Case Report J Korean Geriatr Soc 2014;18(4):232-236 http://dx.doi.org/10.4235/jkgs.2014.18.4.232 Print ISSN 1229-2397 On-line ISSN 2288-1239 류마티스관절염환자에서레플루노마이드사용중발생한크립토코쿠스폐렴 1 예 동아대학교의과대학내과학교실 1, 병리학교실 2 변창규 1 임상우 1 박준용 1 노미숙 2 이성원 1 정원태 1 이상엽 1 Pulmonary Cryptococcosis in Rheumatoid Arthritis Patient Treated With Leflunomide Chang Kyoo Byon, MD 1, Sang Woo Yim, MD 1, Jun Yong Park, MD 1, Mee Sook Roh, MD 2, Sung Won Lee, MD 1, Won Tae Chung, MD 1, Sang Yeob Lee, MD 1 Departments of 1 Internal Medicine and 2 Pathology, Dong-A University College of Medicine, Busan, Korea Leflunomide, a disease-modifying antirheumatic drug, is effective for rheumatoid arthritis as monotherapy or combination therapy with methotrexate. The most common adverse effects are diarrhea, dyspepsia, nausea, abdominal pain, oral ulcer, hepatotoxicity, skin rash, hypertension, weight loss, and interstitial lung disease. The occurrence of pulmonary cryptococcosis in leflunomide treatment has not been reported in Korea. A 74-year-old woman was admitted to hospital due to asymptomatic pulmonary nodule. She was diagnosed rheumatoid arthritis and treated with leflunomide 5 months ago due to treatment failure with methotrexate, hydroxychloroquine, and sulfasalazine. Chest radiograph and computed tomography showed solitary pulmonary nodule in her right lower lung. Pulmonary cryptococcosis was confirmed by needle biopsy of lung stained with Gomori methenamine silver and mucicarmine. The lesion was improved after antifungal therapy for 3 months. Key Words: Cryptococcosis, Leflunomide, Rheumatoid arthritis 서 레플루노마이드는 isoxazol 계통의항류마티스약제로 A77 1726 이라는활성화물질로변환되어약리작용을하는것으로알려져있으며, 류마티스관절염에서단독치료또는메토트렉세이트와병합요법으로많이사용된다 1). 약제사용과관련한흔한부작용으로는설사, 소화불량, 오심, 복통, 구강 론 Received: August 6, 2014 Revised: September 2, 2014 Accepted: September 4, 2014 Address for correspondence: Sang Yeob Lee, MD Department of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, 26 Daesingongwon-ro, Seo-gu, Busan 602-715, Korea Tel: +82-51-240-5134, Fax: +82-51-242-5852 E-mail: leesy@dau.ac.kr 궤양, 간효소증가, 피부발진등이있지만 1), 그중에서특히호흡기계에발생하는경우는심각한부작용으로간질성폐렴 2), 폐농양 3), 결핵의재활성화 4), 폐의공동화 5), 폐아스페르길루스증등 6) 이보고된다. 그러나레플루노마이드를사용하던류마티스관절염환자에서크립토코쿠스폐렴이생긴예는국내에서보고된바가없다. 이에저자들은류마티스관절염으로진단받고, 5개월간레플루노마이드로치료받던환자에서무증상으로발생한크립토코쿠스에의한폐렴을폐생검을통해진단하고항진균치료후호전된예를경험하였기에문헌고찰과함께이를보고하는바이다. 증례 74 세여자가무증상의폐결절을주소로내원하였다. 20 년 Copyright 2014 Korean Geriatric Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).
