Journal of Rheumatic Diseases Vol. 22, No. 4, August, 2015 http://dx.doi.org/10.4078/jrd.2015.22.4.213 Review Article Immunoglobulin G4 연관질환 문수진ㆍ민준기 가톨릭대학교의과대학내과학교실류마티스내과 Immunoglobulin G4-Related Disease Su-Jin Moon, Jun-Ki Min Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, Korea Immunoglobulin G4-related disease (IgG4-RD) is an emerging immune-mediated fibro-inflammatory disorder which can involve any organ. The main characteristics of IgG4-RD are increased serum IgG4 concentration, abundant IgG4+ plasma cells in affected tissues, and painless swollen organs often without general symptoms. Typical pathology features of IgG4-RD are lymphoplasmacytic infiltration, dense storiform fibrosis, and obliterative pheblitis. The pathogenesis of IgG4-RD remains elusive, but involvement of excess production of type 2 T helper cells, regulatory T-cell cytokines, and B-cell activating factor in the development of IgG4-RD has been suggested. Diagnosis of IgG4-RD can be made on the basis of serological, imaging, particularly histopathological findings. Glucocorticoid is the first-line therapy for patients with multiple organ dysfunction and clinical symptoms. Drugs such as azathioprine, mycophenolate mofetil, methotrexate, and cyclophosphamide can be used as steroid-sparing agents. Rituximab is reported to be an effective therapy for treatment of IgG4-RD, even without concomitant glucocorticoid therapy. This review summarizes current concepts on pathophysiology, clinical manifestations, and treatment of IgG4-RD. (J Rheum Dis 2015;22:213-222) Key Words. Immunoglobulin G4-related disease, Physiopathology, Clinical manifestations, Therapy 서론 Immunoglobulin G4 연관질환 (immunoglobulin G4 related disease, IgG4-RD) 은혈청 IgG4 상승, IgG4 양성형질세포및림프구침윤, 섬유화를특징으로하는질환이다 [1]. IgG4 연관질환은비교적최근에알려진질환으로 2001년 Hamano 등 [2] 은자가면역췌장염환자혈청에서 IgG4가상승되어있으며 IgG4 양성형질세포가많이침윤되었음을관찰하고경화성췌장염으로보고하였고, 2003 년 Kamisawa 등 [3] 은이질환을 IgG4 연관자가면역질환으로명명하였다. 2012년국제다학제연구모임 (Inter- National Multidisciplinary Study Group) 에서 IgG4 연관 질환이라는명칭이제시되어현재사용되고있으며다양한장기에서 IgG4 연관질환이보고되고있다 [4]. IgG4 연관질환의발병기전은아직정확히규명되지않았지만, type 2 helper T (Th2) 세포와조절 T (regulatory T, Treg) 세포로부터나오는사이토카인이질병발생에관련된다고알려진자가면역질환의일종이다 [1]. 