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1 대한내과학회지 : 제 76 권제 1 호 2009 특집 (Special Review) - 류마티스관절염진단과치료의최신지견 최근조명된류마티스관절염의병태생리 서울대학교의과대학내과학교실 송영욱 Updated pathophysiology of rheumatoid arthritis Yeong Wook Song, M.D. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Rheumatoid arthritis is a chronic inflammatory disease that primarily affects joint synovium. Although its etiology has yet to be identified, the underlying mechanism of joint inflammation is understood as autoimmune process. The inflamed synovium is thickened due to synovial hyperplasia and infiltrating mononuclear cells such as T and B lymphocytes, macrophages, and plasma cells. Key inflammatory cytokines TNF-α and IL-1, as shown by the significant therapeutic effect of their blockade, are mainly secreted by macrophages whereas IL-17 is secreted by a newly recognized subset of T cells (Th17 cells) and induces TNF-α and IL-1 production by adjacent macrophages, synoviocytes, and chondrocytes. IL-17 has also been shown to induce RANKL from osteoblasts, thereby indicating that this cytokine plays as an upstream molecule that regulates inflammation and osteoclastogenesis. More importantly, IL-17 has been shown to convert acute inflammation into chronic inflammation and when combined with already important cytokines, more marked inflammation occurs. The role of B cells as antigen presenting cells are now being recognized based on the therapeutic effect of rituximab, a B cell inhibitor, in rheumatoid arthritis. Great attention has been turned to anti-citrullinated peptide antibodies because they form immune complex and contribute to inflammation by activating complement system. Recently, clinical trials showed therapeutic efficacy of tocilizumab, monoclonal antibody against IL-6 receptor, suggesting relevant involvement of IL-6 in disease process of rheumatoid arthritis. Thus, various cellular and molecular players seem to interact within rheumatoid synovium to perpetuate inflammation. Further studies are needed to explore the exact mechanisms of development and maintenance of inflammation in rheumatoid arthritis. (Korean J Med 76:1-6, 2009) Key Words: Rheumatoid arthritis; Synovium, and inflammation 류마티스관절염은관절활막 (synovium) 의염증을주된특징으로하는전신질환으로서, 만성경과를거쳐관절의변형과장애를유발하게된다. 일반적으로인구의 1% 를침범하며, 여성의경우남성의 2.5배에이르는유병율을가진다. 모든연령대에발병할수있으나, 40대에서 70대사이의연령대에가장흔하며발병율은연령에따라증가한다. 류마티스관절염의원인은아직완전히알려지지않은상태이나, 자가면역기전으로인한염증반응으로이해되고있으며, 발병에는유전적소인과환경적인요인이모두작용할 것으로추측되고있다. 최근류마티스관절염의병인과활막염 (synovitis) 에대한이해가깊어지면서이를바탕으로한새로운치료제들이활발하게개발되고있다. 류마티스관절염의관절증상및조직병리류마티스관절염에의한관절침범은전신의모든관절에모두적용되나, 특징적으로손과발의관절, 특히근위지간관절과중수 ( 족 ) 지관절을침범하여관절의종창과통증을일으킨다 1). 발병후만성적경과를밟게되며, 치료를하 - 1 -

