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류마티스관절염환자에서 Methotrexate 에의해발생한간질성폐렴 1 예 가톨릭대학교의과대학내과학교실박찬석, 이상학, 심건호, 김완욱, 이숙영, 김석찬, 김관형, 문화식, 송정섭, 박성학 A Case of Methotrexate Induced Pneumonitis in a Patient with Rheumatoid Arthritis Chan Seok Park, M.D., Sang Haak Lee, M.D., Kon Ho Shim, M.E., Wan Uk Kim, M.D., Sook Young Lee, M.D., Seok Chan Kim, M.D., Kwan Hyoung Kim, M.D., Hwa Sik Moon, M.D., Jeong Sup Song, M.D., Sung Hak Park, M.D. Department of Internal Medicine, The Catholic University of Korea, College of Medicine, Seoul, Korea Methotrexate is commonly used in rheumatoid arthritis as an anti-inflammatory agent, but treatment with methotrexate can lead to severe side effects, especially pulmonary complication. Interstitial pneumonitis is one of the most important pulmonary adverse effects of methotrexate and most patient present with a subacute febrile illness and peripheral eosinophilia is seen in about a half of patients. Almost all patients have abnormal chest roentgenograms and bibasilar interstitial infiltration with alveolar pulmonary consolidations is the most characteristic finding. Interstitial inflammation with mononuclear cell infiltration is a characteristic pathologic feature and findings that suggest acute hypersensitivity pneumonitis, such as bronchiolitis, granuloma formation with giant cells, and infiltration with eosinophils are often present. Methotrexate-induced pneumonitis is a potentially life threatening and unpredictable complication but it is difficult to make a definite diagnosis in the absence of high index of clinical suspicion. Early recognition and appropriate management may avoid the serious outcome. Herein we report a case of methotrexate-induced pneumonitis in a patient with rheumatoid arthritis. (Tuberc Respir Dis 2004; 57:273-277) Key words : Methotrexate, Pneumonitis, Rheumatoid arthritis. 서 Methotrexate는엽산환원효소에대한길항체로 1951 년 Gubner 등에의해서 methotrexate의전구체인 ami nopterine 이류마티스관절염과건선에유용하다고보고 1 된이후, 현재는관절의파괴가나타날우려가있는류마티스관절염환자에게제 1차 DMARD(diseasemodifying anti-rheumatic drug) 로저용량의 metho texate 경구요법이널리사용되고있다 2. Metho trexate에의한부작용으로는골수기능억제, 탈모, 간기능이상, 점막염, 피부반점등이있으며폐독성은 1969년고용량의 methotrexate를사용한백혈병환자에서처음보고가되었고 3 이후저용량의 methotre Address for correspondence : Sang Haak Lee, M.D. Department of Internal Medicine, St. Paul s Hospital, The Catholic University of Korea, 620-56, Jeonnong-2-dong, Dongdaemoon-gu, Seoul, 130-709, Korea Phone : 82-2-958-2114, FAX : 82-2-968-7250 E-mail : mdlee@catholic.ac.kr Received : May. 10. 2004. Accepted : Aug. 4. 2004. 론 xate를사용하는류마티스관절염환자에서도보고되었다 4. 저자들은 methotrexate를투여받고있던류마티스관절염환자에서 methotrexate와관련된간질성폐렴 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 여자, 45세주소 : 2일간의노작성호흡곤란현병력 : 환자는내원 12년전류마티스관절염으로진단받고 2년전슬관절치환술을시행받았다. 내원 10개월전부터타병원에서 methotrexate(5 mg/ 주 ) 및 hydroxychloroquine(200 mg/ 일 ), sulfasalazine(1 g/ 일 ), azathioprine(50 mg/ 일 ), deflazacort(3 mg/ 일 ) 를복용하였으며내원 5개월전부터는 methotrexate(12.5 mg/ 주 ) 와프레드니손 (2.5mg/ 일 ) 을복용하고있었다. 내원 1주일전부터발열과오한이있어오다가내원 2 일전부터는운동호흡곤란이발생하여응급실경유입원하였다. 273