대부분의 IgG4 연관질환은스테로이드에좋은치료반응을보이지만스테로이드사용량을줄이면서재발하거나, 스테로이드에대한반응이충분치않을경우에는 azathioprine, cyclosporine, methotrexate와같은면역억제제의사용이효과적일수있다 [1]. 특히 MIkulicz 병처럼일부 IgG4 연관질환은류마티스질환과비슷한임상증상을나타내는경우가있으 Received:July 9, 2015, Revised:July 11, 2015, Accepted:July 13, 2015 Corresponding to:jun-ki Min, Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. E-mail:min6403@catholic.ac.kr pissn: 2093-940X, eissn: 2233-4718 Copyright c 2015 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited. 213
Su-Jin Moon and Jun-Ki Min 므로류마티스전문의는 IgG4 연관질환에대한이해가필요하다. 따라서본종설에서는최근에발표된문헌들을바탕으로 IgG4 연관질환의병태생리, 임상증상, 치료법에대하여정리하고자한다. 본 역학 IgG4 연관질환의유병률은잘알려져있지않으나일본인을대상으로한연구에서 IgG4 연관질환이 100,000명당 0.28 1.02명이발생한다고보고된바있다 [5]. IgG4 연관질환은일반적으로중년과노년남성에서주로발생한다고알려져있지만, 발생성비는발병장기에따라달라제1형자가면역췌장염, 후복막섬유증, IgG4 연관세뇨관간질신염은주로남성에서발병하고, IgG4 연관타액선염, IgG4 연관안질환의발생빈도는남녀사이에차이가없다 [6]. 병태생리 1) T 세포 론 IgG4 연관질환의병변에서는 interleukin (IL)-4, IL-5, IL-13과같은 Th2 사이토카인발현이 Th1 사이토카인에비해증가되어있고, IL-10과 transforming growth factors (TGF)-β를생산하는조절 T 세포가관찰된다 [7]. IL-13 과 TGF-β는섬유화와관련이있으며, IL-4와 IL-10은 IgG4 클래스전환 (class switch) 에관여한다 [8,9]. 이러한연구결과들은 IgG4 연관질환이 CD4+ T 세포가 Th2/Treg 으로편향된질병일것임을시사한다. 하지만현재로서는이를증명하는직접적근거가부족한상태로, T 세포측면에서 IgG4 연관질환의병태생리에대한연구가필요하다. 흥미롭게도최근 IgG4 연관질환에서여포협력 2형 T (CXCR3 CCR6 T follicular helper 2) 세포가증가되어있고, IgG4, IL-4, 형질모세포의증가및이소성배중심 (ectopoic germinal center) 형성이병인과관련되어있음이보고되었다 [10,11]. 2) B 세포 IgG4 연관질환에서성숙 B 세포와 CD19+CD24hiCD38hi 조절 B (regulatory B) 세포수가일차성쇼그렌증후군또는정상인에비해적고, 기억 B 세포와 CD19+CD24-CD38hi B 세포수는 IgG4 연관질환에서일차성쇼그렌증후군또는정상인에비해많다 [12]. B 세포표면의 B-cell activating factor (BAFF) 수용체발현은정상인과일차성쇼그렌증후군보다적고 B-cell maturation antigen, transmembrane activator and calcium modulator는정상인과일차성쇼그렌증후군환자에비교하여차이가없다 [12]. 한편 IgG4 연관질환환자의혈청 BAFF 농도는정상인에비해높지만일차성쇼그렌증후군환자와는차이가없다 [12]. Sellam 등 [13] 은만성적인 BAFF 상승이전사후조절 (post-transcriptional regulation) 을통해 B 세포의 BAFF 수용체발현을감소시킨다고보고한바있다. IgG4 연관질환에서 B 세포표면의 CD40 발현이일차성쇼그렌증후군또는정상인에비해적다고보고되었는데이는 CD40L/ CD40을통한조절 B 세포로의분화를감소시켰을것으로해석된다 [12]. CD40과는달리, IgG4 연관질환에서 B 세포의 CD80과 CD86의발현은일차성쇼그렌증후군또는정상인에비해증가되어있는데이는 CD23/CD21 상호작용을촉진하여 IgG4와 IgE 생성을증가시키는데관여할것으로예상된다 [12]. Wallace 등 [14] 은 IgG4 연관질환에서순환하는형질모세포 (CD19lowCD20 CD38+CD27+) 가혈청 IgG4가정상인환자에서도증가되어있고, 질환치료이후에감소함을보고하고혈액내형질모세포가 IgG4 연관질환의질병활성도를반영하는지표가될수있을것으로주장된다. 