대한내과학회지 : 제 89 권제 6 호 2015 http://dx.doi.org/10.3904/kjm.2015.89.6.690 마이코페놀릭산병합요법으로조절된면역글로불린 G4 연관성질환 고려대학교의과대학내과학교실 김지은 차진주 김선우 홍유아 고강지 권영주 IgG4-related Disease Controlled by a Low-dose Steroid and Mycophenolic cid Ji Eun Kim, Jin Joo Cha, Sun Woo Kim, Yu h Hong, Gang Jee Ko, and Young Joo Kwon Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea IgG4-related disease (IgG4-RD) is a group of fibro-inflammatory diseases affecting multiple organ systems, pathologically characterized by tissue infiltration with abundant IgG4-positive cells. We here report a case of IgG4-RD that was successfully controlled by mycophenolic acid (MP). 62-year-old male visited complaining of dizziness and loss of appetite. He had a clinical history of autoimmune pancreatitis treated with steroids and cyclophosphamide 5 years prior, and had also been diagnosed with Hashimoto s thyroiditis at the age of 55 years. We initially prescribed prednisolone (1 mg/kg), tapered to 5 mg/day over 8 months. However, his eosinophilia gradually deteriorated, and we added cyclophosphamide (1 mg/kg daily) for the next 7 months. His laboratory data fluctuated when he was on low-dose predinisolone and cyclophosphamide, and we thus changed his medication to prednisolone combined with MP for the following 63 months. Currently, his laboratory findings are stable. (Korean J Med 2015;89:690-694) Keywords: IgG4; Mycophenolic acid; MP; Eosinophilia 서론면역글로불린 G4 연관성질환 (IgG4-related disease, IgG4-RD) 은최근보고된새로운질병군으로다발장기를침범하는특징을가진섬유염증성질환이다 [1,2]. 이질환군은다수의면역글로불린 G4 양성세포가조직내침투해있는병리소견을보이며, 여러보고들에의해췌장, 담도, 침샘, 뇌수막, 림프선, 폐, 신장등을침범하는것이알려져있다 [3,4]. IgG4-RD의 치료는아직까지확립된바가없으며, 치료에대한무작위가부족한상태로현재의치료는증례보고및전문가의견에의존하고있다 [1]. 저자는재발성 IgG4-RD 환자에서마이코페놀릭산 (mycophenolic acid, MP) 투약을통해성공적으로질병의활성이조절되어장기간유지된증례를경험하여보고하고자한다. Received: 2015. 3. 6 Revised: 2015. 5. 12 ccepted: 2015. 8. 6 Correspondence to Young Joo Kwon, M.D., Ph.D. Department of Internal Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea Tel: +82-2-2626-3036, Fax: +82-2-2626-1077, E-mail: yjkwon@korea.ac.kr Copyright c 2015 The Korean ssociation of Internal Medicine This is an Open ccess article distributed under the terms of the Creative Commons ttribution - 690 - 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.