CS Park, et al.: A case of methotrexate induced pneumonitis in a patient with rheumatoid arthritis Figure 1. Chest radiography obtained on admis sion, showing ill defined ground glass opacities and infiltrates on both lung fields. 과거력및가족력 : 특이소견없음이학적소견 : 입원당시혈압은 110/70 mmhg, 맥박은분당 84회, 호흡수는분당 22회였으며체온은 38.0 o C였다. 급성병색소견을보였고흉부청진상심음은정상이었고양측폐하부에서수포음이들렸다. 기타복부와사지및신경학적검사상특이소견은없었다. 검사소견 : 내원당시시행한말초혈액검사에서백혈구 7,100/mm 3 ( 호중구 89%, 림프구 6%, 호산구 3%) 였으며헤모글로빈 9.3 g/dl, 혈소판 280,000/ mm 3 이었고 ESR 120 mm/hr였다. 혈액생화학검사상 AST/ ALT 42/34 IU/L, alkaline phosphatase 726 IU/L, LDH 726 IU/L였고그외요소질소, 크레아티닌, 칼슘, 빌리루빈, 총단백질, 알부민, γ-gtp, creatine pho sphokinase 등은정상이었다. 혈액및객담세균배양검사는음성이었으며대기하공기에서시행한동맥혈가스검사는 ph 7.39, PaCO 2 31 mmhg, PaO 2 45 mmhg, HCO - 3 19 mmol/l, SaO 2 81% 였다. 폐기능검사는 FEV 1 1.63 L( 예측치의 68%), FVC 1.90 L( 예측치의 60%), FEV 1 /FVC 86% 였고폐확산능은 15.0 ml/ min/mmhg ( 예측치의 71%) 였다. 방사선소견 : 단순흉부엑스선사진에서양측폐야에미만성간질성음영과페포성침윤이관찰되었으며 Figure 2. HRCT of chest shows diffuse geographic ground glass opacity on both lung fields, mainly on peripheral portions without fibrotic changes. (Fig. 1) 흉부전산화단층촬영에서는주로양측폐야의주변부에섬유성변화를동반하지않은간유리혼탁음영이관찰되었다 (Fig. 2). 기관지내시경소견 : 특이한기관지내병변은관찰되지않았으며우측하엽기관지에서기관지폐포세척과경기관지폐생검조직검사를시행하였다. 기관지폐포세척액의백혈구감별계산결과는대식세포 60.7%, 림프구 21.1%, 호중구 10.7%, 호산구 7.4% 였으며결핵균이나폐포자충및기타진균의소견은관찰되지않았다. 병리소견 : 폐간질의중등도비후와림프구, 형질세포, 조직구, 호산구의간질내침착이관찰되었다 (Fig. 3). 임상경과 : 입원후 methotrexate 투여를중단하였고경험적으로 2세대세팔로스포린계항생제를투여하였다. 2병일째기관지내시경을시행하였으며스테로이드투여를시작하였다. 15병일째환자는증상및흉부방사선소견이호전되어서퇴원하였고이후환자는외래에서 methotrexate를제외한항류마티스약제를복용하면서특별한부작용없이추적관찰중이다. 274

Tuberculosis and Respiratory Diseases Vol. 57. No. 3, Sep, 2004 Figure 3. Transbronchial lung biopsy specimen shows mild interstitial thickening with infiltrates consisting of lymphocytes, plasma cells, histiocytes and eosinophils(a: X100, B: X400, H&E stain). 고찰 Methotrexate에의한폐독성은 1969년처음으로보고된이래그이환율이 0.3% 에서 18% 로다양하게보고되었으며, 국내에서는 1994년첫보고이후현재까지 3예만이보고되어있다 5-7. Hilliquin 등의후향적연구 8 에따르면 methotrexate 를사용한류마티스관절염환자 130명중에서호흡기합병증을일으킨경우는 12 명이었으며이중 methotrexate와연관되어폐렴이나타난경우는 4명으로 3.1% 였다. 이들환자에서사용한 methotrexate 의누적량은 60-250 mg이었으며 metho trexate 투여를시작한후폐렴이발병하기까지의기간은 1-5개월로다양하였다. Methotrexate에의한폐독성의위험요소는남성, 폐기능검사상제한성장애를보이는경우, 비스테로이드성항염증제제의사용여부등이제안된바있으나이후의연구에서그연관성이확인되지못하였고 methotrexate의총투여용량이나투여기간역시폐독성과의관련성이입증되지못하였다. 비교적최근들어다기관, 환자대조군연구를통해고령, 당뇨, 류마티스폐질환의존재, 이전의 DMARD 사용여부, 저알부민혈증이있는경우폐손상의발생위험도가증가하며특히 DMARD 사용력과저알부민혈증이중요한위험요소라밝힌연구 9 가있으며, Ohosone 등 10 은고령, 간질성폐질환의존재, DMARD에대한부작용의 과거력이있는경우에폐손상의빈도가증가한다고하였다. 간질성폐렴의발생을예측하거나조기진단하기위해고해상도컴퓨터단층촬영및폐기능검사를주기적으로시행하는것은도움이되지않는다고알려져있다 11. 본환자의경우에는 DMARD를사용한병력외에다른위험요소는발견할수없었으나, me thotrexate를사용하는환자에서앞에서언급한위험요소가있으면서호흡곤란이나기침등의증상이발생한경우에는 methotrexate에의한간질성폐렴을의심해볼필요가있겠다. Methotrexate에의한간질성폐렴이발생하는병리학적기전은아직밝혀지지않았으나엽산부족이나과민성반응또는특이반응 (idiosyncratric reaction) 에의해나타난다는가설이제시되고있다. 이중엽산부족에의해서간질성폐렴이발생한다는가설은엽산을투여한경우에도간질성폐렴의발생이예방되지않는다는점에서가능성이떨어진다. 간질성폐렴이과민성반응에의해서나타나는것을시사하는소견으로는폐조직검사상비괴사성육아종을동반한간질성폐렴을보이고조직내호산구침착이증가되어있으며기관지폐포세척액에서림프구성폐포염소견을보이고말초혈액에서호산구증가증을보이며임상증상으로발열을동반하며부신피질호르몬에반응을보이는것을들수있다. 그러나 methotrexate 투여도중에도자연회복을보인보고가있으며약제를 275