3) 대식세포대식세포는 Th1 반응에의해유도되는전통적대식세포인 M1 대식세포와 Th2 반응에의해서분비되는 IL-4, IL-10 또는조절 T 세포로부터만들어지는 IL-10에의해유도되는 M2 대식세포로분류된다 [15]. M2 대식세포는 Th2 면역반응을증강시키고 IL-10, IL-13, Chemokine (C-C motif) ligand 18 (CCL18) 과같은섬유화를촉진시키는사이토카인을분비한다 [15]. Furukawa 등 [16] 은 MIkulicz 병환자의턱밑타액선의 M2 대식세포수가일차성쇼그렌증후군환자및정상인에비해증가되어있고섬유화정도와비례하며 IL-10과 CCL18이 M2 대식세포와같은위치에서관찰된다고보고하였다. 단핵세포의 nucleotidebinding oligomerization-like receptor2 (NOD2) 를활성화시키면 BAFF를생성하고 BAFF에의해 B 세포가 IgG4를만들게된다. Watanabe 등 [17] 은 IgG4 연관제1형자가면역췌장염환자의혈액에서얻은단핵세포가정상인에비해 NOD2를통한 IgG4를더많이생산한다고주장하였다. 4) 호산구조직내호산구침윤은 IgG4 연관질환의특징적인조직소견이며 IgG4 연관질환환자의약 30% 정도에서호산구증가증이관찰된다 [1]. 활성화된호산구는호산구량이온단백 (eosinophil cationic protein) 을통한콜라겐수축, TGF-β, IL-1β 생성을통한섬유화유도, T 세포로의항원제시증가를통해 IgG 연관질환발병에관여하는것으로알려져있다 [18,19]. 5) 호염구호염구는 Th2 반응에서항원제시세포역할을한다. 호염구 toll-유사수용체 (toll like receptor) 를자극하면 BAFF, IL-13이합성되고, 이는 B 세포에작용하여 IgG4를생성 214 J Rheum Dis Vol. 22, No. 4, August, 2015
Immunoglobulin G4-Related Disease 한다. 또한 IgG4 연관질환환자의호염구는정상인에비해호염구 toll-유사수용체자극에의해좀더많은양의 IgG4를만든다 [20]. IgG4 연관질환에서 IgG4의역할면역글로불린분자는동일한두개의중쇄 (heavy chain) 와경쇄 (light chain) 로이루어져있어하나의항체분자는두개의동일한항원결합부위를가지고있기때문에두개의동일한구조에동시에결합할수있다. 두개의중쇄는경첩 (hinge) 부위에서이황화결합 (disulfide bond) 들로구성되어있고각각의중쇄는각각의경쇄와이황화결합으로연결되어있다. IgG4는중쇄사이의이황화결합이없고중쇄내부에서이황화결합이형성되어있다 (Figure 1). 이로인해항원결합부위 (Fab-arm) 교환이이루어져두개의다른항원결합부위가만들어지고이는항원과의교차결합과면역복합체형성을감소시킨다 [1]. IgG4는 IgG 아형중가장적게존재하며 Fc 수용체와보체 C1에대해친화력이낮아탐식세포활성화, 항체의존성세포독성 (antibody-dependent cellular cytotoxicity), 보체를통한조직손상과같은면역반응을일으키는능력이다른 IgG 아형보다떨어진다 (Table 1)[21]. 이러한이유들로 IgG4 는면역반응을유발하거나악화시키기보다는오히려완화시키는역할을할것으로생각되어왔다. 이러한주장은 IgG4가관용유도를통한알러지질환치료를한경우에생성되고 IgG4가차단항체로작용하여비만세포표면에있는 IgE에항원이붙는것을억제함으로써알러지질병발생을억제할수있다는연구결과를뒷받침해준다 [22]. Nouri-Aria 등 [23] 은조절 T 세포에의해만들어지는 IL-10이 IgG4 생성을유도하고 IgG4가면역반응을억제하는작용을나타낼수있다고보고한바있다. 그럼에도불구하고 IgG4가질병의발생에관여함을시사하는다음과같은소견들이있다. 혈청 IgG4와질병활성도사이에서관찰되는상관관계 [1], IgG4 연관질환환자의약 50% 70% 에서보체감소 [24], 제1형자가면역췌장염, IgG4 연관세뇨관간질신염기저막에서 C3, IgG4 침착 [25,26], IgG4가중성구표면에있는 Fc-gamma 수용체활성화를 Figure 1. immunoglobulin G (IgG)4 Fab-arm exchange makes bispecific antibodies. The heavy chains of IgG are bound to each other by interchain disulfide bridge. As the disulfide bonds between heavy chains of IgG4 are unstable, IgG4 easily forms intrachain disulfide bonds in the