2 - The Korean Journal of Medicine: Vol. 76, No. 1, 지않았을경우염증으로인한관절의변형과파괴로관절기능의영구적손실을가져오기때문에신속한진단과적절한치료가필수적이다. 류마티스관절염은활막의염증에기인하기때문에활막염은류마티스관절염의가장중심적인병리소견이다. 정상적인활막은 1~2 층의얇은활막세포 (synoviocyte) 로덮여있는조직인데반해, 류마티스관절염에서보이는활막은다음과같은변화들을보인다 ; 1) 활막세포의증식 2) 염증세포의침윤 3) 신생혈관의생성 4) 세포표면의부착물질 (adhesion molecule) 의발현증가그리고 5) 다양한사이토카인과단백분해 / 분해억제물질의발현등이가장뚜렷이관찰되는변화이다 1). 활막에침윤한염증세포들은대개단핵구들로서 T 세포, B 세포, 대식세포 (macrophage), 그리고형질세포 (plasma cell) 등의세포로이루어져있다 2). 신생혈관증식이일어나절대적인혈관의수는늘어나있지만, 조직증식이혈관증식보다활발하기때문에국소저산소증이나타나고혈관생성이더욱촉진된다 3, 4). 활막혈관의내피세포는 high endothelial venule 형태로형질변환 (transformation) 하여백혈구의유입을증진시키며, 침윤한세포들과어울려림프절 (lymph node) 에서볼수있는림프소절 (lymphoid follicle) 과유사한조직구조를이루기도한다 5). 활막세포의증식과침윤한염증세포로인해두꺼워진활막중일부는인접하는연골과골로국소침습하는성질을띠게되는데, 이는류마티스관절염과다른염증성관절염을구분짓는가장큰특징이다 6). 주변조직을파고드는이러한활막조직덩어리를 pannus 라부르고, pannus에의해국소적으로파괴된골은흔히방사선학적검사에서특징적인가장자리미란 (marginal erosion) 으로나타난다. 류마티스관절염의전통적병인론질병의유전적소인을분석한쌍둥이연구에의하면일란성쌍둥이 (12~15%) 의경우가이란성쌍둥이 (4%) 와비교하여높은질병일치도 (disease concordance) 를보여, 질환기전에유전적영향이있음을시사한다 7, 8). 가계도연구에의하면, 류마티스관절염의질병소질의약 60% 가유전적인자에기인한다 9). 류마티스관절염에관여하는유전자를찾으려는노력은지금도활발히진행중이며그중에서가장대표적인유전자가면역반응에관여하는사람백혈구항원유전자 (human leukocyte antigen; HLA) 이다. 이유전자중에서 HLA-DR4의아형인 HLA- DRB1 * 0401, * 0404와 * 0405 대립유전자등을 가진경우, 류마티스관절염의발생빈도가높고관절파괴가심하며관절외증상도많이나타나서예후가나쁜것으로알려져있다 10-12). 류마티스관절염이자가면역질환이라는직접적인증거는현재까지없으나, 다른외부적인원인이밝혀지지않았고, 20세기중반에류마티스인자 (rheumatoid factor) 라는자가항체 (autoantibody) 가환자의혈액에서검출되면서자가면역질환으로인식되기시작했다 13). 류마티스인자가양성일경우, 심한질병경과와불량한예후를시사하지만, 일부정상인들및다른염증성질환에서도류마티스인자가존재하기때문에이것의존재만으로류마티스관절염의특이한증상들을모두설명하기는어렵다. 이후의연구에서류마티스활막에 T세포의침윤이뚜렷함을관찰하면서 T 세포가중요한역할을할것으로생각하게되었다. 더욱이유전학적소인으로 HLA-DR의특정한아형과의연관성이알려지게되었는데, 이또한 T 세포의역할을암시한다. HLA- DR의특정아형의연관성은항원전달세포에의한항원전달단계 ( 자가항원전달 ) 또는 CD4 T 세포에의한항원인식단계 ( 자가반응 T 세포 ) 에이상이있음을시사한다. 그러나활막에침윤한 T 세포의경우 1) 증식이매우제한되어있으며, 2) 기억세포인경우가많고, 3) 활막에서발현되는사이토카인의대부분이 T 세포보다는대식세포에기인하고있어 14-16), T 세포가직접적으로활막염의시작과유지에어떤역할을하는지는확실하지않다. 활막에침윤한세포중 B 세포또는형질세포의경우, 류마티스인자와같은자가항체의생산이외의역할에대해서는최근까지잘알려지지않았으나, B세포를선택적으로제거하는단클론항체 (rituximab; chimeric, anti-cd20 monoclonal antibody) 가류마티스관절염의치료에매우효과적인사실이알려지면서부터항원전달세포로서의 B 세포의역할에대해새롭게인식되었다 17). 