대한내과학회지 : 제 89 권제 6 호 2015 http://dx.doi.org/10.3904/kjm.2015.89.6.609 특집 (Special Review) - 류마티스질환의초음파검사의의미와소견 류마티스관절염의초음파소견 연세대학교원주의과대학류마티스내과학교실 강태영 Ultrasonographic Findings in Rheumatoid Arthritis Tae Young Kang Department of Rheumatology, Yonsei Univeristy Wonju College of Medicine, Wonju, Korea Rheumatoid arthritis (RA) can be evaluated with ultrasound using both gray scale and Doppler mode. Gray scale provides cross-sectional images of joints, whereas Doppler shows the vascularity of the proliferated synovium. In RA, ultrasound can detect sub-clinical or early synovitis, assess arthritis more accurately than through clinical examination, and predict recurrence. In particular, a Doppler signal detected inside the joint cavity correlates with disease activity. Imaging remission can reflect the true remission status more accurately than with clinical remission. In this review, we focus on the use of ultrasonographic findings for the diagnosis, assessment, and prediction of RA. (Korean J Med 2015;89:609-615) Keywords: Ultrasonography; Doppler; Rheumatoid arthritis; Synovitis 서론류마티스내과근골격초음파 (musculoskeletal ultrasound) 는류마티스내과진료에서그유용성으로인해전세계적으로지난 20여년동안빠르게성장해왔으며, 류마티스내과의사의진료의일환으로빠르게통합되어가고있다. 초음파는실시간 (real time) 검사, 동적검사 (dynamic examination), 동시에여러관절검사등다른영상기법들과비교하여여러장점들을가지고있다. 초음파의시술자의존성 (operator dependent) 의단점도표준화와객관화를통해이제는더이상장애물이되지않으며, 따라서류마티스내과진료에서초음파의활용효용성에대한논란은더이상무의미하다. 더욱이초음파는류마티스내과의사가관절염을비롯한류마티스질환의 올바른진단과치료를위해서는반드시갖추어야할진료의필수적인도구가되었다 [1]. 최근에는초음파의영상학적인관절관찰능력을이용하여류마티스관절염 (rheumatoid arthritis, RA) 의조기진단, 활성도평가및예후판정에활용되고있다. 이논문에서는 RA 환자에서초음파소견을진단, 평가및예측의논점으로정리해보고자한다. 본론초음파는두가지측면에서관절및연관구조물들을관찰할수있다. 회색도모드 (gray scale mode) 와도플러모드 (doppler mode) 이다. 회색도모드는 brightness (B)-모드로도불리며, 관절강 (joint cavity) 내부및그주위의건 (tendon) 및건초 ( 힘줄 Correspondence to Tae Young Kang, M.D., Ph.D. Department of Rheumatology, Yonsei Univeristy Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: +82-33-741-0520, Fax: +82-33-744-1257, E-mail: taeyoung@yonsei.ac.