hinge region. Intrachain disulfide bond of IgG4 is linked by noncovalent interaction. When the non-convalent bonds dissociate, half of one IgG4 molecule (a heavy chain-light chain pair) and half of another IgG4 molecule exchange randomly, forming a Fab-arm exchange. Through such processes, the IgG4 molecule becomes bispecific by acquiring two Fab-arms with different epitope specificity. This bispecific IgG4 molecule, however, loses its ability to form immune complexes as the molecules cannot crosslink antigens. Table 1. Characteristics of IgG isotypes Characteristic IgG1 IgG2 IgG3 IgG4 Serum concentration (mg/dl) 5 11 1.5 6 0.2 1 0.08 1.4 Complement fixation +++ + +++ Activating FcγR binding ++ + ++ ++ FcγR: Fc-gamma receptors, IgG: immunoglobulin G. www.jrd.or.kr 215
Su-Jin Moon and Jun-Ki Min 통한 항호중구 세포질항체(antineutrophil cytoplasmic 염 등의 소견이 관찰되면 IgG4 연관 질환의 가능성은 떨 antibodies) 연관 혈관염 발생에 관여[27], 보통천포창 어진다[31]. (pemphigus vulgaris)의 질병 활성도와 desmoglein3에 대 한 IgG4의 비례 관계[28], ADAMTS13에 대한 IgG4가 혈 1) 림프형질세포 침윤 전성 혈소판감소성 자반증(thrombotic thrombocytopenic 주로 작은 림프구가 병변 전반에 걸쳐 분포하면서 곳곳 purpura) 발병과 관련이 있는 점 등이다[29]. IgG4가 보체 에 형질세포가 섞여있다(Figure 2A). 주로 침윤된 림프구 고전 경로를 활성화시키지 못하지만 렉틴(lectin) 경로를 는 T 세포이고 B 세포는 군집을 이루거나 가끔 배중심이 활성화시키거나 또는 보체와 결합하는 능력이 큰 IgG1 상 관찰된다. IgG4 연관 질환을 진단하기 위해서는 IgG4+ 형 승에 의해 IgG4 연관 질환에서 보체가 감소하는 것으로 질세포 침윤이 관찰되어야 하며 IgG4+/IgG 형질세포 비 해석되고 있다[8]. 이와 같이 IgG4 연관 질환에서 IgG4의 율이 진단에 중요하다(Figure 2D and 2E). IgG4+ 형질세 역할에 대해 상반되는 연구 결과가 있으므로 앞으로 이에 포는 IgG4 연관 질환에서뿐만 아니라 염증성 질환, 종양, 대한 연구가 필요하다. 감염질환 등에서도 관찰되기 때문에 면역조직화학 염색에 서 IgG4+ 형질세포 관찰만으로 IgG4 연관 질환을 진단할 조직병리 소견 수 없다[30]. IgG4 연관 질환의 중요한 조직병리 소견으로는 림프형질 세포 침윤, 많은 수의 IgG4 양성 형질세포 침윤, 나선형 2) 나선형 섬유화 섬유화(storiform fibrosis), 폐쇄성 정맥염(obliterative- 나선형 섬유화는 콜라겐 다발이 나선형으로 불규칙하게 pheblitis,), 경도 또는 중증도의 호산구 침윤 등이다[30]. 배열된 것으로 Ig4 연관 질환 대부분에서 관찰되지만 림프 이외에 배중심(germinal center), 림프여포(lymphoid fol- 절이나 눈물샘을 침범하는 경우에는 관찰되지 않는 경우 licle), 비폐쇄성 정맥염, 폐쇄성 동맥염 등의 소견이 관찰 가 많다(Figure 2B). IgG4 연관 질환 초기 조직에선 섬유 되기도 한다[30]. 중성 백혈구, 육아종(granuloma), 호중 모세포와 근섬유모세포에 의해 콜라겐 침착이 일어나지 성구 미세농양(neutrophilic mcicroabscess), 괴사성 혈관 만, 질병이 지속되면 섬유모세포가 주를 이룬다. 