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1 대한안과학회지 2017 년제 58 권제 7 호 J Korean Ophthalmol Soc 2017;58(7): ISSN (Print) ISSN (Online) Case Report 면역글로불린 G4 관련안질환의진단적기준을만족하는전형적인증례 1 예 A Typical Case of IgG4-related Ophthalmic Disease Satisfying Diagnostic Criteria 정새롬 1 이태은 1 유인천 1,2,3 조남천 1,2,3 박호성 2,3,4 안민 1,2,3 Sae Rom Chung, MD 1, Tae Eun Lee, MD 1, In Cheon You, MD, PhD 1,2,3, Nam Chun Cho, MD, PhD 1,2,3, Ho Sung Park, MD, PhD 2,3,4, Min Ahn, MD, PhD 1,2,3 전북대학교의학전문대학원안과학교실 1, 전북대학교임상의학연구소 2, 전북대학교병원의생명연구원 3, 전북대학교의학전문대학원병리학교실 4 Department of Ophthalmology, Chonbuk National University Medical School 1, Jeonju, Korea Research Institute of Clinical Medicine, Chonbuk National University 2, Jeonju, Korea Biomedical Research Institute, Chonbuk National University Hospital 3, Jeonju, Korea Department of Pathology, Chonbuk National University Medical School 4, Jeonju, Korea Purpose: In the present study, a case of IgG4-related ophthalmic disease which met the 2015 IgG4-related ophthalmic disease diagnostic criteria is reported and literature review performed. Case summary: A 51-year-old female presented with both upper eyelid swelling, redness, and a palpable mass. Eye movements were normal and exophthalmos was not observed. Facial computed tomography showed both lacrimal gland hypertrophy. The patient underwent left anterior orbitotomy with incisional biopsy. Immunostained biopsy showed the ratio of IgG4+ to IgG+ cells was 50% and the mean number of IgG4-positive plasma cells was approximately 150 per high-power field. Hematological examination showed elevated serum IgG4 concentrations of 6,930 mg/dl, however, other organs were not involved. The patient satisfied the diagnostic criteria for IgG4-related ophthalmic disease. The patient was given an oral steroid and immunosuppressant and the symptoms improved. Conclusions: IgG4-related ophthalmic disease is currently receiving increased attention. The authors of the present study report a case of IgG4-related ophthalmic disease which met the 2015 IgG4-related ophthalmic disease diagnostic criteria. J Korean Ophthalmol Soc 2017;58(7): Keywords: Eyelid, IgG4-related disease, IgG4-related ophthalmic disease, Lacrimal gland 면역글로불린 G4 관련질환 (IgG4-related disease) 은혈청 Received: Revised: Accepted: Address reprint requests to Min Ahn, MD, PhD Department of Ophthalmology, Chonbuk National University Hospital, #20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea Tel: , Fax: ahnmin@jbnu.ac.kr * Conflicts of Interest: The authors have no conflicts to disclose. IgG4 농도가증가되어있고, IgG4+ 형질세포의조직침윤을보이는임상질환으로여러장기를침범하며, 병인은명확하게알려져있지않다. IgG4 연관경화성질환, IgG4 연관자가면역질환등다양한명칭으로불려왔지만 2012년 Research Program for Intractable disease of the Ministry of Health, Labor, and Welfare (MHLW) 에서면역글로불린G4 관련질환이라고명명하였고, 진단기준을제시하였다. 