phenomenon 3 SSc-related autoantibodies anticentromere, anti topoisomerase I [anti Scl-70], anti RNA polymerase III 3 These criteria are applicable to any patient considered for inclusion in an SSc study. The criteria are not applicable to patients with skin thickening sparing the fingers or to patients who have a scleroderma-like disorder that better explains their manifestations (e.g., nephrogenic sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheiroarthropathy). The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of 9 are classified as having definite SSc. MCP, metacarpophalangeal; PIP, proximal interphalangeal; PAH, Pulmonary arterial hypertension. 내로서되돌릴수없는혈관폐색, 위축, 그리고섬유화가발생하기전이라는의미로사용되었다. 그러므로임상에서조기 SSc란 SSc의분류기준에만족하지는않지만추후이행의가능성이높은피부경화의전임상기라하겠다. 이전의손톱모세혈관검사연구결과를바탕으로 2001년 LeRoy 등 [10] 은조기 SSc를 RP와 SSc 특이적손톱모세혈관의변화가있거나혹은특이자가항체가있는경우로정의하였고이는 SSc로전환될가능성이높은것으로발표하였다 (Table 2). Koenig 등 [11] 이 RP가있는 586명의환자를전향적으로 20 년동안관찰하여 SSc 특이자가항체와손톱모세혈관의이상이동시에있는경우는 79.5% 에서, 두가지모두없으면 1.8% 에서만 SSc로이행되는결과를발표하여조기 SSc의개념을뒷받침했다. 정상적인모세혈관은구불거림이적고 1 mm당 9-11개의빈도로일정한열을유지하는빗모양양상인데반하여 SSc 에서는조기 (esrly phase) 에모세혈관의지름이팽창하는확장과정상의 10배정도되는거대혈관이보이기시작한다. SSc의활성기 (active phase) 에는거대혈관과미세출혈이증가 하고혈관의빈도가감소하며, 후기 (late phase) 에는거대혈관은사라지고모세혈관의배열이불규칙해지면서신생혈관이보이고무혈관지점이관찰되는일련의변화가보인다 (Fig. 1) [6]. 이러한모세혈관의변화는특히무혈관의빈도가 DU 와같은소혈관이상및폐동맥고혈압발생과도상관관계를일부보이며엔도텔린-1과같이사이토카인과도통계학적인연관관계가있어 SSc의조기진단및진행의추적관찰에도사용가능함이제시되고있다 [12] 년미국류마티스학회 / 유럽류마티스학회의전신경화증분류기준 SSc를진단하거나배제가능한진단검사가없으므로 1980년 ACR 예비분류기준의낮은민감도를보완하고이전의여러분류기준을바탕으로조기 SSc의개념을반영하는새로운 SSc 분류기준이필요했다. 이러한기준을재정비하는목적은명확한임상특징이다발현된 SSc뿐아니라조기 SSc를포함하고혈관병증 / 면역학적이상 / 섬유화의병인을모두반영하면서, 임상에서쉽게접근하여진단을하는데도

5 - 김현숙. 전신경화증의새로운분류기준 - 사용가능하여류마티스전문의뿐아니라기초연구자, 그리고다국적제약회사의 SSc 관련임상연구에서도쓰일수있게하는것이다 [13]. 국제전문가위원들이이전의연구와발표기록들을기반으로분류기준에들어갈 168개항목을선정하여 3차델피방식의회의 (Delphi exercise) 를거쳐 23개로간추렸다. 이를유럽과북아메리카의전문가위원들이중요도에따른협의를통해 14개의항목으로줄였다. 양측가락피부경화증, 손가락부종, 수지함요반흔이나 DU, 수지굴곡구축, 모세혈관확장증, 손톱모세혈관의이상, 석회증, RP, 인대의굴곡염발음, 간질성폐섬유화, 폐동맥고혈압, SSc 콩팥위기, 식도확장, 그리고 SSc 특이자가항체양성이여기에포함되었다. 이항목들에대하여전문가위원들이중요도에따른합의과정을위해점수를매겨순위제로하여 56점이상을획득한항목들을민감도와특이도를향상시키기위한보정을거쳐 9개항목으로정리하였다. 이중가락피부경화증과손가락부종은손가락피부경화로통합하여여덟가지항목으로최종정리하고각각의항목은중요도에따른점수를정하였다. 같은항목에해당되는세부항목중에서는점수가높은한항목의점수만을합산하여총 9점이넘으면명확한 SSc로분류하였다 (Table 3) [14]. 손허리손가락관절의근위부를침범하는양측피부경화이는이전 1980년 ACR 예비분류기준의주기준에해당하는것으로이전분류기준에서주기준을만족하면 SSc로분류되듯이 9점으로책정되어이항목이만족되면명확한 SSc 로분류된다. 손가락피부경화손가락부종은 2점이고손허리손가락관절에서원위부이면서중수지관절이내의가락피부경화증은 4점이다. 외부상처로인한반응성경화는배제하며이중높은점수의세부항목 1개만이합산한다. 손가락끝병소 DU나수지함요반흔은중수지관절원위부에발생하며외부상처에의한것은배제한다. 수지함요반흔은외부자극이아닌미세혈관병증으로인한허혈의결과로손가락끝이함몰된것을의미한다. DU는 2점에해당하고허혈을반영하는수지함요반흔은 3점이며둘중높은점수의항목 1개만합산한다. 모세혈관확장증모세혈관확장은소동맥, 소정맥및모세혈관의확장에의해발생한다. 얼굴및손가락, 손바닥, 손등의피부, 혀, 입술, 그리고입안점막등에도생기며피부표면에압력을가했다떼면붉은빛이천천히차오르는특징을가진다. 위와같은특성의모세혈관확장증이확인되면 2점에해당한다. 전신경화증에특이적인손톱모세혈관검사소견조기 / 활성기 / 후기 SSc의특징인대칭적으로커진거대혈관, 미세출혈그리고허혈이진행함에따라모세혈관이소실되고무혈관지점이증가하는전형적인손톱모세혈관의소견이있으면 3점을더한다. 폐동맥고혈압이나간질성폐질환폐동맥고혈압은허파심장증 (cor pulmonale), 좌심실부전, 혈전색전증을배제하여야하며우심실도관삽입 (right heart catheterization, RHC) 으로진단한다. RHC 에서폐동맥쐐기압 (pulmonary wedge pressure) 이 15 mmhg 미만이면서평균폐동맥압이 25 mmhg 을넘으면 2점이다. 간질성폐질환은 X-ray 뿐아니라 HRCT에서간질성폐섬유화소견이보이면 2점에해당하며병변은주로폐하부에서보이고미세한흡기말기수포음 (late inspiratory crackle, velcro rale) 이잘들리나울혈성심질환의동반은배제하여야한다. 레이노현상 RP는추위나심리적스트레스에노출되었을때손가락, 발가락끝이창백하게 (pallor) 변하고, 시간이경과하면청색증 (cyanosis) 이발생하며이상부위를다시따뜻하게해주면발적 (rubor) 이생기는일련의변화중 2단계이상의색조변화를환자가명확하게기술하거나검사자가관찰하면 2점에해당하며보통창백하게변하는것을포함하여나타난다. 전신경화증특이자가항체 SSc 특이자가항체는항centromere 항체나항topoisomer- ase-1 ( 항 Scl-70) 항체, 항RNA polymerase III 항체와같은세포내단백질에대한항핵항체로표준검사절차에따라이중한가지이상양성이면 3점에해당한다. 일부환자에서는피부경화없이 RP나다른전형적인 SSc 에의한장기침범만보이는데이를 SSc sine scleroderma 라고부른다. 이런경우에서 RP, 특이자가항체양성, 손톱모