변창규외 : 류마티스관절염환자에서발생한크립토코쿠스폐렴 전부터항고혈압제를복용중이었고, 사회력은가정주부로서음주와흡연은전혀하지않았다. 1년이상지속된양측손목과손가락의다발성근위지관절통으로 2010년 11월본원내원하였으며, 검사소견상 anticyclic citrullinated peptide antibodies는정상수치였으나, 류마티스인자가 219.6 IU/mL ( 정상, 0-15 IU/mL) 로상승하였으며, C-반응단백은 10.27 mg/dl ( 정상, 0-0.5 mg/dl) 로상승하였고, 수부방사선검사에서양측근위지관절과중수지관절주위의골감소, 골미란소견이관찰되었다. 미국류마티스학회진단기준상 (2010 American College of Rheumatology criteria) 류마티스관절염으로진단받고칼코트 (deflazacort) 12 mg/day, 메토트렉세이트 12.5 mg/wk, 항말라리아제 (hydroxychloroquine) 200 mg/day, 설파살라진 1,000 mg/day 의삼제요법으로치료를시작하였으며, 내원시 Disease Activity Score with 28-joint assessment (DAS28)-C- Reactive Protein (CRP) 은 5.32 로높은질병활성도를보였다 7). 환자는 3개월간의치료에도불구하고지속적인손목관절통을호소하였으며, DAS28-CRP 는 5.56 으로높은질병활성도소견을보였다. 이에 2011 년 2월부터메토트렉세이트 12.5 mg/wk 와레플루노마이드 20 mg/day 로약제를변경하여치료를하였으며, 약제교체후관절염증상은호전을보였고, DAS28-CRP 는 2.62 으로활성도감소소견을보였다. 이후환자의류마티스관절염활성도는낮게유지되었으며, 관절통을호소하지않았다. 환자는외래에서정기적인혈액검사와방사선흉부촬영을하였던중 2011 년 7월우연히무증상의폐결절을발견하였다. 내원당시혈압은 130/90 mmhg, 맥박분당 90회, 호흡수분당 20회, 체온은 36.2 였다. 호흡음은정상이었고, 목및겨드랑이의림프절비대는관찰되지않았다. 복부와양측상하지에특이소견이없었다. 신경학적검사에서특이소견은없었다. 말초혈액검사에서백혈구 8,510/mm 3 ( 호중구 60.1%, 림프구 28.6%), 혈색소 11.5 g/dl, 혈소판 376,000/mm 3 이었고, 적혈구침강속도 28 mm/hr ( 정상, 0-30 mm/hr) 이었다. 일반생화학검사에서 aspartate aminotransferase 15 IU/L, alanine aminotransferase 9 IU/L, alkaline phosphatase 204 IU/L, T-bilirubin 0.5 mg/dl, 총단백 7.5 g/dl, 알부민 4.4 g/dl, blood urea nitrogen 14 mg/dl, 크레아티닌 0.6 mg/dl, C- 반응단백은 0.48 mg/dl ( 정상, 0-0.5 mg/dl) 이었다. Human immunodeficiency virus 항체는음성이었고, 혈청크립토코쿠스항원은양성이었다. 소변검사결과는정상이었으며, 혈액, 객담, 소변배양검사에서균이배양되지않았다. 폐조직배양검사는검체부족으로시행하지못하였다. 신경학적검사상특이소견이없어뇌척수액검사는시행하지않았다. 한달전단순흉부방사선검사에서특이소견보이지않았으나내원시단순흉부방사선검사에서우측폐중간구역에고립성결절이관찰되었고 (Fig. 1A), 흉부전산화단층촬영상우하엽에경계가분명한비석회화결절소견이관찰되었다 (Fig. 1B). 초음파유도하폐생검조직검사상 hematoxylin-eosin 염색에서진균포자로추정되는수많은이스트형태의유기체 (yeast form organism) 들이만성육아종성염증반응을일으킨병변이보였다. 관찰된이스트형태의유기체들은 Gomori Methenamine Silver, mucicarmine 염색에양성반응을보여크립토코쿠스폐렴으로진단되었다 (Fig. 2). 폐결절에대해 Cryptococcus fungal ball 확진후사용중이던레플루노마이드와메토트렉세이트를중단하고저용량의스테로이드와타크로리무스 (tacrolimus) 로치료약제를변경하였고, DAS28-CRP 는 2.65로낮은질병활성도를유지하였다. Amphotericin B (0.7 mg/kg/day) 와 flucytosine (100 mg/kg/day) 를입원 2주간투여후외래에서경구 fluconazole (400 mg/day) 로바꾸어 17주동안투여하였다. 치료후 3개월뒤추적검사한단순흉부방사선검사및흉부전산화단층촬영소견상크립토코쿠스에의한폐결절은관해소견을보였다 (Fig. 3). Fig. 1. Chest radiograph and computed tomography scan images. (A) Chest radiograph showing nodular opacity in the right middle lung zone (white arrow); (B) Chest computed tomography scan showing well defined noncalcified nodule about 20 mm size in the right lower lobe (white arrow). J Korean Geriatr Soc 18(4) December 2014 233