나선형 Figure 2. Histological and immunohistochemical findings of biopsy specimens of the lymph node (A) and submandibular gland (B E). (A) The germinal centersare predominantly composed of small lymphocytes, centrocytes, centroblasts, and numerous mature plasma cells (H&E, 200). (B) The storiform pattern of fibrosis is present, indicating dense fibrosis within which lymphocytes, plasma cells, and occasional eosinophils are embedded (H&E, 100). (C) Veins occluded by inflammatory infiltrate composed of lymphocytes and plasma cells are noted (arrowheads) (H&E, 200). (D, E) The IgG4+/IgG+ plasma cell ratio is estimated at 90%. D: Immunoglobulin (Ig) G-immunohistochemical stain, E: IgG4-immunohistochemical stain; 100. 216 J Rheum Dis Vol. 22, No. 4, August, 2015
Immunoglobulin G4-Related Disease 섬유화는띄엄띄엄존재하기때문에침생검 (needle biopsy) 을시행할경우나선형섬유화가관찰되지않을수있다 [31]. 3) 폐쇄성정맥염정맥이림프형질세포침윤에의해폐쇄가일어날수있으며림프구와형질세포가정맥벽또는혈관내부에서관찰된다 (Figure 2C). 중간크기의정맥이폐쇄되면대부분인근동맥에도병변이관찰이되는데정맥에비해염증변화가작다. 폐쇄성동맥염도 IgG4 연관질환중폐나췌장을침범한경우관찰되기도한다. 육아종증다발혈관염 (granulomatosis with polyangiitis), 현미경다발혈관염 (microscopic polyangiitis), 결절다발동맥염 (polyarteritis nodosa) 등과같은전신혈관염에서관찰되는혈관벽괴사나섬유소침착은 IgG4 연관질환의조직병리소견이아니다 [31]. 4) 호산구침윤 IgG4 연관질환환자의약 50% 정도에서호산구침윤이있으며안구또는상기도를침범할경우호산구침윤이주된조직생검소견인경우가있다 [32]. 임상증상 IgG4 연관질환은대부분의장기를침범할수있으며이에따른증상과함께체중감소, 피곤함, 관절통증과같은전신증상을나타내기도한다. 1) 췌장 췌장은 IgG4 연관질환이처음으로알려지게된장기이며 IgG4 연관질환으로가장많이보고된장기다 [3]. 자가면역췌장염은제1형과제2형으로분류되는데제1형자가면역췌장염은 IgG4와연관된질병으로림프형질세포가주로침윤되나제2형자가면역췌장염에서는중성구가췌도상피세포쪽으로침윤된다 [33]. 제1형자가면역췌장염은주로남자에서발생하며초기증상은주로동반된경화담관염에의한황달이며이외에복통, 요통, 체중감소, 2차성당뇨병, 지방변이동반하기도한다 [34]. 대부분의제1 형자가면역췌장염환자에서 IgG4가증가하며질병활성도와관련이있지만제2형자가면역췌장염에서는 IgG4의상승이흔하지않다 [2]. 췌장암환자의 4% 10% 에서도혈액내 IgG4가상승되어있다는보고가있어해석에주의가필요하다 [35]. 제1형자가면역췌장염은담관, 타액선, 신장, 후복막등과같은장기침범이흔하며제2형자가면역췌장염에서는이러한장기의침범은없으나궤양성대장염이잘동반된다 [36]. 스테로이드에대한반응은제 1형과제2형자가면역성췌장염에서서로차이가없는것으로알려져있다 [36]. 자가면역췌장염의특징적인컴퓨터단층촬영의소견은췌장의미만성종대, 저음영띠가췌 장가장자리에관찰되는것 (low density-rim), 균일한조영증강 (homogeneous enhancement) 등이다 [34]. 내시경적역행성담췌관조영술 (endoscopic retrograde cholangiopancreatography) 또는자기공명담췌관조영술 (magnetic resonance cholangio-pancreatography) 을통한자가면역췌장염의췌관에대한영상소견으로는주췌관의긴협착 ( 전체주췌관길이의 1/3 이상또는 3 cm 이상 ), 협착상류주췌관의확장의부재 ( 주췌관의직경이 5 mm 이하 ), 다발성주췌관협착등이다 [37]. 2) 타액선주타액선과소타액선모두 IgG4 연관질환이발생하며주타액선중턱밑샘이가장흔히침범되고혀밑샘이가장드물게침범된다 [38]. 대칭적인눈물샘염과귀밑침샘또는턱밑침샘종대를특징으로하는 Mikulicz 병은쇼그렌증후군의아형으로알려져왔으나최근에 IgG4 연관질환임이밝혀졌다 [39]. 