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 609 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 89, No. 6, 2015 - A B Figure 1. Gray-scale and Doppler ultrasound findings of the tarsal (talonavicular and naviculocuneiform) joint. Although synovitis of the tarsal (or carpal) joints usually cannot be detected through a clinical examination, ultrasound can detect it. (A) Gray scale shows effusion and synovial hypertrophy (arrows) of the talonavicular joint and adjacent naviculocuneiform joint. (B) Power Doppler hyperemia, which represents active synovial inflammation, is present in both the talonavicular and naviculocuneiform joints. 윤활막, tenosynovium) 의단면해부학적인이상을관찰할수있다. 반면에도플러모드는현재진행중인염증의유무및중증도 (severity) 를파악할수있다 (Fig. 1). 진단 RA는활막염 (synovitis) 으로특징되는만성적인전신성자가면역질환이다. 사지의활막관절 (synovial joint) 을침범하여호전과악화를반복하며비가역적인관절파괴를유발한다. 류마티스내과초음파연구는 RA 활막염에가장많이집중되어왔다. 정상활막은매우얇은두께로인해초음파로명확하게관찰되지않는다. 그러나활막염으로인한활막비후 (synovial hypertrophy) 가발생하면비후된활막이초음파로관찰될수있다. 관절염증에의한활막비후는초기의작은증식부터삼출이들어있고융모 (villi) 가형성되어있는중증의증식까지병에이환된정도에따라초음파에서다양하게관찰될수있다. 초음파로활막염을검사한최초의보고는 1978 년 Cooperberg 등 [2] 이 RA 환자에서슬관절에대한 yttrium-90 주사치료효과를보기위해 5 MHz 탐촉자를이용하여삼출과활막비후를관찰한것이었다. 활막비후와관절삼출은감별이때때로어려울수있다. 또한활막비후와활막염은비슷한의미로쓰이나, 활막비후는회색도모드에서관찰되는활막의증식을지칭하고, 활막염은증식된활막에도플러신호가검출되는경우를의미한다. 삼출, 활막비후등을포함한기본적인초음파병변에대한정의는 Outcome Measures in Rheumatoid Arthritis Clinical Trial (OMERACT) 에서제시한기준 [3] 이현재사용되고있다. 초음파는관절강을영상을통해시각적으로실시간으로보여줄수있기때문에신체진찰 (physical examination) 에서발견되지않는병변을더민감하게검출해낼수있다 [4]. 초음파는활막염의검출에진찰 (clinical examination) 보다우수하다. Kane 등 [5] 은슬관절상슬개점액낭염 (suprapatellar bursitis), 슬관절삼출및 baker 낭종의검출에진찰보다초음파가더민감함을보고하였다. 또한 40명의 RA 환자를대상으로시행한 Szkudlarek 등 [6] 의연구에서, 조영증강자기공명영상 (contrast enhanced magnetic resonance imaging [MRI]) 을기준으로하였을때중족지관절 (metatarsophalangeal joint) 활막염검출의민감도가진찰의 0.43에서초음파를사용한경우 0.87로크게증가되었다. 더욱이 RA를포함한염증성관절염환자의수지관절 (finger joint) 병변에대한초음파, 방사선촬영및 MRI 검출능력을비교한 Backhaus 등 [7] 의연구에서도, 초음파는 MRI 보다더민감하게수지관절활막염을검출해냈다. 이러한초음파의월등한활막염검출능력은관절내부를영상학적으로관찰할수있는초음파의태생적인능력에서기인한다. RA 진단은고식적으로미국류마티스학회 (American College of Rheumatology, ACR) 의진단기준을사용하여왔으나, 최근에는 2012년에발표된 2010 미국 / 유럽류마티스학회 (ACR/ European League against Rheumatism [EULAR]) 진단기준 [8] 을사용한다. 이두진단기준에는모두신체진찰을기준으로하는압통및종창관절수가포함되어있다. 그러나신체진찰에의한압통및부종관절의결정은검사자의경험과방법에따라그결과가다르게나타날수있을뿐만아니라조기 (early) 또는무증상 (subclinical) RA를검출해내기어렵다. 그 - 610 -