Chang Kyoo Byon, et al: Pulmonary Cryptococcosis in Rheumatoid Arthritis Patient Fig. 2. Histologic findings of lung biopsy. (A) Hematoxylin-eosin stain showing chronic granulomatous inflammation associated with yeast form organisms ( 400); (B) Gomori methenamine silver staining showing numerous yeast cells (white arrows) ( 400); (C) mucicarmine stain revealing numerous yeast forms identifiable as cryptococcus by their mucicarmine-stained capsules (white arrows) at 5-10 μm ( 400). Fig. 3. Chest radiograph and computed tomography images after three months of antifungal therapy. (A) Chest radiograph showing improvement of nodular lesion (white arrow); (B) Chest computed tomography showing improvement of noncalcified nodule (white arrow) after antifungal therapy. 고 류마티스관절염의질병활성도평가법으로 DAS28-CRP 가주로사용되는데, 본증례에서도이를적용하여평가하였다. DAS28-CRP 는일반적건강상태 (global health visual analogue scale, GHVAS) 를포함한 4개변수를사용하여다음과같은식으로계산한다. [DAS28-CRP = 0.56 (tender joint count with 28 joint assessment) + 0.28 (swollen joint count with 28 joint assessment) + 0.014 GHVAS + 0.36 ln (CRP 10 + 1) + 0.96] DAS28-CRP 2.6을관해, 2.6 < DAS28-CRP 3.2를낮은질병활성도, 3.3 <DAS28-CRP 5.1을중등도질병활성도, DAS28-CRP >5.1을높은질병활성도라정의한다 8). 플루노마이드는생물학적제재와비슷한시기에 U.S. Food 찰 and Drug Administration 승인을받아시판되고있는약제로, 류마티스관절염환자의사용에선택할수있는항류마티스약제 (disease-modifying antirheumatic drug) 중하나이다. 레플루노마이드는경구복용후곧바로위장관및간을통과하면서 A77 1726로대사되어작용을나타낸다. A77 1726 은 dihydroorotate dehydrogenase 라는효소를억제하여생체내 pyrimidine 생성을차단하고, 그결과생체내 pyrimidine 을필요로하는활성화된 T 림프구의증식이억제된다. 이외에도 A77 1726은 in vitro에서 tyrosine kinase와 nuclear factorkappa B의활성화도억제할수있다는사실이밝혀졌다 9). 크립토코쿠스증 (cryptococcosis) 은 Cryptococcus neoformans 등에의해서발병되는비전염성기회감염혹은불현성감염으로, 주로호흡기를통하여인체내로들어와폐, 피부, 간, 림프절등을침범하며, 특히뇌막염등중추신경계병소를잘형성하는질병이다. 후천성면역결핍증이대표적위험군이고그외에장기이식, 림프종및악성종양, 스테로이드장기복용환자등에서기회감염의형태로나타난다 10). 레플루노마이드약제에의한대표적인호흡기계부작용으로는간질성폐렴, 폐농양, 결핵의재활성화, 폐의공동화, 폐아스페르길루스증등의보고가있으며 2-6), 특히국내에서는 Jung 등 11) 이 mycophenolate mofetil (MMF) 를사용중이던전신홍반루프스환자에서파종성크립토코쿠스증을보고하였고, Lee 등 12) 은싸이클로스포린을사용한환자에서크립토코쿠스폐렴을보고하였다. 이들보고는모두면역억제제에의해크립토코쿠스증이발생한것으로추측하고있다. 또한외국에서는류마티스관절염치료에많이사용되는종양괴사 234 J Korean Geriatr Soc 18(4) December 2014