쇼그렌증후군에비해 Mikulicz 병은입마름증상이덜심하고쇼그렌증후군과는달리스테로이드로치료하면증상이호전될수있다 [40]. 주타액선중주로턱밑샘의편측또는양측의단단한종창을특징으로하고 Kuttner 종양으로도알려진만성경화성타액선염또한 IgG4 연관질환으로알려져있다 [41]. IgG4 연관된침샘염은림프종과의감별이필요하다 [42]. 3) 림프절 IgG4 연관질환과관련된림프절침범은단독적으로나타나거나또는 IgG4 연관질환에서침범된장기주변에서발생한다. IgG4 연관림프절병증은조직학적다양성을나타내는데각각의특성에따라 multicentric Castleman disease-like, reactive follicular hyperplasia-like, interfollicular hyperplasia-like, progressively transformed germinal centers (PTGC)-type, inflammatory pseudotumor-like의다섯가지유형으로나뉠수있다 [43]. 다른네가지아형의 IgG4 림프절병증의경우 IgG4 양성형질세포가여포세포사이 (interfollicular) 에서관찰되는반면에 PTGC-type IgG4 림프절병증의경우 IgG4 양성형질세포가배아중심내 (intragerminal center) 에나타나는것이특징이다 [44]. IgG4 연관병증환자에서림프종의발현이보고되기도하는데, 특히 PTGC는결절림프구우세호지킨병 (nodular lymphocyte predominant Hodgkin lymphoma) 의발생과관련이있다 [45,46]. 이는 IgG4 연관병증에서림프구의활성과증식그리고만성적인항원자극이림프종의발병위험성을증가시킬수도있음을시사한다. IgG4 연관림프절질환에서는다른장기와달리나선형섬유화, 폐쇄성정맥염등의조직소견이흔하지않다 [47]. 4) 신장 IgG 연관신장질환은주로남성에서발생하며대부분 www.jrd.or.kr 217
Su-Jin Moon and Jun-Ki Min 다른장기의 IgG4 연관질환을동반한다. IgG4 연관신장질환에서는다클론성고감마글로불린혈증, IgG와 IgG4의상승, 혈청보체감소, IgE 증가등이특징적으로나타난다 [48]. IgG4 연관신장질환중세뇨관간질신염이가장흔하며이외에막성콩팥병증, IgA 콩팥병, 국소성분절성증식사구체신염 (focal and segmental proliferative glomerulonephritis), 막증식사구체신염, 혈관간세포질증식사구체신염등이발생한다 [49]. IgG4 연관세뇨관간질신염진단에가장도움이되는방사선검사는조영제증강컴퓨터단층촬영이며다발저밀도음영병변이가장흔한소견으로약 65% 의환자에서관찰되고전반적인신장크기증가가 20% 30% 의환자에서나타난다 [50]. IgG4 연관세뇨관간질신염에서특징적인병리소견은둥지모양 (nest) 의염증세포들을섬유 (fiber) 가불규칙하게둘러싸는것이다 (bird s-eye fibrosis) [51]. 특발성막성콩팥병증에서는 M type phospholipase A2 수용체에대한 IgG4 자가항체가관찰되지만 IgG4 연관질환에서는이항체가관찰되지않는다 [52]. 5) 안와눈물샘종대 (dacroadenitis) 에의한안검부종, 외안근침범으로인한안검하수등의증상이발생할수있다. 드물게공막염, 비루관폐색, 황색육아종, 주변골파괴 3차신경분지압박등이발생하기도한다. 감별해야할질환으로는육아종증다발혈관염, 유육종증, 쇼그렌증후군, 림프종등이있다 [53]. 폐실질이침범되면원형혼탁 (round opacities) 이나간질성폐질환의양상을주로나타내며각각악성종양과비특이적간질성폐렴과의감별진단이필요하다 [59]. IgG4 연관질환에의한늑막질환은늑막결절, 늑막삼출로나타난다. 종격동병변으로는림프절종대가가장흔하고이외에종격동결절, 섬유화종격동염이발생한다 [58]. 9) 대동맥, 관상동맥 IgG4 연관질환에서흉대동맥이침범되면대동맥확장, 동맥류, 대동맥박리등의형태로나타난다 [60]. 대동맥파열로인해급사하는경우가있으며관상동맥침범도드물게보고된바있다 [61]. 거대세포동맥염, 타카야수동맥염과달리쇄골하동맥은침범하지않는다 [62]. 10) 만성대동맥주위염 (chronic periaortitis) IgG4 연관만성대동맥주위염에는 IgG4 연관후복막섬유증 (retroperitoneal fibrosis), IgG4 연관복부대동맥염 (abdominal aortitis), IgG4 연관동맥류주변섬유화 (perianeurysmal fibrosis) 등이있다 [63]. 