- Tae Young Kang. Ultrasound in rheumatoid arthritis - A B Figure 2. Gray-scale ultrasound findings of the carpus (A) and 1st metatarsophalangeal joint (B). (A) In the carpal joint, Grade 2 gray-scale synovitis (arrow; synovial thickening bulging over the line linking the tops of the periarticular bones but without extension along the bone diaphysis) is observed according to the semiquantitative 4 point scale (0-3) scoring system proposed by Szkudlarek et al. [16]. (B) In contrast, in the 1st metatarsophalangeal joint, Grade 3 gray-scale synovitis (synovial thickening bulging over the line linking the tops of the periarticular bones with extension to at least one of the bone diaphyses) is observed (arrows). 러나초음파는조기단계의활막삼출과비후를검출하여줄수있기때문에조기 RA를보다정확하게진단할수있다. 골미란 (bone erosion) 골미란은 RA 질환특이징후는아니며모든염증성관절염에서관찰될수있는병변으로, 활막염과연관되어나타나거나또는국소적인생화학적인자에의해발생할수있다 [9,10]. 골미란은보편적인활용성으로인해주로단순방사선촬영에의해주로검사되어왔으나, 단순방사선촬영은초기단계의골미란을잘보여주지못한다. 더욱이방사선촬영에서골미란이검출되려면약 30% 의골손실이있어야한다 [11]. 컴퓨터단층촬영 (computerized tomography, CT) 이골손상을잘보여줄수있지만, 전리방사선에노출되기때문에여러관절에대해반복적인활용에는제한이있다. MRI 는미란의검출에민감하나, 시간소모적이고비용효과적인면에서제한이따른다. 초음파는미란의검출에다른영상기법들에비해우월성을가지며, 이것은한관절을여러면에서관찰할수있는초음파의능력에기인한다. RA 환자 100명을대상으로시행한 Wakefield 등 [12] 의연구에서초음파는중수지관절 (metacarpophalangeal joint) 에서단순방사선촬영에비해초기단계에서 7.5배많은환자에서 6.5 배많은미란을검출하였고, 후기단계에서이수치는각각 3.4 배와 2.7배였다. 비슷하게, Weidekamm 등 [13] 에의해수행된연구에서초음파는단순방사선촬영보다약 2배많은미란 을손목과수지관절에서검출하였다. 그러나 Backhaus 등 [7] 및 Hoving 등 [14] 의연구에서는초음파가단순방사선촬영보다더많은미란을손에서검출해내지는못하였다. 이는탐촉자 (probe) 의위치와초음파기계의성능차이로인한것으로여겨진다. 초음파와 MRI의중수지관절미란검출능력을비교한연구에서, CT를기준으로하였을때, 단순방사선촬영의민감도와특이도는각각 19% 와 100%, 초음파는 42% 와 91%, MRI는 68% 와 96% 였다 [15]. 평가회색도초음파에서활막증식은그중증도를반정량적 (semiquantitative) 4 point scale (0-3) 을통해등급화할수있다. Szkudlarek 등 [16] 이제시한활막비후의반정량적점수평가법은 grade 0: 활막비후없음, grade 1: 활막비후가관절골 (articular bone) 상부연결선내에들어있으나연결선을위로밀고있지않음, grade 2: 관절골상부연결선이위로밀려돌출되었으나골간단 (diaphysis) 을따라확장되어있지않음, grade 3: 관절골상부연결선이위로밀려돌출되고골간단을따라더확장되어있음으로분류하였다 (Fig. 2). 그러나이러한점수평가법을건강정상인에게적용하였을때에도 grade 1 또는 2 정도의활막증식이일부관찰되었으며, 이는반정량적등급화를이용한회색도초음파소견만으로는정상과비정상의구분에어려움이있을수있음을시사한다 [17]. 따라서활막염을평가할때회색도소견만가지고는충분하지않다. 도플러검 - 611 -
- 대한내과학회지 : 제 89 권제 6 호통권제 664 호 2015 - 사를통하여활막염의활성정도 ( 중증도 ) 를측정하여야한다. 활성도평가도구로서의도플러도플러초음파는 1842년오스트리아의물리학자인 Christian Andreas Doppler가발견한원리인도플러효과 (Doppler effect) 를기초한초음파이다. 초음파탐촉자에서방출된음파가움직이는혈류 ( 주로적혈구 ) 에반사되어되돌아올때, 이반사파는도플러효과로인해원래의음파에비해주파수가차이가발생하며, 이주파수차이가도플러변이 (Doppler shift) 이다. 이도플러변이를분석하면혈류의방향과속도를계산할수있다. 도플러변이에기초하여혈류의방향을적색과청색으로표시해주며, 그속도는색상의휘도 (luminosity) 로표시해주는도플러모드가컬러도플러 (colour Doppler) 이다. 반면에, 파워도플러 (power Doppler) 는도플러변이를사용하지않고, 그대신에혈류에서후방산란된 (backscattered) 음파의총에너지, 즉파워 (power) 를합산하여단일색상의휘도로표시해준다. 