- Ji Eun Kim, et al. Well controlled IgG4 related disease - 증례환자 : 62세남자주소 : 어지러움및식욕부진현병력 : 내원 3주전부터어지러움, 식욕부진, 전신쇠약감및오한을동반하지않는미열이지속되어외부병원을내원하여시행한초음파에서신장종양이의심되어의뢰되었다. 과거력 : 55세경부터하시모토갑상선염을진단받고신시로이드 (synthyroid) 를복용중이었다. 내원 5년전췌장미부종양으로수술후자가면역성췌장염으로진단받고 4개월간시클로포스파미드 (cyclophosphamide) 와스테로이드치료로호 전된병력이있다. 내원 3년전부터단백뇨로조직검사후막사구체신염진단하여신장내과진료중이었고, 내원 1년전뇌기저동맥갈림동맥류 (basilar tip aneurysm) 에대해묶음술을시행받은기왕력이있었다. 또한혈담소견에대해호흡기내과진료를시행중에있었다. 진찰소견 : 내원당시혈압 140/80 mmhg, 맥박 68회 / 분, 호흡수 20회 / 분, 체온 38.2 였다. 급성병색을보이고있었으며의식은명료하였고, 두경부진찰에서아래턱밑림프절이촉진되었다. 흉부진찰에서심음및호흡음의이상소견은없었고, 복부진찰에서압통, 장기비대및종물은촉지되지않았다. Figure 1. Chest x-ray and computed tomography scan reveal enlarged lymph nodes in both hila. Figure 2. bdominal computed tomography and ultrasonography reveal infiltrative disease of both kidneys and multiple lymphadenopathies. - 691 -
- 대한내과학회지 : 제 89 권제 6 호통권제 664 호 2015 - 방사선소견 : 흉부단순방사선촬영및흉부전산화단층촬영에서양측폐문부및종격동의림프절크기증가를보이며 (Fig. 1), 복부전산화단층촬영에서대동맥주위와대동정맥주위다수의림프절증가및양측신장주변지방침윤및피질수질접합부의흐려짐을동반한신장크기가증가되며, 췌장미부의위축이관찰되었다 (Fig. 2). 검사실소견 : 말초혈액검사는헤모글로빈 8.1 g/dl, 백혈구 22,100/μL ( 호산구 65.0%), 혈소판 505,000/μL이었으며, 말초혈액도말검사에서정적혈구고색소성빈혈, 절대호산구증가 (68%) 및경도의혈소판증가가관찰되었다. 혈청생화학검사에서혈중요소질소 23 mg/dl, 크레아티닌 2.8 mg/dl 소견을보이며, 간기능검사는정상이었다. 단백면역검사에서면역글로불린 G 4,470 mmg/dl ( 참고치 650-1,500 mg/dl) 와면역글로불린 G4 1,630 mg/dl ( 참고치 11-157 mg/dl) 였으며, 요검사에서비중 1.010, 요단백 2+, 요미세적혈구 5-9/ HPF 소견이있었다. 내원후시행한 24시간요검사에서요단백 899.3 mg/ 일을보였다. 혈액질환감별을위하여시행한골수검사에서호산구증식을동반한세포과다성골수로진단되었다. 단백뇨원인을감별하기위해시행한초음파유도신장조직검사에서 Ehrenreich 와 Churg 분류 2단계의막사구체신염 (membranous glomerulonephritis) 과동반하여사이질콩팥염 (interstitial nephritis) 이관찰되었고사이질에침윤된세포는형질세포로면역조직화학적염색법으로확인되었다 (Fig. 3). 치료및임상경과 : 자가면역성췌장염의기왕력과호흡기질환, 호산구수치의증가, 신장조직검사결과및방사선소견의림프절침범의심소견을종합하여 IgG4-RD로생각되어프레드니솔론 (prednisolone) 1 mg/kg로치료를시작하였으며, 8개월에걸쳐서프레드니솔론은 5 mg/day으로점진적으로감량하였다. 이후점차혈청호산구증가악화소견을보여시클로포스파마이드 (1 mg/kg) 를추가하여 7개월간유지하였다. 그러나저용량프레드니솔론과시클로포스파마이드를유지하는동안환자의크레아티닌, 요단백수치등의검사실소견이변동을보여시클로포스파마이드대신 MP (720 mg/day) 로대체하였고, 이후 62개월간동일한치료를유지하였으며 C D Figure 3. () PS staining of the kidney reveals patchy infiltration of chronic inflammatory cells and severe fibrosis (PS, 400). (, C, D) On immunohistochemical staining, almost all plasma cells in various specimens were strongly positive for IgG4. The IgG4: total IgG ratio was >80%. (. CD138, 400; C. IgG, 400; D. IgG4, 400). PS, periodic acid-schiff stain; IgG4: immunoglobulin G 4. - 692 -
- 김지은외 5 인. 면역글로불린 G4 연관성질환의치료 - Figure 4. Trends in the patient s laboratory data over time. CCr, creatinine clearance ratio; CP, cyclophosphamide; MP, mycophenolic acid; IgG4, immunoglobulin G 4. MP로변경후 6년경과후까지환자의검사소견은안정적으로유지되고있다 ( 헤모글로민 16.1 g/dl, 백혈구 6,100/μL, 혈소판 153,000/μL, 호산구 7.8%, 혈청크레아티닌 1.07 mg/dl, 24시간요단백 42.4 mg/day, 혈청면역글로불린 G4 250.1 mg/dl) (Fig. 4). 고찰본증례의특징은저용량의프레드니솔론에 MP 추가로 6년이상안정적으로추적함과치료반응을호산구증가로판단한점이다. IgG4-RD는비교적최근에그개념이확립된질병군으로병태생리와진단기준에대한의견은발표되고있으나아직까지최선의치료에대해확립된바는없다 [1,5,6]. 