특발성후복막섬유증환자의약 2/3 정도가 IgG4 연관질환에의한것으로밝혀졌다 [64]. IgG4 연관후복막섬유증에서는신장, 요로등을침범하기도하며요로폐색을동반한수신증이흔히발생한다 [65]. 특발성만성대동맥주위염에비해 IgG4 연관만성동맥주위염에서는혈청 IgG4가상승하고, 남자에서주로발생하며, 다양한장기침범, 동맥벽의칼슘침착등이좀더흔하다 [66]. 6) 귀, 코, 인후가피형성, 콧물, 후비루등의증상이발생하며알러지비염또는부비동염으로오인되는경우가많아조직생검을통한감별진단이필요하다 [54]. 인두, 하인두, 발데이어링 (Waldeyer s ring) 을침범하여종괴를형성하기도한다. 드물게청력감소, 중이염등이보고된바있다 [55]. 7) 갑상샘리델갑상샘염 (Riedel s thyroiditis) 과섬유화하시모토갑상샘염이대표적인 IgG4 연관갑상샘질환이다. 하시모토갑상샘염환자의일부는 IgG4 연관질환의형태로나타난다 [56]. IgG4 연관갑상샘염환자는 IgG4와관련성이없는갑상샘염환자에비해갑상샘글로불린 (thyroglobulin), 갑상샘과산화효소 (thyroid peroxidase) 에대한자가항체양성률이높다 [57]. 8) 폐, 늑막, 종격동 IgG4 연관질환의일환으로기도, 폐실질, 늑막, 종격동에병변이발생할수있다. 기도에병변이발생하면컴퓨터단층촬영에서기관지혈관분지가두꺼워지는특징적인소견을나타낸다 [58]. 11) 담도와담낭경화담관염 (sclerosing cholangitis) 은자가면역췌장염과밀접한관련이있어경화담관염환자의약 83% 에서자가면역췌장염을동반하고자가면역췌장염환자의약 40% 에서 IgG4 연관경화담관염을동반한다는보고가있다 [67]. IgG4 연관경화담관염은조직검사를통해일차성경화담관염및폐문음염담관암 (hilar cholangiocarcinoma) 과의감별진단이필요하다 [62]. IgG4 연관경화담관염또는자가면역췌장염환자중 50% 이상에서담낭벽에림프형질세포침윤이관찰된다 [68]. IgG4 연관담낭염의경우영상검사에서담낭벽이두꺼워져있으며대부분무증상이다 [67]. 12) 신경계뇌와척수의경막 (dura mater) 에발생하는비대경수막염 (hypertrophic pachymeningitis) 의일부가 IgG4 연관질환으로보고되고있다 [69]. IgG4 연관질환에의해형성된종괴에의해뇌신경이눌려이에따른증상이발생할수있다. 예를들면 IgG4 연관질환으로발생한안구종양에의한시신경또는삼차신경압박, 비대경수막염에의한안면신경 (facial nerve), 내이신경 (vestibulocochelar nerve), 218 J Rheum Dis Vol. 22, No. 4, August, 2015
Immunoglobulin G4-Related Disease 설인신경 (glossopharyngeal nerve), 미주신경 (vagus nerve). 설하신경 (hypoglossal nerve) 압박증상이나타날수있다 [67]. 드물게뇌하수체에 IgG4 연관질환이발생하여뇌하수체저하증또는요붕증이발병할수있다 [70]. 진단조직생검이진단에가장중요하다. IgG4 연관질환의방사선소견은대부분비특이적인소견을나타내지만제1형자가면역췌장염진단에는방사선소견이매우유용하다 [2]. 현재다양한진단기준이제시되고있다 [71]. 1) 포괄적인 IgG4 연관질환의임상진단기준 [72] (1) 장기침범 : 미만성 / 국소성종창또는종괴 (2) 혈액검사 : 혈청 IgG4>135 mg/dl (3) 조직병리소견 1 림프형질세포침윤과섬유화 2 IgG4 양성형질세포침윤 : IgG4/IgG 비율 0.4 이상그리고고배율에서 IgG4 양성세포가 10개이상관찰 Definite ( 확실한 ): (1)+(2)+(3) Probable ( 가능성높은 ): (1)+(3) Possible ( 가능성있는 ): (1)+(2) 이진단기준에의해 IgG4 연관질환으로진단되지않더라도각장기에특이적인 IgG4 연관질환진단기준을만족한다면 IgG4 연관질환으로진단될수있다 ( 예 : IgG4- Mikulicz 병, IgG4-자가면역췌장염, IgG4-신질환 ). IgG4 연관질환진단에있어서혈청 IgG4 상승 (IgG4 >135 mg/dl) 의민감도는 67% 95%, 특이도는 90% 97% 로알려져있다 [73]. 혈청 IgG4 상승은정상인의약 5% 와췌장암, 양성췌장종양, 췌장염, 아토피피부염, 보통천포창, 항호중구세포질항체연관전신혈관염, 저보체혈증두드러기혈관염 (hypocomplementemic vasculitis) 등에서도혈청 IgG4 상승이보고된바있다 [74]. 혈청 IgG4 상승이미비한경우에 IgG4/ 총 IgG 상승 (>10%) 이 IgG4 연관질환진단에특이적이라는연구결과가있다 [75]. 