6 - The Korean Journal of Medicine: Vol. 87, No. 4, 세혈관의이상이있으면서폐동맥고혈압이나간질성폐질환이있으면 2013년 ACR/EULAR SSc 분류기준에서 10점으로진단이가능하나내부장기침범이관절, 근육, 위식도기능이상, 혹은신장이상으로나타나면분류기준에서제외된다. 이러한문제는추후개선해야할점으로언급되었다 [15]. 결 SSc는내피세포기능이상, 자가면역항진으로피부를포함한전신장기에섬유화가진행되는드문자가면역질환이다. 섬유화가시작되기이전에피부경화가아닌부종, 비특이적인혈관확장이나 RP가선행되나이를조기에진단하고분류하기가어렵다. 이상적인분류기준이란질병의초기발견이가능하며질환의경과를예측가능한세분류에도움이되고, 이를뒷받침할실험실적검사결과를포함하며쉽게적용가능하고, 여러국가에서유효성이검증되어야한다. 조기진단이강조된이번 2013년 ACR EULAR SSc 분류기준은위의바램을거의충족시키고임상에서쉽게활용될수있게개정되었다. 이를토대로다기관에서비교가능한역학조사와단일화된임상실험을진행하여피부경화전임상기 (preclinical) 의생물학적병리생태및적극적인치료에활용하여야겠다. 중심단어 : 전신경와증 ; 2013 ACR/EULAR 분류기준 ; 진단 론 REFERENCES 1. Mayes M, Assassi S. Epidemiology and classification of scleroderma. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 5th ed. Philadelphia: Elsevier, 2011: Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 2013;65: Boin F, Wigley FM. Clinical features and treatment of scleroderma. In: Firestein GS, Budd RC, Gabriel SE, Mclnnes IB, O dell JR, eds. Kelley s Textbook of Rheumatology. 9th ed. Philadelphia: Elsevier, 2013: Preliminary criteria for the classification of systemic sclerosis (scleroderma): subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23: Singh JA, Solomon DH, Dougados M, et al. Development of classification and response criteria for rheumatic diseases. Arthritis Rheum 2006;55: Kallenberg CG, Wouda AA, Hoet MH, van Venrooij WJ. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis 1988;47: Cutolo M, Sulli A, Smith V. Assessing microvascular changes in systemic sclerosis diagnosis and management. Nat Rev Rheumatol 2010;6: Luggen M, Belhorn L, Evans T, Fitzgerald O, Spencer- Green G. The evolution of Raynaud s phenomenon: a longterm prospective study. J Rheumatol 1995;22: Medsger TA Jr. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am 2003;29: LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28: Koenig M, Joyal F, Fritzler MJ, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58: Kim HS, Park MK, Kim HY, Park SH. Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol 2010;29: Avouac J, Fransen J, Walker UA, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 2011;70: Van den Hoogen F, Khanna D, Fransen J, et al classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013;65: Valentini G, Marcoccia A, Cuomo G, Iudici M, Vettori S. The concept of early systemic sclerosis following 2013 ACR\EULAR criteria for the classification of systemic sclerosis. Curr Rheumatol Rev 2014 Apr 3 [Epub]. DOI: /

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R