CS Park, et al.: A case of methotrexate induced pneumonitis in a patient with rheumatoid arthritis 다시투여하였어도재발하지않은경우가있는것은 methotrexate에의한폐독성이특이약물반응에의해일어날수있음을시사하는소견이다 10). 흉부방사선에서정상흉부엑스선사진소견을보이는경우도있으나이는극히드물어흉부엑스선사진이정상인경우에는 methotrexate에의한폐독성의가능성을배제할수있다. 흉부엑스선사진에서가장특징적인소견은양측폐의간질성혹은폐포성침윤으로특히양측폐하부에흔히나타난다. 폐상부나한쪽폐에서만병변을보이는경우는드물고폐기능검사에서는폐확산능의감소가특징적으로나타난다. 기관지내시경을시행할때에는폐조직검사및기관지폐포세척검사를시행하여야하는데기관지폐포세척액의세포분석검사에서는림프구증가증과 CD4/ CD8의비가증가된소견을보이며이는류마티스관절염에의한폐질환과의감별에도움을줄수있다 13. Methotrexate에의한폐독성의가장흔한폐조직의병리소견은림프구와형질세포, 조직구, 드물게는다핵거대세포등의폐간질내침착에의한만성간질성폐렴소견이다. 호산구가약절반가량에서관찰되며비괴사성육아종이관찰되기도한다. 그외의소견으로과민성폐렴이나폐쇄세기관지기질화폐렴 (bron chiolitis obliterans organizing pneumonia, BOOP) 의소견이이러한만성간질성폐렴과같이관찰되기도하며드물게는미만성폐포손상 (diffuse alveolar da mang) 의형태로발현되기도한다 12. 본증례의경우단순흉부엑스선사진에서양측폐야에미만성간질성음영과폐포성침윤이관찰되며폐확산능도 71% 로감소되어있었고기관지폐포세척액에서림프구 21.1% 로증가되어있어 methotrexate 에의한폐독성에합당하였다. 또한조직검사에서폐간질의중등도비후및림프구와형질세포, 호산구등의폐간질내침윤이관찰되어아급성기에해당하는소견을보이고있었다. 치료는우선적으로 methotrexate의투여를중단하여야하고스테로이드를사용하는데스테로이드는회복을빠르게하는것으로알려져있고임상적호전이있을때까지고용량을사용하는것이추천되며스테로이드에반응이없는환자에서는 cyclophosphamide 를투여할수있다 14. 대부분의환자에서는치료후폐기능이완전히회복이되나일부환자에서는영구적인폐손상이나타나게되며사망에이른경우도있어 methotrexate에의한간질성폐렴의사망률은 13% 로보고되고있다 10). 이전에 methotrexate 투여후간질성폐렴이발생한환자에서 methotrexate를재투여한경우재발률은 67% 에달하였고사망률은 33% 로나타나재투여는바람직하지않다 15. 요약 저자들은급성호흡곤란을주소로내원한류마티스관절염환자에서임상소견과흉부방사선소견, 기관지폐포세척액및경기관지폐생검을통해 methotrexate에의한간질성폐렴 1예를진단하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Gubner R, August S, Ginsberg V. Therapeutic sup pression of tissue reactivity II. Effect of amino phterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951;221:176-82. 2. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of lowdose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818-22. 3. Clarysse AM, Cathey WJ, Cartwright GE, Wintrobe MM. Pulmonary disease complicating intermittent therapy with methotrexate. JAMA 1969;209:1861-8. 4. Cannon GW, Ward JR, Clegg DO, Samuelson CO Jr, Abott TM. Acute lung disease associated with lowdose pulse methotrexate therapy in patients with rheumatoid arthritis. Arthritis Rheum 1983;26: 1269-74. 5. Ryu JC, Kim DH, Oh SI, Park SH, Lee YW, Kim DS, et al. A case of interstitial pneumonitis com plicating low dose methotrexate therapy in rheu matoid arthritis. Korean J Med 1994;46:867-71. 6. Kim JY, Kim WU, Lim SI, Yoo WH, Park SH, Hong YS, et al. A case of methotrexate-associated pneu monitis in rheumatoid arthritis. J Korean Rheum Assoc 1998;5:126-32. 7. Seo HJ, Jeong MP, Park EH, Sin SC, Jeon GM, Yu 276

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