최근 IgG4 연관질환에서혈액내형질모세포증가가혈청 IgG4 상승보다좀더유용한생물학지표가될수있다는보고가있다 [14]. 우선감별해야할질환으로종양이있으며캐슬만병, 유육종증, 림프종, 육아종증다발혈관염등과감별이필요한경우가있다 [72]. 치료 IgG4 연관질환환자중일부는치료없이저절로좋아지기도한다 [76]. 눈물샘또는타액선이단독으로침범된 IgG4 연관질환은치료없이경과를관찰할수있지만주요장기가침범된경우에는조기에치료를시작하는것이필요하다. 치료가늦어질수록섬유화가진행되어치료효과가좋지않을수있다. 담도나요관협착으로인해응급 으로감압이필요한경우에는일시적인스텐트삽입이나수술을고려해야한다 [11]. 대부분의 IgG4 연관질환치료에우선적으로스테로이드 (prednisolone 40 mg/d 또는 0.6 mg/kg/d) 가사용되며신체검사, 혈액검사, 방사선검사소견등을종합하여서서히감량한다 [77]. IgG4 연관질환은스테로이드에대한반응이좋기때문에스테로이드사용약 2주후에혈액검사를하는것이좋고췌장, 담도, 폐, 신장이침범된경우에는 2 4주후에방사선검사를시행하여치료에대한반응을판단하는것이추천된다. 스테로이드에대해반응이좋지않다면 IgG4 연관질환이외의다른진단을고려해야한다 [62]. 스테로이드에대한치료반응정도는침범된장기및조직소견에따라다르게나타날수있다 [1]. 제1형자가면역췌장염과 IgG4 연관타액선염은후복막섬유증, 경화장간막염 (sclerosing mesenteritis), 섬유화종격동염 (fibrosing mediastinitis) 에비해스테로이드에대한반응이좋다 [78]. 염증세포나근섬유모세포가드물게관찰되고섬유화가주로나타나는조직생검소견을보이는것보다는림프형질세포침윤이많이관찰되는경우가면역억제제의치료효과가좋다 [79]. 스테로이드를감량하면 20% 30% 환자에서재발한다고알려져있다 [80]. 스테로이드초치료에반응이없거나, 재발한경우, 또는당뇨병을동반하여추천되는용량의스테로이드를사용하지못할경우에는 azathioprine, mycophenolatemofetil, mizoribin, methotrexate, cyclophosphamide, bortezomib, rituximab 등이사용되기도한다 [80]. 결론 IgG 연관질환은경화성췌장염이 IgG4 연관질환의하나인제1형자가면역췌장염으로밝혀진이후다양한장기에서발생되고있는새로운질환이다. IgG 연관질환은혈액내 IgG4 상승, IgG4 양성형질세포침윤, 나선형섬유화, 폐쇄성정맥염등의조직소견을특징으로하는질환이다. IgG4 연관질환은섬유화를동반하고장기종대를나타내는경우가흔하므로종양과의감별진단이필요하다. IgG4 연관질환에서혈액내 IgG4가증가되어있으나 Fc 수용체와보체 C1에대해친화력이낮아면역반응을일으키는능력은다른 IgG 아형보다적다. 앞으로 IgG4 연관질환에서 IgG4의역할에관한연구가필요한상황이다. IgG4 연관질환의발병기전은아직정확히밝혀져있지않지만 Th2 세포와조절 T 세포에서분비되는사이토카인이섬유화등을유발하는것으로알려져있다. 대부분의 IgG4 연관질환은스테로이드치료에좋은반응을보이기때문에스테로이드가우선적으로우선적으로사용되는약제이다. 그러나스테로이드사용량과기간에대한일치된지침은없는실정이다. 스테로이드사용량을줄이기위해 azathioprine, cyclosporine, methotrexate과같은면역억제제 www.jrd.or.kr 219
Su-Jin Moon and Jun-Ki Min 를같이사용할수있다. 최근연구에의하면 B 세포제거약제인 rituximab이 IgG4 연관질환관해유도와스테로이드사용을줄이는데효과적이라고알려져있다. IgG4 연관질환을추적관찰한결과악성종양발생빈도가증가한다는일부보고가있어이에대한관심이필요하다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-51. 2. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344:732-8. 3. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38: 982-4. 4. Stone JH, Khosroshahi A, Deshpande V, Chan JK, Heathcote JG, Aalberse R, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum 2012;64:3061-7. 5. Uchida K, Masamune A, Shimosegawa T, Okazaki K. 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