파워도플러는태생적으로기인하는여러기술적인장점들이있다. 즉, 파워도플러는도플러변이를사용하지않기때문에컬러도플러에서나타날수있는앨리어싱 (aliasing, 혈류의방향과속도의잘못된표시 ) 이발생하지않으며, 탐촉자의기울기 (tilting) 에따른음파의입사각변화에의존적이지않다. 또한미세혈류에대한민감도가기술적으로컬러도플러에비해높다. RA를포함한류마티스질환에서는혈류의방향과속도에대한정보보다는, 활막의증가된미세혈류에대한정보가필요하므로컬러도플러보다는파워도플러가선호된다. 관절강내에서관찰되는도플러신호는모두비정상적인소견으로, 관절강내염증, 주로활막염으로인한것이다. 도플러초음파에서관류의정도를수치적으로평가할수있으며, 회색도초음파와비슷하게 4 point scale (0-3) 을사용하는반정량적방법이주로이용된다 [18,19]. 도플러에서관찰되는관류는조영증강-MRI 에서관찰되는조영증강과연관관계가있다. Terslev 등 [20] 은 RA 환자에서 29개의손목관절과 197개의수지관절에서관찰되는컬러도플러신호의반정량적및정량적 (quantitative) 평가를조영증강-MRI 와비교하였다. 이연구에서 MRI에서관찰된증강된활막의두께와관심영역 (region of interest) 의총픽셀 (pixels) 에대한컬러픽셀의분율로정의되는컬러분율 (color fraction) 사이에는서로연관관계가있었다 [20]. 또한 5명의 RA 환자와 15명의건선성관절염환자를대상으로시행한 Weil 등 [21] 의연구에서도, 수지와족지 (toe) 관절활막염및염증성병변의검출에활막비후, 파워도플러 양성등의초음파소견과 MRI는약 73-100% 의좋은일치율을보였다. 더욱이파워도플러에서관찰되는활막의충혈 (hyperemia) 은조직학적검사로관찰되는활막의혈관분포 (vascularity) 와서로일치한다. 즉, 고관절과슬관절관절치환술을받기전도플러초음파로평가된활막의정량적충혈은절개된관절활막검체를조직학적으로평가한활막혈관분포와서로연관관계가있었다 [22,23]. RA 치료후치료반응평가에또한도플러가사용될수있다. Methotrexate (MTX) 와 infliximab 복합요법으로치료한 RA 환자를 54주간추적관찰한 Taylor 등 [24] 의연구에서, 회색도로측정된활막두께감소와도플러로측정한혈류분포의감소가 MTX와위약을투여한군과비교하여치료 18주후부터의미있게나타났다. 또한종양괴사인자 (tumor necrosis factor, TNF) α 차단제로치료한 367명의 RA 환자를 1년간추적관찰한 Naredo 등 [25] 의연구에서, 반정량적으로평가된파워도플러충혈의호전은 disease activity score (DAS) 28의호전과서로일치하였고, 파워도플러는 TNFα 차단제치료효과추적관찰에타당한도구임을보여주었다. 임상적관해 (clinical remission) RA 치료에서생물학적제제를비롯한새로운치료제의출현과이에따른치료전략의변화로인해, 관해는도달될수있는일차적인치료목표가되었다 [26]. 실제로관해는많은환자에서도달될수있다 [27]. 낮은질병활성도 (low disease activity) 는관절손상의진행과이에따른기능손상이최소화된상태로, 장기간의이환, 동반질환, 환자또는약제적인요인등에의해관해에도달될수없는환자에서관해를대체할수있는전략적치료목표이다. 관해는 활막염의완전소실 로정의될수있다. RA 환자에서활성도평가는, 신제검진으로측정한압통관절과부종관절수를기본으로하여평가하는 DAS [28], DAS 28 joints (DAS 28) [29], simplified disease activity index (SDAI) 및 clinical disease activity index (CDAI) 와같은측정도구들을이용한다. 이들도구들은각각측정하는내용및평가기준수치 (cut-off level) 등에서서로차이가있으며, 관해의기준이되는수치를각각제시하고있다. 이를이용한관해기준에충족되었다하더라도, 진성 (true) 관해에도달되었다고간주될수는없다. 왜냐하면이들측정도구들은모두신체진찰로평가하는압통과부종관절수를포함하고있으며, 이는 RA 진단에가장중요한소견이지만관찰자간 (interobserver) 신뢰도차이가항시내재해있기때문이다. 더욱이, 변형된관절에서활성도가없 - 612 -
