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대한구강내과학회지 Vol. 32, No. 4, 2007 쉐그렌증후군의합리적진단및관리 연세대학교치과대학구강내과학교실 태일호 권정승 전영미 최종훈 심우현 안형준 쉐그렌증후군은만성자가면역질환으로특히눈물샘과침샘에영향을주어구강건조증, 건성각결막염, 이하선확대등을나타낸다. 일반적으로, 특발성으로발생하여쉐그렌증후군이단독으로나타나는원발성쉐그렌증후군과류마티스관절염, 전신성홍반성낭창등과같은다른자가면역질환과함께나타나는이차성쉐그렌증후군으로분류할수있다. 쉐그렌증후군의경우, 구강건조감으로인한불편감을호소하는대신, 불쾌한맛, 이하선부위의붓는느낌등구강건조증이외의증상을호소하기도한다. 따라서구강건조증을호소하는환자에있어서만쉐그렌증후군을감별진단에서고려할것이아니라, 쉐그렌증후군의관련소견중구강건조증이외의증상이나징후에대해서도충분히주목하여, 관련증상이나징후를보이는경우쉐그렌증후군관련검사를고려하고시행하는것이필요하며, 2002 년수정된쉐그렌증후군진단기준에부합되는검사들을통해조기에진단을하는것이필수적일것으로사료된다. Manthorpe 등은처음쉐그렌증상이발생한때로부터진단이될때까지평균 10 년이라는긴시간이소요된다고보고였는데, 이는쉐그렌증후군진단이조기에잘이루어지지않는다는것을반영하는것임을알수있다. Kassan 등에의하면, 쉐그렌증후군의여러전신적증상중림프종의발생정도는건강한사람들에비해쉐그렌증후군을갖고있는환자의경우 44 배정도높은것으로보고되고있다. 따라서쉐그렌증후군환자의정확하고신속한진단은쉐그렌증후군과관련하여발생될수있는합병증등을예방, 관리하는데있어서중요한의미를지닌다고할수있다. 주제어 : 쉐그렌증후군, 진단기준, 임파종 1)I. 서 쉐그렌증후군은만성자가면역질환으로광범위하게장기특이적이거나전신적인증상이나타난다. 특히누선과타액선에영향을주어구강건조증, 건성각결막염이주된증상으로나타나게되며면역세포인 B 세포와 T 세포가표적장기에침투하여파괴한다고보고되고있으나정확한병인론은아직밝혀지지않고있다. 1) 쉐그렌증후군은외분비선만침범하는원발성쉐그렌증후군과외분비선의침범및결체조직진환을 교신저자 : 안형준서울시서대문구신촌동 134 번지연세대학교치과대학구강내과학교실전화 : 02-2228-8880 Fax: 02-393-5673 E-mail: hjahn@yuhs.ac 론 동반하여나타나는이차성쉐그렌증후군으로구분된다. 2) 미국의경우 60% 의쉐그렌증후군환자들은류마티스관절염이나, 전신홍반루푸스, 혹은전신경화증의전신질환과동반된이차성질환으로나타난다. 남성과여성의비율은 9:1 정도로여성에게서더욱호발하며어떤연령대에서도발생할수있으나주호발연령대는 30 대에서 50 대이다. 3) 1986 년제안되었던쉐그렌증후군의진단기준은 1989 년부터 1996 년에걸쳐검증되고적용되었으며이후미국과유럽의공동연구그룹에의해수정되어진진단기준이 2002 년에제안되었다. 2) 본증례보고에서는 2002 년개정된쉐그렌증후군국제진단기준에의해원발성쉐그렌증후군으로진단된증례를통해쉐그렌증후군의진단및관리에있어서중요한고려사항들을문헌고찰을통해되짚어보고자한다. 원고접수일 : 2007-09-12 심사완료일 : 2007-12-03 397

태일호 권정승 전영미 최종훈 심우현 안형준 II. 증 례 1. 환자 : 이, 여자, 44 세, 전업주부 2. 주소 : 양측이하선부위의반복된종창 3. 과거병력 : 8 년전부터 2~3 년마다한번씩양측이하선부위가붓는증상이발생하여 2~3 일후소실되는것이반복되었다. 내원하기 1 일전다시증상이재발하였으나내원당일종창은감소하였고, 국소적인열과신음식먹을때아프고식사시뻐근하다는증상을호소하였다. 눈마르는증상이있으며약 2 년전류마티스인자가증가되었다. 4. 현증초진당시양측촉진시이하선부위의파동성이느껴지는경미한종창이있었으며, 국소적인열이있었으나통증은없었다. 그외특기할만한이상소견은관찰되지않았다. 5. 임상혈액검사소견 WBC 3.17 103/μL (4.0~10.8) RBC 3.70 106/μL (4.0~5.4) Hemoglobin 11.0g/dL (12.0~16) Monocyte(%) 9.5% (3.3~9) Neutrophil (#) 1.44 (2~7) Lymphocyte (#) 1.41 (1.5~4) ESR 119mm/hr (0~20) Total protein 8.9g/dL (6.0~8.0) 일반혈액검사상백혈구, 절혈구, 헤모글로빈수치는 다소감소되어있었고적혈구침강속도가증가된소 견을보였다. 6. 임상면역검사 RF quantification 1400 IU/mL (<20) Anti-SS-A/Ro 114.9AU (positive) (<20) Anti-SS-B/La 117.3AU (positive) (<20) 류마티스인자가증가되어있었고 Anti-SS-A/Ro, Anti-SS-B/La 가양성반응을보였다. 7. 전타액분비검사비자극 0.17ml/min 자극 0.55ml/min 타액분비율검사상비자극전타액분비율이감소되어있기는하나진단기준 0.1ml/min을만족하지는않았다. 껌베이스를이용한자극전타액분비율도감소된소견을보였다. 8. 타액선신티그라피검사 Technetium pertechnetate (99mTcO 4) 를이용한타액선신티그라피 (salivary scintigraphy) 상결과양측이하선과악하선의조영제흡수가감소되어있으며특히악하선의경우가더욱현저하게감소되어있는소견을나타내었다. 9. 병리조직학적검사소견 Daniels 가제시한방법 4,5) 에의해하순부의소타액선을생검하였다. 총 7 개의소타액선을채취하였다. 병리조직학적소견으로는모든소타액선에서 4mm 2 당관찰되는 lymphocyte foci(50 개이상의임파구 ) 의수를의미하는 focus score 가 1 이상이었다. 10. 진단상기진찰및검사결과 2002 년개정된국제쉐그렌증후군진단기준의항목 I, IV, V, VI 의기준에부합하여원발성쉐그렌증후군으로진단되었다 (Table 1, 2). 11. 치료및경과양측이하선의종창과국소적인열에대해 anitbiotics, 비스테로이드성소염제 (NSAIDs) 를처방후증상은소실되었으나주관적인구강건조증상을호소하기시작하였다. 인공타액스프레이를사용하고충분한물섭취와무설탕껌사용을권장하였다. 류마티스내과와안과에의뢰하여추가적인검사를시행한결과류마티스관절염등의쉐그렌증후군과관련된전신질환은관찰되지않았으나안구결막에는미란이관찰되어안과에서의치료가진행되었다. 구강건조증에대한 Pilocarpine hydrochloride 처방후구강건조증상은많이감소되었다. 현재류마티스내과와안과에서주기적인경과관찰을시행하고있다. 쉐그렌증후군진단 2 년후류마티스내과의정기적인검사상다세포군감마글로불린병증소견이나타났고, 백혈구파괴혈관염이양측하지에발생하였으며, 398

쉐그렌증후군의합리적진단및관리 Table 1. Revised international classification criteria for Sjögren s syndrome I. Ocular symptoms: a positive response to at least one of the following questions: 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months? 2. Do you have a recurrent sensation of sand or gravel in the eyes? 3. Do you use tear substitutes more than 3 times a day? II. Oral symptoms: a positive response to at least one of the following questions: 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrently or persistently swollen salivary glands as an adult? 3. Do you frequently drink liquids to aid in swallowing dry food? III. Ocular signs -that is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests: 1. Schirmer 's I test, performed without anaesthesia (<5 mm in 5 minutes) 2. Rose bengal score or other ocular dye score (>4 according to van Bijsterveld 's scoring system) IV. Histopathology: In minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score >1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 mm 2 of glandular tissue V. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests: 1. Unstimulated whole salivary flow (<1.5 ml in 15 minutes) 2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary or destructive pattern), without evidence of obstruction in the major ducts 3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer VI. Autoantibodies: presence in the serum of the following autoantibodies: 1. Antibodies to Ro(SSA) or La(SSB) antigens, or both Table 2. Revised rules for classification For primary SS In patients without any potentially associated disease, primary SS may be defined as follows: a. The presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (Histopathology) or VI (Serology) is positive b. The presence of any 3 of the 4 objective criteria items (that is, items III, IV, V, VI) c. The classification tree procedure represents a valid alternative method for classification, although it should be more properly used in clinical-epidemiological survey For secondary SS In patients with a potentially associated disease (for instance, another well defined connective tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary SS Exclusion criteria: Past head and neck radiation treatment Hepatitis C infection Acquired immunodeficiency disease (AIDS) Pre-existing lymphoma Sarcoidosis Graft versus host disease Use of anticholinergic drugs (since a time shorter than 4-fold the half life of the drug) 399

태일호 권정승 전영미 최종훈 심우현 안형준 손목부위의통증과기관지천식소견, 건성각결막염, 질염소견이나타났다. 호흡기내과검사상섬유화는관찰되지않았고, 손목과무릎의방사선사진및 anti cyclin citrullinated peptide antibody( 류마티스관절염을발병수개월에서수년전에검출할수있는검사로류마티스인자검사에비해특이도는높고민감도는유사하다 ) 검사상정상소견으로나타났다. 현재인공누액및스테로이드점안액, NSAIDs, 비타민 D, 질감염치료제, 스테로이드, 면역억제제인 azathioprine 을복용중이며류마티스내과, 안과, 호흡기내과, 산부인과, 혈액종양학과에서정기적인경과관찰중이다. 치과에서쉐그렌증후군의치료는주로대증요법으로무스카린작용제의투약과인공타액, 다발성충치예방을위한불소양치액사용, 구강위생관리, 타액분비를촉진시키는음식권유등으로한정되어있다. Ⅲ. 총괄및고찰 쉐그렌증후군은구강건조증이주된증상이므로치과에내원하는구강건조증이주소인환자들의진단에있어서쉐그렌증후군과다른원인에의한구강건조증을감별진단하는것은필수적이다. 그러나알려진바와같이건성각결막염이나구강건조증이항상주된증상은아닐수있으며구강건조증상이외에불쾌한맛을호소하거나본증례에서와같이이하선의종창과같은불편감만을호소하기도한다. 6) 또한전신적인질환이나약물에의한이차적인구강건조증상이나타나는경우도있고쉐그렌증후군이신체여러장기에영향을주기도하므로이런복잡성으로인하여정확히조기에진단하는것이용이하지는않다. 쉐그렌증후군의주된징후인구강건조증은아미로이드증, 당뇨, 사르코이드증, 바이러스감염, 외상, 방사선조사및심인성원인에의해서나타날수있으며고혈압약, 부교감신경억제제와같은투약에의해서도나타날수있다. 안구건조증또한아미로이드증, 사르코이드증, 염증 ( 만성안검염, 결막염, 스티븐스존스증후군 ), 비타민 A 결핍증, 누선이나안검과관련된신경병에의해발생할수있으므로앞의질환과의감별진단이필요하다. 1) 누선과타액선의침범이외의전신적인질환으로는일차성쉐그렌질증후군환자의약 50% 에서피로가나타나며외분비선침범에의한불편감보다피로에의한불편감이더크다고한다. 7) 근골격계에도일차성쉐그렌증후군환자에게 53% 에서관절통, 22% 에서근육통이나타났다는연구가있었으며 이차성쉐그렌증후군환자에게서는류마티스관절염이종종발견된다. 8) 피부에서는한연구에의하면약 55% 의환자에게서피부건조증상이동반되었으며약 10% 에서는피부발진이나타났다고한다. 9) 흔하지는않으나기침이나기관건조증과같은증상이폐에나타날수있으며 10) 위장관의경우임파구의침윤에의한흡수장애, 혈액검사상경도의췌장염, 간염의소견이나타나기도하며 C형간염의경우구강건조증이나타날수있으므로감별진단이필요하다. 11) 신장의경우세뇨관간질신염이나타날수있으며사구체질환이나혈뇨, 단백뇨등이나타날수있다. 몇몇의환자에게있어신혈관염으로고혈압이나신부전으로발전할수있다는보고가있다. 12-18) 또한가장빈번한전신적인증상으로는신경계질환이있으며뇌신경이나말초신경에영향을준다. 약 22% 의일차성쉐그렌증후군환자에게서주로감각신경과관련된말초신경병증이관찰되었다. 이는신경내막의미세혈관의변화와관련이있는것으로여겨지고있다. 19) 2002년수정되어진쉐그렌증후군진단기준에의하면 I. 안구건조증, II. 구강건조증에대한주관적증상, III. 안구건조증에대한객관적징후, IV. 소타액선생검의조직학적소견, V. 객관적인타액선기능검사 ( 전타액분비량검사, 타액선조영술 ), VI. 자가항체의 6가지항목중조직학적소견혹은혈청학적소견을포함한 4가지소견이양성으로판명되면쉐그렌증후군으로진단할수있다. 또한객관적인소견인 III, IV, V, VI 의 4가지항목중 3가지이상의항목이양성으로나타나는경우쉐그렌증후군으로진단할수있다. 이차성쉐그렌증후군의진단은결체조직을동반한 I 또는 II 항목중한가지, III, IV, V 항목중 2가지이상에서양성반응을나타낼때진단할수있다. 2) Manthorpe R. 등에의하면쉐그렌증후군의진단까지걸리는평균기간이 10년정도라고보고되고있어 6) 이미진단을받고치료를시작하는시기에있어서는질환이상당히진행되어구강내에서는광범위한치아우식증, 캔디다증, 혀, 협점막, 입술부위의통증과균열, 궤양등의증상이나타나며전신적으로는피로감, 근골격계, 피부, 호흡기, 위장관, 신장, 신경계에복합적인증상들이나타난다. 특히 Kassan등의연구에의하면쉐그렌환자의임파종발병률은 5% 정도로조사되었으며건강한사람에비해 44배정도높다. 자가면역질환에서비호지킨림프종으로발전하는과정에서단세포군 B세포의증식이발생하며주로외분비선에서발생하고내장기관이나임파선에서는발생하지않 400

쉐그렌증후군의합리적진단및관리 는다. 20,21) 악성임파구증식은쉐그렌증후군의초반이나후반에나타날수있다고하며국소적으로발생하여주로타액선, 위장관, 갑상선, 폐, 신장, 안와에발생한다. 쉐그렌증후군환자는임파종이발생할가능성이높으므로이하선의증대가지속되는지, 비장비대, 림프절병증, 촉진가능한자반, 다리의궤양존재여부등을임상적으로확인하고, 혈청학적으로 C4감소, 혼합단세포한랭글로불린혈증, 단세포류마티스인자들의교차반응인자의유무를긴밀하게감시하여야한다. 22,23,24) 비록본증례에서는구강건조증상을동반하지않은자기한정성이하선종창이발생함으로인해처음발병후 8년이라는꽤오랜시간이지난후치과에처음내원하게되었으나체계적인쉐그렌증후군진단기준에따라쉐그렌증후군으로진단함으로써류마티스내과등여러전문분약적접근이가능하게되었다. 구강건조증뿐아니라타액선종창과같은구강및안면부의관련증상및징후의감별진단시쉐그렌증후군을포함시켜고려한다면쉐그렌증후군의조기진단이가능할것이며이때적절한진단을위한진단기준의이용및관련검사의시행은필수적이라할수있다. 따라서쉐그렌증후군의조기진단에있어서치과의사의역할이매우중요하다고할수있으며, 구강증상에대한관리및합병증예방뿐아니라전신증상에대한예방및조기관리를위해조기진단을위한쉐그렌증후군의진단기준, 증상및징후에대해충분히숙지하여야한다. 참고문헌 1. Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med 2004;164(12):1275-1284. 2. Vitali C, Bombardieri S, Jonsson R et al. European Study Group on Classification Criteria for Sjögren s Syndrome. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61(6):554-558. 3. Dafni UG, Tzioufas AG, Staikos P et al. Prevalence of Sjögren s syndrome in a closed rural community. Ann Rheum Dis 1997;56(9):521-525. 4. Daniels TE. Labial salivary gland biopsy in Sjögren's syndrome. Assessment as a diagnostic criterion in 362 suspected cases.arthritis Rheum 1984;27(2):147-156. 5. Daniels TE. Salivary histopathology in diagnosis of Sjögren s syndrome. Scand J Rheumatol Suppl 1986;61:36-43. 6. Manthorpe R, Asmussen K, Oxholm P. Primary Sjögren s syndrome: diagnostic criteria, clinical features, and disease activity. J Rheumatol 1997; 24(suppl):8-11. 7. Kassan SS. Managing dry eyes and dry mouth in Sjögren s syndrome.am J Manag Care 2001;7 (Suppl):S444-450. 8. Koopman WJ, Moreland LW. Arthritis and Allied Conditions. 13th ed., Philadelphia, 1997, Williams & Wilkins, pp.561-1580. 9. Al-Hashimi I, Khuder S, Haghighat N et al. Frequency and predictive value of the clinical manifestations in Sjögren s syndrome. J Oral Pathol Med 2001;30:1-6. 10. Franquet T, Diaz C, Domingo P et al. Air trapping in primary Sjögren s syndrome: correlation of expiratory CT with pulmonary function tests. J Comput Assist Tomogr 1999;23:169-173. 11. Moutsopoulos HM. Sjögren s syndrome: autoimmune epithelitis. Clin Immunol Immunopathol 1994;72:162-165. 12. Tu WH, Shearn MA, Lee JC et al. Interstitial nephritis in Sjögren s syndrome. Ann Intern Med 1968;69: 1163-1170. 13. Cohen EP, Bastani B, Cohen MR et al. Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjögren s syndrome and distal renal tubular acidosis. J Am Soc Nephrol 1992;3:264-271. 14. Shearn MA, Tu W. Nephrogenic diabetes insipidus and other defects of tubular function in Sjögren s syndrome. Am J Med 1965;39:312. 15. Wrong OM, Feest TG, Maclver AG. Immunerelated potassium-losing interstitial nephritis: a comparison with distal renal tubular acidosis. Q J Med 1993;86:513-534. 16. Bloch KJ, Buchanan WW, Wohl MJ et al. Sjögren s syndrome: a clinical, pathological, and serological study in 62 cases. Medicine(Baltimore) 1965;44:187-231. 17. Bailey RR, Swainson CP. Renal involvement in Sjögren s. N Z Med J 1986;99:579-580. 18. Talal N, Zisman E, Schur PH. Renal tubular acidosis, glomerulonephritis and immunologic factors in Sjögren's syndrome. Arthritis Rheum 1968;11:774-786. 19. Gemignani F, Marbini A, Pavesi G et al. Peripheral neuropathy associated with primary Sjögren s syndrome. J Neurol Neurosurg Psychiatry 1994;57: 983-986. 401

태일호 권정승 전영미 최종훈 심우현 안형준 20. Kassan SS, Thomas TL, Moutsopoulos HM et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med 1978;89:888-892. 21. Freimark B, Fantozzi R, Bone R et al. Detection of clonally expanded salivary gland lymphocytes in Sjögren's syndrome. Arthritis Rheum 1989;32:859-869. 22. Kassirer JP, Greene HL. Current Therapy in Adult Medicine. 4th ed., Baltimore, 1997, Mosby, pp.1291-1298. 23. Skopouli FN, Dafni U, Ioannidis JP et al. Clinical evolution, and morbidity and mortality of primary Sjögren's syndrome. Semin Arthritis Rheum 2000;29:296-304. 24. Tzioufas AG, Boumba DS, Skopouli FN et al. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor crossreactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren's syndrome. Arthritis Rheum 1996;39:767-772. - ABSTRACT - Rational Diagnosis and Management of Sjögren s Syndrome Il-Ho Tae, D.D.S., Jeong-Seung Kwon, D.D.S.,M.S.D., Young-Mi Jeon, D.D.S., Jong-Hoon Choi, D.D.S.,M.S.D.,Ph.D., Woo-Hyun Shim, D.D.S.,M.S.D., Hyung-Joon Ahn, D.D.S.,M.S.D.,Ph.D. Department of Oral Diagnosis & Oral Medicine, Dental Hospital, Yonsei University, College of Dentistry Sjögren s syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Primary SS presents alone as xerostomia, keratoconjunctivitis sicca and patotid gland enlargement, secondary SS occurs in connection with other autoimmune disorder such as rheumatitoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. Among many other systemic complication, lymphoma is considered seriously. Patient with SS had a 44 times higher relative risk of lymphoma, and clinically identifiable lymphoma occurs in approximately 5% of patients with SS. So, patients with SS should be closely monitored. In dental office, diagnosis of SS is important in view of high risk of lymphoma. When a dentist diagnose and manage dry mouth, he or she should consider possibility of SS all the times and have knowledge of diagnostic criteria of SS. Key words: Sjögren s syndrome, Diagnositic criteria, Lymphoma 402