병태생리적으로 IgG4-RD의발생에면역학적방아쇠가되는것은자가면역성, 유전학적위험인자와세균감염등으로생각되며, 질환의진행에있어 Th2 cell 면역반응에따른과발현된인터루킨 4, 5, 10, 13과 TGF-β가호산구증가및섬유화의진행에기여하여 IgG4-RD 임상양상이발현되게하며장기손상을일으킨다는연구들이발표되었다 [1,5]. IgG4-RD의치료와연관된증례는상당수보고되었으나 MP의사용에대한근거는적은수의증례보고에한정되어있는상태이다. 대부분의증례에서스테로이드가주치료약제로사용되었으며, 스테로이드치료에반응이좋지않은경우추가약제로는 rituximab 을사용한증례보고가여럿있었으며, 그외에본증례와유사하게 mycophenolate mofetil 를투약하였거나, azathioprine, cyclosporine, 혹은 mizoribine을사용한증례들이보고되어있다 [7-10]. 현재까지본증례와같은신장의막사구체신염이주증상으로발현된 IgG4-RD는 23예가보고되었고 [7-10], 그중치료제로써 mycophenolate mofetil 를투약한증례는현재까지 3 증례가보고되었으며, 세증례는혈청크레이티닌수치및단백뇨의일부호전을보였으나치료후 3 증례모두단백뇨는 1 g 이상으로지속되는것을보고하였다 [8]. 본증례에서는환자의단백뇨가 0.9 g/ 일정도로비록이전의세증례에비해치료전요단백수치가낮은편이나 MP를유지하면서요단백은 42.4 mg/ 일까지완전관해가되었다. 본증례에서는프레드니솔론치료시작후임상경과는호산구증가수치, 면역글로불린 G4 및크레아티닌수치등을통해추적관찰하였으며, 그중호산구증가가가장먼저나타났고이에치료약제를변경하였다. 이전증례들은주로요단백수치와크레아티닌수치변경을측정한반면에본증 - 693 -
- The Korean Journal of Medicine: Vol. 89, No. 6, 2015 - 례에서는호산구증가를치료반응을평가하는주된지표로사용하였다 [7,8,10]. 치료반응및질병활성의조기지표로의호산구수치유용성에대해서다른증례보고를통한향후연구가필요할것으로생각된다. MP는면역억제제중하나로여러임상연구에서신장이식환자의거부반응을억제하기위해사용될뿐아니라, 루프스신염이나혈관염, 면역매개성사구체신염과같은자가면역질환의치료제로도잘알려져있다. 본증례는재발성의 IgG4-RD 환자에서스테로이드감량으로악화소견이보여저용량의스테로이드를유지하면서 MP의추가적인투약으로장기간추적에도신기능의호전및혈청면역글로불린 G4 수치의호전, 요단백수치의호전을확인하였다. 결론적으로 MP가 IgG-RD 유지치료의방안이될가능성과치료반응지표로호산구수치에대한가능성이있다고생각되며본증례가그에대한연구에참고가될것으로판단되어보고하고자한다. 중심단어 : 면역글로불린 G4; 마이코페놀릭산 ; 호산구증가증 REFERENCES 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-551. 2. Raissian Y, Nasr SH, Larsen CP, et al. Diagnosis of IgG4- related tubulointerstitial nephritis. J m Soc Nephrol 2011; 22:1343-1352. 3. Monach P. IgG4-related disease: 2013 update. Curr Treat Options Cardiovasc Med 2013;15:214-223. 4. Stone JH, Khosroshahi, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. rthritis Rheum 2012;64:3061-3067. 5. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25: 1181-1192. 6. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. m J Surg Pathol 2010;34:1812-1819. 7. Saeki T, Kawano M, Mizushima I, et al. The clinical course of patients with IgG4-related kidney disease. Kidney Int 2013;84:826-833. 8. lexander MP, Larsen CP, Gibson IW, et al. Membranous glomerulonephritis is a manifestation of IgG4-related disease. Kidney Int 2013;83:455-462. 9. Jindal N, Yadav D, Passero C, et al. Membranous nephropathy: a rare renal manifestation of IgG4-related systemic disease. Clin Nephrol 2012;77:321-328. 10. Cravedi P, bbate M, Gagliardini E, et al. Membranous nephropathy associated with IgG4-related disease. m J Kidney Dis 2011;58:272-275. - 694 -