- 강태영. 류마티스관절염초음파 - 는섬유화조직이있는경우에는진찰만으로활성적부종과감별이되지않을수있다. 관해에대한새로운정의의필요성으로인해 2011년 ACR/EULAR 가제시한관해기준은압통관절수, 부종관절수, C-reactive protein (CRP) level (mg/dl) 그리고 patient global assessment (0-10 scale) 이모두 < 1 또는 SDAI < 3.3이다. 그러나이기준도여전히압통및부종관절수에기초를하고있다. 더욱이 CRP 등과같은염증표지자는 RA 활성도와관련없이비특이적으로증가될수있다. 이러한요소들은결국 RA 활성도측정결과의부정확성으로귀결된다. 따라서이들기준에의한관해도달은진정한관해를의미한다기보다는전반적인낮은 RA 활성도를의미한다 [30]. 영상학적관해 (imaging remission) RA 활성도측정도구를이용한임상적관해보다는, MRI 나초음파에서관찰되는영상학적관해가진정한관해를반영해줄수있다는새로운개념이대두되고있다. 이것은 2006 년 Brown 등 [31] 에의해처음제시되었다. 이들연구에서, DAS 28과 ACR 관해기준을충족한 107명의 RA 환자중약 25-50% 에서초음파에서활막비후및도플러신호양성, MRI 에서조영증강소견등의잔유하고있는활성적활막염이관찰되었다. 따라서이들은관해기준을충족한 RA 환자는진찰및검사실소견에서정상을보일수있지만, 진성관해유무와보다정확한 RA 상태평가를위해서는영상학적평가가필수적임을제시하였다. 더욱이임상적관해에도달된 RA 환자에서관찰되는회색도와도플러초음파활막염은심한질병활성도와나쁜예후와연관되어있다는것이보고되어왔다. TNFα 차단제와 MTX 병합요법이조기투여된그룹과지연투여된그룹에서 DAS 28 관해에도달된환자의초음파소견을비교한 Saleem 등 [32] 의연구에서, 조기투여된그룹에서회색도초음파에서관찰되는활막비후가의미있게적었다. Peluso 등 [33] 은조기 RA 환자와긴유병기간을가지고있는 RA 환자에서얼마나많은환자가파워도플러관해에도달될수있는지를비교하였다. 조기 RA 환자에서는약 43.7% 에서파워도플러관해에도달하였으나, 긴유병기간을가진 RA 환자에서는오직 17.4% 에서만도달하였다. 예측 Boyesen 등 [34] 은회색도초음파에서관찰되는활막증식소견은 MRI에서관찰되는미란의독립적예측인자가될수있다고하였다. 하지만도플러는회색도에비교하여더정밀한 예측능력을가지고있다. 파워도플러신호양성소견은장기 (long standing) RA에서뿐만아니라조기 RA에서도미란, 관절파괴등과같은방사선학적진행의예측인자가될수있다 [34,35]. 또한파워도플러는임상적관해에있는환자에서재발의예측인자가될수있다. 관해에도달한환자에서 6개월이내재발을예측할수있는인자로 DAS, 부종관절수, 스테로이드치료등을비교한 Scire 등 [36] 의연구에서, 파워도플러신호는재발을예측할수있는유일한인자였다. 결 RA 환자에서회색도초음파를통해영상학적인새로운질환특성들을관찰할수있다. 또한도플러초음파를통해조기활막염을민감하게검출해낼수있고, 임상경과를모니터링할수있으며치료효과를판정할수있다. 도플러초음파로관찰되는관절강내혈관신생의중증도를반정량적또는정량적으로수치화함에의해 RA 질환활성도를측정할수있다. 임상적관해에도달한환자에서검출되는도플러신호양성은 RA 재발의예측인자가될수있다. 결론적으로, 류마티스내과에서 RA 환자에대한초음파의활용은치료성과를획기적으로향상시킬수있다. 론 중심단어 : 초음파 ; 도플러 ; 류마티스관절염 ; 활막염 REFERENCES 1. Kang T, Emery P, Wakefield RJ. A brief history of ultrasound in rheumatology: where we are now. Clin Exp Rheumatol 2014;32(1 Suppl 80):S7-S11. 2. Cooperberg PL, Tsang I, Truelove L, Knickerbocker WJ. Gray scale ultrasound in the evaluation of rheumatoid arthritis of the knee. Radiology 1978;126:759-763. 3. Wakefield RJ, Balint PV, Szkudlarek M, et al. Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 2005;32:2485-2487. 4. Grassi W. Clinical evaluation versus ultrasonography: who is the winner? J Rheumatol 2003;30:908-909. 5. Kane D, Balint PV, Sturrock RD. Ultrasonography is superior to clinical examination in the detection and localization of knee joint effusion in rheumatoid arthritis. J Rheumatol 2003;30:966-971. 6. Szkudlarek M, Narvestad E, Klarlund M, Court-Payen M, Thomsen HS, Østergaard M. Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, - 613 -
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