1 면역글로불린G4관련질환은침범하는장기에따라임상양상과 c2017 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 852

2 - 정새롬외 : 면역글로불린 G4 관련안질환 - 병리학적특징이다르기때문에각기관의세분화된진단기준이필요하다. 면역글로불린G4관련질환중타장기침범없이안와에만국한되는경우면역글로불린G4관련안질환 (IgG4 related ophthalmic disease) 이라고하는데 2015년에면역글로불린G4관련안질환의진단기준이발표되었다 (Table 1). 2 면역글로불린G4관련질환은최근에서야명명되었고, 진단의어려움으로인하여보고가되지않는경향이있는데새로운진단기준의도입은질환의특징과역학적이해에도움이될것으로생각된다. 저자들은면역글로불린G4관련안질환의진단기준에완벽하게부합하는환자를경험하여문헌고찰과함께보고하고자한다. 증례보고 51세여자환자가 2년전부터시작된양측윗눈꺼풀부종및발적을주소로내원하였다. 2년전부터호전과악화를반복하였으나완전히없어지지는않았으며, 항생제를 1 주일복용하였지만증상의호전이없었고, 경구스테로이드치료는시행한적이없었다. 내원당시양측윗눈꺼풀에약 cm 크기의딱딱한결절이촉지되었으며 (Fig. 1A), 안구운동검사에서운동장애와안구돌출은없었다. 시행한안과적검사에서양안나안시력 1.0, 안압 20 mmhg 이고, 전안부검사및안저검사에서특이사항이없었다. 시행한안와전산화단층촬영에서양측눈물샘비대소견을보였고, 주위구조물의침윤은없었다 (Fig. 1B). 결절에대 한진단및악성종양과의감별을위해좌측앞쪽안와절개술및절개생검을시행하였다 (Fig. 2A). 조직검사결과림프형질세포의침윤 (Fig 2B-D), 면역화학염색에서 IgG4/IgG 양성형질세포비율이약 50%, 현미경고배율관찰시 IgG 양성림프형질세포가약 300개 (Fig. 2E), IgG4 양성형질세포가약 150개관찰되었다 (Fig. 2F). 혈청단백전기영동검사에서는 IgG4가 6,930 mg/dl로증가되어있었다. 눈꺼풀이외환자의호소병변은없었으나, 다른기관침범여부를확인하기위하여류마티스내과에의뢰하여흉부및복부전산화단층촬영시행하였으나다른기관침범은없었고, 환자의검사결과를모두종합해보았을때면역글로불린 G4관련안질환으로진단하였다. 치료는 methotrexate 10 mg, prednisolone 10 mg 경구복용 2주, methotrexate 12.5 mg, prednisolone 7.5 mg 1달복용후증상의호전을보였으며투약용량을조절하며경과관찰중이다. 고찰 2012년 MHLW 에서 IgG4 연관경화성질환, IgG4 연관자가면역질환등다양한명칭으로불리던질환을면역글로불린G4관련질환이라고명명하였고, 진단기준을제시하였다. 1 침범장기마다임상양상과, 병리학적특징이다르기때문에면역글로불린 G4관련질환진단기준과더불어각각의기관의특징에부합하는세부적인진단기준이필요하고신장과췌장에해당하는세부진단기준은발표된바있다. 면역 Table 1. Diagnostic criteria for IgG4 related ophthalmic disease, (1) Imaging studies show enlargement of the lacrimal gland, trigeminal nerve, or extraocular muscle as well as masses, enlargement, or hypertrophic lesions in various ophthalmic tissues (2) Histopathologic examination shows marked lymphocyte and plasmacyte infiltration, and sometimes fibrosis. A germinal center is frequently observed. IgG4+ plasmacytes are found and satisfy the following criteria: ratio of IgG4+ cells to IgG+ cells of 40% or above, or more than 50 IgG4+ cells per high-power field ( 400) (3) Blood test shows elevated serum IgG4 ( 135 mg/dl) Diagnosis is classified as definitive when (1), (2), and (3) are satisfied; probable when (1) and (2) are satisfied; and possible when (1) and (3) are satisfied. A B Figure 1. Photograph and orbital computed tomography of the patient. (A) Both upper eyelid swelling was observed at the first visit. (B) Orbital computed tomography revealed bilaterally enlarged lacrimal glands. 853