류마티스관절염의활막에서발현되는사이토카인은주로대식세포와활막세포로부터분비되며, 주변의염증세포들을활성화 / 유입시키고활막세포의증식을촉진하여활막염을항진, 지속시킨다 1). 활막에서발현되는여러가지사이토카인중대식세포에서생산되는 TNF-α와 IL-1은상위사이토카인으로서, IL-6, GM-CSF, IL-8, 각종 chemokine 및단백분해효소와같은하위염증매개물의생성을유발하여염증을증폭시키고, 활막세포의증식을항진시켜관절의손상을일으킨다. 최근개발되어사용중인 TNF-α 차단제가류마티스관절염에높은효과를나타냄은사이토카인이 - 2 -

3 - Yeong Wook Song. Updated Pathophysiology of rheumatoid arthritis - Table 1. Current biologic therapies indicated for rheumatoid arthritis Etanercept, infliximab, adalimumab, Anakinra Rituximab Abatacept TNF-alpha inhibitor IL-1 inhibitor B cell ablator Costimulatory T-cell inhibitor 염증지속과활막증식에중요한역할을함을시사한다 17). 류마티스관절의관절파괴즉, 연골과골의파괴기전은다음과같다. 연골의파괴는주로활막내세포들에서만들어지는단백분해효소와기질내로파고드는 pannus의침투로야기된다 18). 한편, 골미란의경우에는 receptor activator of nuclear factor kb (RANK) 와 RANK ligand (RANKL) 체계가중요한역할을담당하는데, T 세포와활막세포에서발현되는 RANKL과파골모세포의 RANK가상호작용하면서파골세포로의분화가촉진된다 19). RANKL의 soluble decoy receptor 인 osteoprotegerin (OPG) 은골의흡수와파골세포의기능을억제한다 20). 그러나 OPG는염증이나연골손상에는큰영향을미치지않는다. 최근 10년간, 류마티스관절염의치료는 methotrexate를근간으로하는기존의질병조정항류마티스약제 (disease modifying anti-rheumatic drug) 들외에생물학적제제들의개발로눈에띠는발전을이루었다 ( 표 1). 그러나일부의환자들은이들생물학적제제의사용에도불구하고, 불완전한반응을보이거나아예반응을보이지않는경우도있다. 이는질병기전에중심적인역할을하는세포나매개물이개개의환자마다차이가있음을시사한다. 앞으로, 질병기전에대해새로운사실들이밝혀지면서, 새로운생물학제제의도입과기존의생물학제제의복합요법이활발해질것으로예상된다. 최근밝혀진류마티스관절염의병인론 1. Th17 T 세포는활막의하층 (sublining layer) 을침윤하는염증세포중많은부분을차지한다. T 세포의활성화와활막으로의이동은류마티스관절염의초기에일어난다. 최근까지활막에존재하는대부분의 T 세포가기억세포의표현형을나타내고, 활막액의사이토카인이 T 세포보다는대식세포에서기인한다고생각되었기때문에관절내염증에기여하는 T 세포의직접적인역할에대해의문이많았던것이사실이다. 그러나흥미롭게도질병초기에유입된 T 세포들의대다수가 IL-17을분비한다는것이최근에밝혀졌다 21, 22). Figure 1. Differentiation and effect of Th17 cells. T17 cells are induced by cytokines including TGF-beta and IL-6 etc, and secrete IL-17. These cells interact with a variety of inflammatory cells like fibroblasts and macrophages in the joints and sustain inflammation and joint distruction

4 - 대한내과학회지 : 제 76 권제 1 호통권제 581 호 IL-17을분비하는 T 세포군은최근에새롭게인식된세포집단으로서종래의 Th1과 Th2와는다른분화기전으로생성되며, 기존의 Th1, Th2 사이토카인과는다른 IL-17을분비한다 ( 그림 1) 23). IL-17은관절내세포들 ( 대식세포, 활막세포, 연골세포 ) 로부터 TNF-α와 IL-1 같은주요사이토카인들과 IL-6, IL-8, 단백분해효소등의분비를유도하여염증반응을항진시키고, RANKL 발현을촉진하여파골세포의분화를유도한다. 또한급성관절염을만성화시키는역할을할뿐아니라 24), 기존의사이토카인들 (TNF-α, IL-1) 과상승작용을통하여염증반응을더욱심화시킴이밝혀졌다 25). 