변창규외 : 류마티스관절염환자에서발생한크립토코쿠스폐렴 인자억제제 (tumor necrosis factor inhibitors) 로인한크립토코쿠스폐렴보고도있다 13). 그러나레플루노마이드와연관되어발생한크립토코쿠스폐렴의보고는국내에서없다. 본증례는 5개월간레플루노마이드복용후크립토코쿠스폐렴이발생한경우이다. 그리하여레플루노마이드와메토트렉세이트를중단하고저용량의스테로이드와타크로리무스로약제를변경하였다. 류마티스관절염치료에있어서저용량스테로이드유지요법은스테로이드에의한부작용을최소화하면서류마티스관절염을효과적으로치료할수있고, 타크로리무스는기존의항류마티스약제에불응성류마티스관절염환자에게투여할수있는효과적이고안전한약제중에하나이다. 물론타크로리무스는면역억제제로진균감염같은기회감염의발생을증가시킬수있으나장기이식환자보다는류마티스관절염환자에서부작용이더적다고알려져있다 14). 국내에서 Jeon 등 15) 이신이식환자에서타크로리무스, MMF 투여후크립토코쿠스증을보고하였으나류마티스관절염환자에서타크로리무스투여후진균감염이생긴국내보고는없다. 크립토코쿠스에의한폐침범은폐조직침윤이있어도무증상인경우가흔하며, 기침, 가래, 흉통등의비특이적인증상을보인다. 대부분의경우흉부방사선사진상우연히발견이되고, 주로폐하부를침범하며, 경계가분명한단일또는다발성결절이나종괴를보이지만, 후천성면역결핍증후군환자에서는경계가불분명한종괴, 폐렴양침윤으로도보이는경우가있다 16). 진단은조직에서균을배양하거나조직병리학적인관찰을통하여피막항원을증명하여확진한다. 또한추가적으로혈액, 뇌척수액, 객담등을배양하고혈액, 뇌척수액에서크립토코쿠스항원검사를시행하여중추신경감염을비롯한파종성감염여부에대한확인이필요하다 17). 본증례는신경학적신체검사상특이소견을보이지는않아서뇌척수액검사는시행하지않았지만, 혈액검사에서혈청크립토코쿠스항원이양성소견을보였으며, 폐생검에서크립토코쿠스가확진되었다. 크립토코쿠스의치료는반드시감염부위와환자의전신상태를고려하여치료법을결정하여야한다. 면역이정상인폐크립토코쿠스증환자의치료는 fluconazole 을하루 200-400 mg씩 3-6 개월간투여하는것이권고된다. 그러나중증환자에서는 amphotericin B를하루 0.5-1.0 mg/kg 의용량으로 4-6 주간투여하고, 면역저하상태가아닌크립토코쿠스수막 뇌염의경우 amphotericin B (0.5-1.0 mg/kg/day) 와 flucytosine (100 mg/kg/day) 를병합하여 6-10 주간투여하는것이권고된다. 또한최근에는 amphotericin B (0.5-1.0 mg/ kg/day) 와 flucytosine (100 mg/kg/day) 을 2주간병합투여하고, 이후 fluconazole (400 mg/day) 을최소 10주간투여하는방법이있다 18). 본환자에서는진단초기에신경학적침범증상을보이지않아서뇌척수액검사를하지않았다. 따라서중추신경계감염을완전히배제하기어려운상태였다. 이에저자들은신경과와협진후 amphotericin B (0.7 mg/kg/day) 와 flucytosine (100 mg/kg/day) 을 2주간병합투여하고, 이후경구로 fluconazole (400 mg/day) 을 17주간투여하였다. 외래에서추적관찰중에환자는중추신경계를침범한증상호소를하지않고, 흉부방사선검사상폐결절이치료약제투여뒤 3개월이후소멸되어더이상관찰되지않아서완치판정을하였다. 결론적으로류마티스관절염치료에서는레플루노마이드같은면역억제제의사용으로인하여기회감염의발생빈도가증가하기때문에, 류마티스관절염치료를받는환자는특별한증상을호소하지않더라도정기적인흉부방사선촬영과혈액검사를통하여기회감염을조기에진단치료하는것이중요할것으로사료된다. 이해관계명시 (Conflict of Interest Disclosures) : 저자 ( 들 ) 은본논문과관련하여이해관계의충돌이없음을천명합니다. REFERENCES 1. Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 2003;30:1182-90. 2. Takeishi M, Akiyama Y, Akiba H, Adachi D, Hirano M, Mimura T. Leflunomide induced acute interstitial pneumonia. J Rheumatol 2005;32:1160-3. 3. Ulusoy H, Bilgici A, Kuru O, Celenk C. Pulmonary abscess due to leflunomide use in rheumatoid arthritis: a case report. Rheumatol Int 2005;25:139-42. 4. Hocevar A, Rozman B, Praprotnik S, Lestan B, Erzen D, Petric V, et al. Leflunomide-associated tuberculosis? Rheumatology (Oxford) 2006;45:228-9. 5. Ravindran V, Kiely PD. Pulmonary cavitation: a rare complication of leflunomide therapy. Int J Adv Rheumatol 2007;5: J Korean Geriatr Soc 18(4) December 2014 235
Chang Kyoo Byon, et al: Pulmonary Cryptococcosis in Rheumatoid Arthritis Patient 85-8. 6. Tomos P, Lachanas E, Agathos EA, Grigorakos L. Pulmonary aspergillosis in chronic leflunomide treatment. Surg Infect (Larchmt) 2012;13:282-3. 7. Kim HO, Yoon HS, Kwok SK, Ju JH, Park KS, Park SH, et al. Clinical characteristics of elderly onset rheumatoid arthritis. J Korean Geriatr Soc 2010;14:227-33. 8. Salomon-Escoto KI, Gravallese EM, Kay J. Assessment of control of rheumatoid arthritis disease activity. Best Pract Res Clin Rheumatol 2011;25:497-507. 9. Cannon GW, Kremer JM. Leflunomide. Rheum Dis Clin North Am 2004;30:295-309. 10. Gladman DD, Hussain F, Ibanez D, Urowitz MB. The nature and outcome of infection in systemic lupus erythematosus. Lupus 2002;11:234-9. 11. Jung HR, Kwon HH, Choe JY. A case of disseminated crytococcosis in a patient with systemic lupus erythematosus. J Korean Rheum Assoc 2010;17:194-9. 12. Lee KC, Lee HS, Lee SE, Ryu U, Yoon BY, Kim SY, et al. A case of pulmonary cryptococcosis in a patient with rheumatoid arthritis. J Korean Rheum Assoc 2003;10:189-94. 13. Shrestha RK, Stoller JK, Honari G, Procop GW, Gordon SM. Pneumonia due to Cryptococcus neoformans in a patient receiving infliximab: possible zoonotic transmission from a pet cockatiel. Respir Care 2004;49:606-8. 14. Dutta S, Ahmad Y. The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2011;3: 283-91. 15. Jeon JM, Oh JS, Kim SM, Son YK, Park YK, Sin YH, et al. A case of asymptomatic disseminated cryptococcosis in a renal transplant patient. Korean J Nephrol 2010;29:310-4. 16. Eng RH, Bishburg E, Smith SM, Kapila R. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med 1986;81:19-23. 17. Baddley JW, Perfect JR, Oster RA, Larsen RA, Pankey GA, Henderson H, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis 2008;27:937-43. 18. Casadevall A. Cryptococcosis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison s principles of internal medicine. 18th ed. New York: McGraw-Hill; 2011. p. 1648-51. 236 J Korean Geriatr Soc 18(4) December 2014