3 - 대한안과학회지 2017년 제 58 권 제 7 호 - A B C D E F Figure 2. Biopsied specimens from lacrimal gland. (A) Gross finding of the eyelid mass. (B) Low-power view of the mass showed diffuse lymphoid proliferation consisting of hyperplastic follicles of variable size and intervening sclerotic area (H-E stain, 20). (C, D) High-power view of the mass showed entrapped epithelial glands in the sclerotic stroma and a lot of plasma cells (arrows) (H-E stain, 400). (E) There were many plasma cells with IgG immunoreactivity (IgG, 100, Inset: 400). The mean number of IgG-positive plasma cells (arrows) was about 300 per a high-power field. (F) There were many plasma cells with IgG4 immunoreactivity (IgG4, 100, Inset: 400). The mean number of IgG4-positive plasma cells (arrows) was about 150 per a high-power field. 2 글로불린G4관련질환 중 타 기관의 침범 없이 안와만 침범 로불린G4관련안질환 진단기준을 Goto et al 이 제시하였고, 한 경우를 면역글로불린G4관련안질환이라 명명하며, 2015 이는 질환을 더 잘 이해할 수 있는 기회가 될 것으로 생각 년 안와 침범만 있는 경우에 한하여 적용할 수 있는 면역글 한다. 854

4 - 정새롬외 : 면역글로불린 G4 관련안질환 - Goto et al 2 은세가지진단기준을제시하였고, 만족하는정도에따라 definitive, probable, possible로분류하여진단했다. 첫번째진단기준은영상검사에서눈물샘, 삼차신경, 외안근을포함한다양한안와조직에서종양이나비대소견을보이는것이다. 두번째는병리조직학적검사에서저명한림프구와형질세포의침윤이나경화를보이고종자중심이관찰되기도하고, IgG4+/IgG+ 세포비율 40% 이상또는고배율현미경관찰시 IgG4+ 세포가 50개이상보이는것이다. 세번째는혈액검사에서혈청 IgG4 135 mg/dl 이상인것이다. 3가지모두를만족하면 definitive, 첫번째와두번째조건만족시 probable, 첫번째와세번째조건만족시 possible 면역글로불린G4관련안질환으로진단한다. 2 면역글로불린G4관련안질환의진단기준은 2011년 comprehensive diagnostic criteria for IgG4-related disease 2011 을바탕으로하였지만안질환의특성에맞추어바꾸었다. 눈물샘, 삼차신경, 외안근뿐만아니라다양한안와조직에대한기술이추가되었으며, 조직병리학적인경화소견이진단의필수사항이아니라고하였다. IgG4/IgG 양성형질세포의비율이 40% 이상이거나, 현미경고배율에서 IgG4 양성형질세포가 50개이상관찰된다는점이면역글로불린 G4관련질환의진단기준과다르다. 2 앞서대한안과학회지에 2010년 hyper-igg4 증후군 3예, 년시신경을침범한 IgG4 연관경화성질환 1예, 년특발성경화성외안근염환자에서발생한눈꺼풀 IgG4 연관경화병증 1예 5 가보고된바있으나 hyper-igg4, IgG4 연관경화성질환으로진단명이혼용되어사용되었고발표된 5 증례중여러장기를침범한경우면역글로불린 G4관련질환, 또는안조직에만침범한경우에해당하는면역글로불린G4관련안질환의진단기준중 definitive에부합하는환자는없었다. 본원환자의경우영상학적검사에서눈물샘비대를확인하였고, 조직병리학적검사에서 IgG4/IgG 양성형질세포비율이 50%, 고배율관찰시 IgG4 양성형질세포가 150 개이며, 혈청 IgG4 6,930 mg/dl로 2015년발표된면역글로불린G4관련안질환의 definitive 진단기준에해당한다. IgG4 양성형질세포의침윤은면역글로불린G4관련질환뿐만아니라류마티스활막염, 피부의염증병변, 암종의종양부근의염증반응에서와같이다양한질환에서보고되기때문에면역글로불린G4관련질환의진단기준에있어병리학적소견은엄격하며, 그결과민감도가낮고특이도가높은경향을보인다. 오래된병변같은경우 IgG4 양성형질세포가적게측정될수있기때문에다양한상황을고려해야하고, 조직병리학적과임상병리학적인연관성을고려해야한다. 6 점막연관림프조직 (Mucosa associated lymphoid tissue) 림프 종의경우 IgG4 양성소견을보일수있어감별에주의해야한다. 림프종의경우양안침범은드물며, 눈물샘보다는연부조직이나결막침범이흔하며, 조직병리학적검사를통해감별할수있다. 6 본원환자의경우림프종에특징적인림프상피성병변을보이지않고 bcl-2가발현되지않는반응성증식소견을보여림프종과감별할수있었다. 혈청 IgG4 900 mg/dl 이상일경우안와이외의기관침범가능성이높다. 7 본원환자는 IgG4 6,930 mg/dl로전신침범여부검사를시행하였지만안와이외침범소견은보이지않았다. 면역글로불린G4관련질환의장기침범은동시성또는이시성으로일어날수있기때문에 6 적절한치료및지속적인경과관찰이필요할것으로보인다. 사르코이드증, 랑거한스조직구증과같은전신질환과의관련성이없고, 바이러스, 세균, 진균감염에의한염증이아닌비특이, 특발로발생한안와의염증을특발안와염이라정의하는데, 특발안와염의경우조직검사를하지않고스테로이드치료를시행하는경우가많고, 그동안면역글로불린G4 관련질환에대한이해가부족했기에특발안와염증으로진단하고치료한증례들의일부가면역글로불린 G4관련질환이었을것으로생각된다. 6 눈꺼풀부종및염증이있는환자를진단할때안와종양, 안와자가면역질환, 특발안와염과더불어면역글로불린G4관련질환을감별질환에포함하고진단기준에부합하는지를고려한다면안와질환의이해가높아질것이다. 면역글로불린G4관련안질환은스테로이드에반응을잘하며, 전신면역질환이므로종양전체의절제가필요하지않기때문에정확한진단이필요하다. 본증례는면역글로불린G4관련안질환 definite 진단기준에완벽하게부합하는첫증례이며, 면역글로불린G4관련질환과면역글로불린G4 관련안질환의명칭과진단기준을상기할수있는교육적인자료가될것으로생각한다. REFERENCES 1) Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), Mod Rheumatol 2012;22: ) Goto H, Takahira M, Azumi A; Japanese Study Group for IgG4- Related Ophthalmic Disease. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol 2015;59:1-7. 3) Kim KE, Lee MJ, Kim NJ, et al. Three cases of Hyper-IgG4 syndrome involving ocular adnexa. J Korean Ophthalmol Soc 2010; 51: ) Cho HS, Choi JY, Yum JH. A case of IgG4-related sclerosing disease involving the optic nerve. J Korean Ophthalmol Soc 2012;53: ) Yoon JH, Jung JW, Chi MJ. A case of IgG4-related sclerosing dis- 855

5 - 대한안과학회지 2017 년제 58 권제 7 호 - ease involving the eyelid in an idiopathic sclerosing myositis patient. J Korean Ophthalmol Soc 2013;54: ) Wallace ZS, Deshpande V, Stone JH. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum 2014;43: ) Kubota T, Katayama M, Moritani S, Yoshino T. Serologic factors in early relapse of IgG4-related orbital inflammation after steroid treatment. Am J Ophthalmol 2013;155:373-9.e1. = 국문초록 = 면역글로불린 G4 관련안질환의진단적기준을만족하는전형적인증례 1 예 목적 : 2015 년발표된면역글로불린 G4 관련안질환진단기준을완벽하게만족하는증례를경험하여문헌고찰과함께보고하는바이다. 증례요약 : 51 세여자환자가 2 년전부터시작된양안윗눈꺼풀부종및발적을주소로내원하였다. 내원당시양측윗눈꺼풀결절이촉지되었으며, 안구운동장애, 안구돌출은없었다. 안와전산화단층촬영에서양측눈물샘비대소견을보였고, 좌측앞쪽안와절개술및절개생검을시행한결과면역화학염색에서 IgG4/IgG 양성형질세포비율이약 50%, 현미경고배율관찰시 IgG4 양성형질세포가약 150 개관찰되며, 혈청단백전기영동검사에서는 IgG4 가 6,930 mg/dl 로증가되었고다른기관의침범이없어면역글로불린 G4 관련안질환으로확진하였다. 경구면역억제제와스테로이드치료를시행하였고호전양상을보여경과관찰중이다. 결론 : 면역글로불린 G4 관련안질환은최근가장주목받고있는안과적질환의하나로, 면역글로불린 G4 관련안질환진단기준을완벽하게만족하는증례를경험하여보고하고자한다. < 대한안과학회지 2017;58(7): > 856

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