이러한사실들은 IL-17 이초기류마티스관절염에작용하여질환을만성화시킬뿐아니라, 중요한염증매개체역할을함을시사한다. IL-17의발견과그에연관된연구들은앞으로초기류마티스관절염에서작용하는세포와사이토카인들을밝히는데도움이될것이다. 2. 항사이클릭시트룰린화펩타이드항체 (anti-cyclic citrullinated peptide antibody, 항 CCP 항체 ) 류마티스관절염에서발견되는자가항체중에, 류마티스인자와항 CCP 항체가가장임상적으로의미가있다. 이들항체는류마티스관절염환자의약 60~70% 에서관찰되며, 진단과예후판정에유용하다. 최근의연구에서항 CCP 항체를가진 50% 의환자에서시트룰린화펩타이드를포함한면역복합체가환자의혈청과 pannus에침착됨이밝혀졌고, 조직내에서이들면역복합체와 C3가동일부위에존재함이밝혀져항 CCP 항체를포함한면역복합체가보체를고정및활성화시키고, 보체활성화를통해면역세포의소집과활성화가이루어짐을시사하였다 26). 한편, 시트룰린화효소는세포가사멸하는과정에서유출된다. 특히, 과립구와대식세포는이들효소를가지고있다. 염증반응중생성되는이들세포들의사멸로시트룰린화효소가세포외로유출되고, 관절내기질단백들이시트룰린화된다고생각된다 27). 항원전달세포의 HLA를통해시트룰린화된단백들을항원전달할수있는유전적소인을가진사람들은항 CCP 항체를생성하게되고, 이들항체에의해면역복합체가생성되면보체활성화를통해염증반응이지속된다. 더욱이, 시트룰린화된피브리노겐이 DR4-IE 유전자를가진쥐에서관절염을유발시킴이보고되어서 28), 단백의시트룰린화와적절한유적적소인이있을경우, 관절염의지속단계뿐아니라, 촉발단계에도 관여할수있음이밝혀졌다. 3. 류마티스관절염에서 IL-6 의역할 Il-6는류마티스활막조직과활막액에서발현이증가되어있는사이토카인들중하나이다. IL-6는인체내의다양한세포들에의해생성되며, 그생물학적작용도광범위하다. IL-6의향염증작용 (pro-inflammatory effect) 은 T 세포의증식과활성화및 B 세포의분화를통해일어난다. 또한, 조혈모세포의분화와증식을일으키고, 파골세포를활성화시킨다. 이와같은 IL-6의작용은류마티스관절염에서나타나는다음과같은소견들에서잘확인할수있다. 류마티스관절염의질병활성도를반영하는혈소판증가증, 감마글로불린증가증, C-반응단백수치와적혈구침강속도의상승등은혈청과활막액의 IL-6 수치와양의상관관계를보이며, 전신적인골감소증과관절주변의골감소증은골수의 IL-6 수치와비례한다 29-31). 더욱이이러한소견들은 IL-6가질환에밀접히관련되어있음을나타낸다. 류마티스관절염에서 IL-6의차단에의한치료효과는항 IL-6 수용체항체를사용한두개의 2상연구와한개의 3상연구에서이미확인된바있다 32-34). 4. 관절염과골파괴의양분론앞서밝힌류마티스관절염의전통적인병인론에따르면, 염증과관절파괴는동일선상에위치한다. 그러나현실적으로류마티스관절염의질병활성도 (disease activity) 와관절손상정도는일치하지않는다. 더욱이, 임상적으로관해가유지된환자들의일부에서는지속적인관절파괴가진행된다 35). 이러한관찰에근거하여, 류마티스관절염의병태생리에는두가지독립적인기전이존재한다는주장이대두되었다 36). 즉활막의염증과활막의증식이그것이다. 전자는관절의종창, 통증, 그리고연골손실을가져오고, 후자는종창과골파괴를가져온다. 이주장에따르면, 두가지기전중어느한가지만을목표로하여치료하게되면, 관절의염증과관절파괴의치료반응이확연히분리되어나타나므로앞서기술한바와같이임상적관해에도불구하고관절파괴가지속되는현상이일어난다. 그러나관절의염증과파괴를하나의기전으로이해하는기존병인론에의하면, 관절염과관절파괴의이분적인현상은임상적관해로판정받은경우에도낮은정도의염증이지속될수있기때문에나타나는것으로설명되고있다 37). 즉, 임상적으로관해판정을받았다하더라도, MRI 나초음 - 4 -

5 - 송영욱. 최근조명된류마티스관절염의병태생리 - 파검사를통해약하지만지속적인염증이있는것을확인할수있고, 이런무증상염증이있는환자들의경우관절파괴가진행될가능성이높다는것이밝혀진바있다 38). 그러나임상적관해를판정받은환자의 80% 에서관절파괴의진행이없었기때문에임상적소견으로관해를판정하는것이아직까지는적절하다고여겨지며, 질환의초기에복합요법으로신속한관해를이루는것이관절기능을보존하는주효한치료전략이다. 중심단어 : 류마티스관절염 ; 활막 ; 염증 REFERENCES 1) Lee DM, Weinblatt ME. Rheumatoid arthritis Lancet 358: , ) Gay S, Koopman WJ. Immunopathology of rheumatoid arthritis. Curr Opin Rheumatol 1:8-14, ) FitzGerald O, Soden M, Yanni G, Robinson R, Bresnihan B. Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected knee joints of patients with rheumatoid arthritis. Ann Rheum Dis 50: , ) Jackson JR, Minton JA, Ho ML, Wei N, Winkler JD. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 24: , ) Girard JP, Springer TA. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today 16: , ) Shiozawa S, Shiozawa K, Fujita T. Morphologic observations in the early phase of the cartilage-pannus junction. Light and electron microscopic studies of active cellular pannus. Arthritis Rheum 26: , ) Aho K, Koskenvuo M, Tuominen J, Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 13: , ) Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 32: , ) MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30-37, ) Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A 86: , ) Rønningen KS, Spurkland A, Egeland T, Iwe T, Munthe E, Vartdal F, Thorsby E. Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues Tissue Antigens 36: , ) Hong G, Park MH, Takeuchi F, Oh MD, Song YW, Nabeta H, Nakano K, Ito K and Park KS. Association of specific amino acid sequence of HLA-DR with rheumatoid arthritis in Koreans and its diagnostic value. J Rheumatol 23: , ) Holborow EJ. The relationship of autoimmunity to rheumatoid arthritis. Proc R Soc Med 57:59-62, ) Nykänen P, Bergroth V, Raunio P, Nordström D, Konttinen YT. Phenotypic characterization of 3H-thymidine incorporating cells in rheumatoid arthritis synovial membrane. Rheumatol Int 6: , ) Kohem CL, Brezinschek RI, Wisbey H, Tortorella C, Lipsky PE, Oppenheimer-Marks N. Enrichment of differentiated CD45RBdim,CD27- memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 39: , ) Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: , ) Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 370: , ) Firestein G.S. Invasive fibroblast-like synoviocytes in rheumatoid arthritis: Passive responders or transformed aggressors? Arthritis Rheum 39: , ) Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim KJ, Saito S, Nishikawa T, Takahashi N, Togari A, Tomatsu T, Suda T, Kamatani N. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 44: , ) Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89: , ) Aarvak T, Chabaud M, Miossec P, Natvig JB. IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol 162: , ) Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid - 5 -

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract