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남희 강
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1 대한내과학회지 : 제 71 권부록 2 호 2006 임상강좌 베체트병의진단과치료 서울대학교의과대학내과학교실 이은봉 베체트병은원인불명의자가면역질환으로서구강및성기부궤양, 포도막염을특징으로한다. 아직정확한발병기전은알려져있지않으나 HLA-B51 유전자와같은유전적요인, 헤르페스바이러스와같은환경요인및 Th1 사이토카인의과도한분비와같은면역학적요인이발병에중요한역할을하는것으로알려져있다. 본논고에서는베체트병의진단과치료에관한최신지견을고찰해보고자한다. 베체트병의임상상베체트병의역학베체트병은주로중동지방및중국, 일본, 한국등아시아지역에호발하는질환으로서인구 100,000 명당유병율은일본의경우 명, 터키의경우 명, 미국의경우 4명, 영국의경우 0.64명정도로보고되어있으며, 남녀비는연구결과에따라차이가나나 1:1 정도로유사한비율을보인다. 구강궤양구강내점막궤양은베체트병환자에서발생하는가장흔한증상으로서, 거의모든환자에서발생하고, 베체트병의여러증상중가장먼저나타나는증상이다. 궤양은한개만나타나거나혹은여러개가동시에발생하기도하며, 대개동통을동반한다. 궤양의크기도다양하여서직경 1cm 이하의소궤양에서부터 1cm 이상의대궤양까지다양하게발생하는데, 대개 1주에서 3주정도지속되다가아무런흔적을남기지않고소실된다. 성기부병변성기부궤양은대개구강궤양과비슷한모양으로발생하는데, 여성의경우는음문 (vulva) 부근에주로발생 하고, 남성의경우는음낭 (scrotum) 에주로발생한다. 대개수주간지속되다가소실되는데, 음낭에발생한경우는반흔을남기기도한다. 재발은구강궤양만큼흔하지는않아서수개월에한번씩발생한다. 성기부증상으로는궤양이가장흔한증상이지만이외에도, 부고환염, 나팔관염및기타염증성병변이발생하기도한다. 피부병변베체트병의대표적인피부병변은여드름양병변, 홍반성결절, 표재성혈전정맥염 (superficial thrombophlebitis) 등이있다. 여드름양병변은일반적인여드름병변과유사한구진또는농포성병변으로나타나며, 관절염이있는환자에서보다흔히발생한다. 안병변베체트병에서발생하는안병변은실명을초래할수있는병변으로서, 가장위중한임상양상중의하나이다. 앞포도막염, 뒤포도막염및망막혈관염은실명을일으킬수있는대표적합병증이며, 안병변이있는환자중약 25% 가최종적으로시력을잃게되며, 안증상이발생하고평균 3.36년후에시력을상실하게된다. 베체트병의안병변은양측눈에모두오며, 호전과악화를반복하다가, 최종적으로는시력상실에이르게된다. 전방부에발생하는앞포도막염은안구의동통, 눈부심, 안구발적등의증상을일으키고, 전방축농증을유발하나, 대개시력저하까지유발하지는않는다. 일부환자에서는포도막염이반복적으로발생하며, 홍채와수정체간의유착 (synechia) 을일으키거나, 녹내장을유발하기도한다. 또한반복적인스테로이드제제의사용에따라백내장도흔히발생한다. 베체트병환자에서가장문제가되는것은뒤포도막의침범으로서대개는앞포도막과뒤포도막이모두침 - S 825 -

2 - 대한내과학회지 : 제 71 권부록 2 호 Table 1. Diagnostic criteria of the Behcet s syndrome research committee of Japan Major Recurrent aphthous ulceration of the oral mucous membrane Skin lesions Erythema nodosum Subcutaneous thrombophlebitis Folliculitis, Acne like lesions Cutaneous hypersensitivity Eye lesions Iridocyclitis Chorioretinitis, retino uveitis Definite history of chorioretinitis or retino uveitis Genital ulcers Minor Arthritis without deformity and ankylosis Gastrointerstinal lesions characterized by ileocaecal ulcers Epididymitis Vascular lesions Central nervous system symptoms Diagnosis Complete Four major features Incomplete Three major features Or two major + two minor Or typical ocular symptom + one major or two minor features Table 2. Criteria for diagnosis of international study group for Behcet s disease Recurrent oral ulceration Minor aphthous, major aphthous or herpetiform ulceration observed by a physician or reported reliably by patient, which recurred at least 3 times in one 12 month period Plus 2 of Recurrent genital ulceration Aphthous ulceration or scarring, observed by physician or patient Eye lesions Anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or Retinal vasculitis observed by ophthalmologist Skin lesions Erythema nodosum observed by physician or patient,pseudofolliculitis, or papulopustular lesions,or Acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment. Positive pathergy test Read by physician at h (Findings applicable only in absence of other clinical explanations.) 범되는범포도막염 (panuveitis) 의형태로발생한다. 수정체혼탁이나시력저하의형태로증상이나타나며, 서서히시력이감퇴되면서최종적으로는시력을잃게된다. 망막병변은약 50% 이상의환자에서발견되며반복적인포도막염과혈관염에의하여, 만성출혈성및삼출성병 변을보이게되며, 혈관주위에이차적인섬유화소견을보이게된다. 섬유화에의해망막박리가일어나고최종적으로는안구위축 (phthisis bulbi) 에빠지게되면서시력을상실하게된다. - S 826 -

3 - 이은봉 : 베체트병의진단과치료 - 신경학적병변신경학적병변은크게두가지형태로발생한다. 첫째는뇌혈관의장애로서뇌혈관특히경질막정맥동굴 (dural sinus) 의혈전증으로발생하며, 두통, 유두부부종및, 뇌척수액압의증가를일으킨다. 드물게, 뇌동맥의혈전증이발생하기도한다. 둘째는뇌실질에발생하는병변으로서, 겉질척수로 (corticospinal tract), 뇌간 (brain stem), 뇌실주위백질 (periventricular white matter), 척수 (spinal cord), 대뇌기저핵 (basal ganglia) 에원인불명의염증성병변이발생하여신경학적이상을보이는형태이다. 뇌정맥에혈전증이발생하는경우에비하여, 뇌실질에염증이발생하는경우는예후가불량하여서재발하거나불구또는조기사망에이르는경우가더흔하다. 혈관병변베체트병의혈관병변은정맥염과동맥염으로나눌수있다. 정맥에발생하는경우가혈관베체트병전체의 88% 이고대개는혈전증의형태로발생한다. 표재성혈전정맥염 (Superficial thrombophlebitis) 이외에, 대퇴정맥, 슬와정맥, 쇄골하정맥, 액와정맥, 상완정맥, 간정맥 (Budd Chiari 증후군 ), 상공정맥, 하공정맥, 경질막정맥동굴 (dural sinus) 등다양한정맥이침범될수있다. 동맥염은혈관베체트병의 12% 를차지하는데, 대동맥, 폐동맥등이침범될수있으며, 동맥류의형태로발현하거나드물게혈전증의형태로발현한다. 동맥류는복부대동맥, 대퇴동맥, 장골동맥, 슬와동맥, 쇄골하동맥, 경부동맥및관상동맥에발생할수있다. 동맥의폐색역시다양한혈관에서발생할수있는데, 폐동맥, 쇄골하동맥, 노동맥 (radial artery), 슬와동맥, 대퇴동맥, 정강동맥 (tibial artery), 자동맥 (ulnar artery), 관상동맥, 외장골동맥, 경부동맥, 뇌내동맥등에발생할수있다. 특히폐혈관계의합병증은치명적일수있어서신속한진단을요한다. 혈관자체병변이외에심장판막에도병변이발생할수있으며, 대동맥판막부전과승모판막부전이가장흔하며, 이외에삼첨판부전도발생할수있다. 혈관베체트병은여성보다는남성에더흔하게나타난다. 소화기계병변베체트병에서는모든위장관이침범될수있다. 위장 관에는다양한형태의궤양병변을남기며, 반복적으로재발하는경향이있다. 구강이외에흔한침범병소는회장말단부또는맹장부위이고이외에도, 대장, 식도, 위, 십이지장에발생할수있다. 드물게, 간, 신장, 췌장에합병증이오기도한다. 베체트병의진단베체트병을진단할수있는특이검사법은아직없으며, 따라서베체트병을진단하기위해서는베체트병에서나타나는여러임상양상을종합해서판단해야한다. 몇가지의진단기준들이제시되어있는데세계적으로가장널리사용되는진단기준으로는일본류마티스연구회의진단기준 ( 표 1) 과국제베체트병연구회의진단기준이 ( 표 2) 있다. 이들진단기준은정확히는진단기준이라기보다는임상연구에참여시키는환자를표준화시키기위한분류기준에해당한다. 따라서환자에따라서는이러한분류기준을충족시키지못하더라도실제로베체트병환자일수도있고, 분류기준을모두만족하더라도실제로는베체트병환자가아닐수도있다. 그럼에도불구하고, 이러한분류기준들은환자의임상양상을잘정리하고있다는점에서, 임상진단시도매우유용하게참고할수있다. 베체트병의질병활성도베체트병의질병활성도는한가지의검사로파악할수없으며, 베체트병과관련된다양한증상및징후를종합하여판단하여야한다. 국제적으로비교적통용되는활성도측정방법은 Bhakta 등이제안한베체트병현재활동도표 (Behcet s disease current activity form, BDCAF) 로측정 28일내의질병활성도를측정한다 ( 표 3). BDCAF는환자가느끼는질병활성도정도, 피곤함, 두통, 구강궤양, 성기부궤양, 피부병변, 관절통, 위장관계증상의유무, 눈의이상, 중추신경계의이상, 주요혈관의이상및의사의평가를종합하여점수를낸다. 베체트병의치료 ( 표 4) 구강궤양병변의치료구강궤양은베체트병에서가장훈한증상으로증상이경미할때는, 국소스테로이드도포나, 스테로이드제제를 - S 827 -

4 - 대한내과학회지 : 제 71 권부록 2 호 Table 3. Behcet s disease current activity form Date of assessment: Name: Tel: Center: Sex: M/F DOB: Clinician Address: Self rating scale of wellbeing over last 28 days (Patient to tick face chosen) Self rating scale of wellbeing today (Patient to tick face chosen) CLINICAL FEATURES ACTIVITY Other clinical details Fatigue Headache Oral ulceration Genital ulceration Skin lesions Joints Erythema nodosum or superficial thrombophlebitis pustules Arthralgia Arthritis Gastrointestinal Nausea or vomiting or abdominal pain Diarrhea with altered/frank blood Eye Is there eye activity? Yes/No Behcet s ocuopathy index (completed by ophthalmologist) CNS Is there new nervous system activity? (If yes, answer questions below) Yes/ No (ask question overleaf) Q1. Yes/No Q2. Yes/No Q3. Yes /No Q4. Yes/No Q5. Yes/No Major vessel Is there new major vessel activity? (If yes, answer questions below) Yes/ No (ask question overleaf) Q1. Yes/No Q2. Yes/No Q3. Yes /No Q4. Yes/No Clinician s impression of activity over last 28 days: Intention to initiate or change treatment? Current medication on arrival: Yes / No Change in medication: (Bhaket et al. 1999) - S 828 -

5 - 이은봉 : 베체트병의진단과치료 - Scoring system for Activity form All scoring depends on the symptoms present over the preceding 4 weeks prior to assessment. Only clinical features that the clinician feels are due to Behcet s Disease should be scored. (1) To complete the self rating scale of overall wellbeing for the last 4 weeks, please ask the patient the following question: Here are some faces expressing various feelings, thinking about your Behcet s disease only, which of these faces describes how you have been feeling over the last 4 weeks? To complete the self rating scale of wellbeing today, please ask the patient the following question: Here are some faces expressing various feelings, thinking aobut your Behcet s disease only, which of these faces describes how you feel today? (2) Scoring for fatigue, headache, oral and genital ulceration, skin lesions, joint symptoms, and gastrointestinal symptoms is based on duration of symptoms (round up to nearest week). Please ask the fowllowing question and fill in the blank with the organ system to be assessed: Over the last 4 weeks, for how many weeks in total have you had? 0 no symptoms 0 symptoms for 1 week (1 7 days in total) 0 symptoms for 2 weeks (8 14 dyas in total) 0 symptoms for 3 weeks (15 21 days in total) 0 symptoms for 4 weeks (22 28 days in total) (3) Eye involvement Eye activity may be present if the following symptoms are present: (1) red eye, (2) blurred vision, (3) painful eye. Please ask the following question (Tick if symptom present): over the last 4 weeks have you had a red eye_, a painful eye_ or blurred or reduced vision_? If any of these symptoms are present, or if you feel there may be eye activity refer patient to ophthalmologist who will determine the eye score (Behcet s Oculopathy Index) (4) Nervous system Please ask the following question (Tick if symptom present); Over the last 4 weeks have you had any blackouts_, difficulty with speech or hearing_, double vision_, weakness or loss of feeling in the face, arm or leg_, memory loss_ or loss of balance_? If the answer to all of these is no then answers to Q1 5 are deemed negative; otherwise determine the following; Q1. Are there new symptoms or signs consistent with meningeal involvement? Q2. Are there new symptoms or signs consistent with isolated cranial nerve involvement? Q3. Are there new symptoms or signs consistent with brainstem or cerebellar involvement? Q4. Are there new symptoms or signs consistent with cerebral hemisphere involvement? Q5. Are there new symptoms or sings consistent with spinal cord involvement? (5) Major vessel involvement (exclude neurological involvement) Please ask the following question (Tick if symptom present): Over the last 4 weeks have you had chest pain_, breathlessness_, coughed up blood_ or had any pain, swelling or discoloration of either the face_, arm _ or leg_? If the answer to all of these is no then answers to Q1 4 are deemed negative: otherwise determine the following: Q1 Are there new symptoms or signs consistent with peripheral deep venous thrombosis? Q2 Are there new symptoms or signs consistent with central deep venous thrombosis? Q3 Are there new symptoms or signs consistent with peripheral arterial thrombosis/aneurysm? Q4 Are there new symptoms or signs consistent with pulmonary arterial thrombosis/aneurysm? (Bhaket et al. 1999) - S 829 -

6 - 대한내과학회지 : 제 71 권부록 2 호 이용한가글이도움이된다. 하지만대부분의환자에서, 국소요법만으로는불충분하며, 전신성약제가필요하게된다. Colchicine 은비록이중맹검연구에서는구강궤양에효과가뚜렷하지않은것으로밝혀졌으나, 아직도임 상에서는구강궤양의억제목적으로널리사용되고있다. Colchicine 이외에임상에서널리쓰이는약제로는 glucocorticoid 제제가있다. Glucocorticoid 제제역시, 최근이중맹검연구에서구강궤양에대해서효과가없는 Table 4. Behcet 병의치료 임상양상경미한경우중증의경우 피부점막병변구강궤양성기부궤양결절성홍반여드름관절염 / 관절통안병변앞포도막염범포도막염, 뒤포도막염망막혈관염혈관염정맥염동맥염 Mouth washes Topical steroids (Colchicine) Topical steroids Non steroidal anti inflammatory drugs Topical steroids Symptomatic treatment (Glucocorticoids), thalidomide Dapsone, azathioprine, cyclosporine A infliximab, etanercept colchicine in females thalidomide, azathioprine, cyclosporine A, Infliximab, etanercept colchicine, corticosteroids local corticosteroid/antibiotic colchcine, corticosteroids, azathioprine, interferon-α corticosteroids azathioprine, cyclophosphamide oral cyclosporine A, interferon-α infliximab, azathioprine, oral cyclosporine A pulsed IV/oral corticosteroids interferon-α, infliximab azathioprine, low dose aspirin pulsed IV/oral corticosteroids pulsed IV/oral corticosteroids azathioprine 신경학적병변경질막정맥동굴혈전증뇌실질병변소화기계병변소장 / 대장궤양 corticosteroids, (anticoagulation) azathiprine pulsed corticosteroids, corticosteroids, cyclophosphamide azathioprine, interferon-α, Corticosteroids, sulfasalazine, azathioprine, infliximab (Moditied from Bhaket et al. 1999) - S 830 -

7 - 이은봉 : 베체트병의진단과치료 - 것으로밝혀졌지만, 연구디자인상의문제로인하여, 임상에서는여전히널리사용되고있다. 객관적으로구강궤양에효과가있다고밝혀진약제로는 thalidomide, azathioprine, cyclosporine A, infliximab, etanetept 등이있다. 하지만이들약제들은다양한부작용도일으킬수있기때문에증상이경미한경우에는사용되지않고, 국소제제나 colchicines, 또는 glucocorticoid 에반응하지않는경우에한해서사용한다. 성기부궤양의치료성기부궤양은증상이경미할때는국소스테로이드연고가효과적으로사용될수있다. 국소제제에반응을하지않는경우에는다양한약제를사용해볼수있는데, 여성의경우는 colchicine 이효과적인것으로밝혀졌고, 이외에도, thalidomide, azathioprine, cyclosporine A, infliximab, etanercept 가효과적인것으로알려져있다. 하지만이들면역억제제는부작용을감안해서신중하게사용해야한다. 홍반성결절의치료홍반성결절은베체트병의특징적인증상중의하나로서우선 colchicine을사용해보고, 반응이없는경우는 glucocortitoid 제제를사용할수있다. 여드름의치료여드름의치료는주로국소제제가사용되며, glucocorticoid 제제와항생제가복합되어있는연고가효과적으로사용될수있다. 막염및망막신경염으로나눌수있다. 앞포도막염은국소스테로이드제의도포에잘반응을한다. 뒤포도막염과범포도막염 (panuveitis) 의경우는실명에이를수있기때문에보다강력한치료가필요하다. 고용량의 glucocorticoid, azathioprine, cyclophosphamide, oral cyclosporine A, interferon-α, infliximab이사용된다. 망막혈관염의경우도강력한면역억제제치료를요하며, azathioprine, cyclosporine A, 고용량의 glucocorticoid, interferon-α, infliximab이치료제로서사용된다. 혈관병변에대한치료정맥염의경우증상이경미한경우는대증적치료를시행하면되나, 증상이심각한경우는면역억제치료가필요해서, azathioprine, 저용량의 aspirin 또는고용량의 glucocorticoid 제제를사용한다. 동맥염이발생한경우는고용량의 glucocorticoid 나 azathioprine, cyclophosphamide 등의면역억제제를사용할수있다. 동맥류가파열의위험이있는경우에는수술적치료가필요하다. 하지만베체트병환자의수술적치료시에는재발, 이식편의혈전증, 접합부위의동맥류등술후합병증이흔히수반되므로수술여부는신중하게결정해야한다. 신경병변에대한치료신경병변은경질막정맥동굴 (dural sinus) 의혈전증과뇌실질자체에발생한병변으로나눌수있다. 경질막정맥동굴에발생한혈전증은고용량의 glucocorticoid 로치료하며, 뇌실질에대한치료는 glucocorticoid, cyclophosphamide, azathioprine, interferon-α 등을사용할수있다. 관절염 / 관절통의치료베체트병환자에서관절염이발생한경우는비스테로이드성항염제를우선적으로사용한다. 대개는비스테로이드성항염제에잘반응을하나, 반응을하지않는경우에는 colchicine, glucocorticoids, azathioprine 또는 interferon-α 제제를시도해볼수있다. 안병변에대한치료베체트병에서발생하는안병변은앞포도막염, 뒤포도 장병변에대한치료 소장및대장에발생한궤양병변의치료에는 corticosteoroids, sulfasalazine, azathioprine 을사용하며, 치료에반응이없는경우는 infliximab 등을사용해볼수있다. REFERENCES 1) Barnes CG. Treatment of Behcet s syndrome. Rheumatology. 45:245-47, S 831 -

8 - 대한내과학회지 : 제 71 권부록 2 호 ) Behcet s disease research committee of Japan. Behcet s disease: guide to diagnosis of Behcet s disease. Jpn J Ophthalomol 18:291-4, ) Bhakta BB, Brennan P, James TE, Chamberlain MA, Noble BA, Silman AJ. Behcet s disease: evaluation of a new instrument to measure clinical activity. Rheumatology 38:728-33, ) Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behcet disease. Curr Opin Rheumatol 17:1-8, ) International study group for Behcet s disease;criteria for diagnosis of Behcet s disease. Lancet 335: , ) Mat C. Yurdakul S, Uysal S, et al. A double blind trial of depot corticosteroids in Behcet s syndrome. Rheumatology 45:348-52, ) Melikoglu M, Fresko I, Mat C, et al. Short term trial of etanercept in Behcet s disease: a double blind, placebo controlled study. J Rheumatol 32:98-105, ) Sakane T, Takeno M, Suzuki N, Inaba G. Behcet s disease. N Engl J Med 341: , ) Sharquie KE, Najim RA, Abu Raghif AR. Dapsone in Behcet s disease: a double-blind, placebocontrolled, cross over study. J Dermatol 29: , ) Tugal Tutkun I, Mudun A, Urganciouglu M, et al. Eficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet s disease. An open label trial. Arthritis Rheum 52: , ) Tugal Tutkun I, Onal S, Altan Yaycioglu R, Altunbas HH, Urgancioglu M. Uveitis in Behcet s disease: an analysis of 880 patients. Am J Opthalmol 138: , ) Yate PA, Michelson JB. Behcet s disease. Int Ophthalmol Clin. 46:209-33, ) Yurdakul S, Mat C, Tuzeun Y, et al. A double-blind trial of colchicines in Behcet s syndrome. Arthritis Rheum 44: , S 832 -

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Jksvs019(8-15).hwp Grade I Grade II Grade III 12 대한혈관외과학회지 : 제 20 권 제 1 호 2004 Control Group A Group B Fig. 4. Microscopic findings of vein wall in control, group A and group B on the day of 7 after venous occlusion. The