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1 대한류마티스학회지 Vol. 15, No. 2, June, 2008 증례 류마티스관절염환자에서 Etanercept 사용중발생한 Candida Parapsilosis 윤활낭염 1 예 중앙대학교의과대학내과학교실, 정형외과학교실 * 이광선ㆍ이하연ㆍ이상원ㆍ정호중 * ㆍ송정수 =Abstract= A Case of Candida Bursitis Associated with Etanercept Treatment in a Patient with Rheumatoid Arthritis Kwang Sun Lee, Ha Yeon Lee, Sang-Won Lee, Ho Joong Jung*, Jung Soo Song Departments of Internal Medicine and Orthopedic Surgery*, Chung-Ang University College of Medicine, Seoul, Korea Tumor necrosis factor (TNF)-alpha blockade has been well proved to significantly improve the disease course of rheumatoid arthritis. However, since TNF-alpha plays an important role in the immune system against external infectious organisms, it was reported that TNF-alpha blockade could increase the frequency of serious opportunistic infections such as tuberculosis. Fungal bursitis is a rare infectious disease following sever infections, malignancies and immune deficiencies. Moreover, there was no report on fungal bursitis occurring after administration of TNF-alpha blockade in Korea to date. Recently we experienced a 58-year-od female patient with rheumatoid arthritis who presented soft buttock mass after treatment with etanercept and was finally diagnosed as fungal bursitis by Candida parapsilosis. Key Words: Etanercept, Candida parapsilosis, Bursitis, Rheumatoid arthritis <접수일 :2007년 10월 8일, 심사통과일 :2008년 5월 7일> 통신저자 : 송정수서울시동작구흑석동 중앙대학교병원류마티스내과 Tel:02) , Fax:02) , drsong@cau.ac.kr 175

대한류마티스학회지제 15 권제 2 호 2008 서 론 종양괴사인자-α(TNF-α) 억제제는류마티스관절염, 강직척추염, 크론병과같은여러만성염증성질환에서우수한효과로그사용이증가되고있으며현재국내에서는 etanercept, infliximab, adalimumab 등이사용되고있다.

2 대한류마티스학회지제 15 권제 2 호 2008 서 론 종양괴사인자-α(TNF-α) 억제제는류마티스관절염, 강직척추염, 크론병과같은여러만성염증성질환에서우수한효과로그사용이증가되고있으며현재국내에서는 etanercept, infliximab, adalimumab 등이사용되고있다. 이약물들은기존항류마티스제제에불응성인류마티스관절염환자에서증상을호전시킬뿐아니라관절손상의진행을늦출수있다. Infliximab과 adalimumab이 TNF-α에대한단일세포항체로서작용하는것과는달리 etanercept는기존 TNF-α수용체에결합하여작용을억제한다 (1). TNF-α는정상인에서감염원에대한숙주반응에중요한역할을하며, 특히육아종에의해제거되는병원체에대한중요한방어인자이다. 따라서 TNF-α 억제제의사용은중증감염과각종기회감염의위험성을증가시키는부작용을가지고있다 (2). 특히결핵에대해서는잘알려져있으며 TNF-α억제제사용전에잠복결핵에대한선별검사 ( 예 : 투베르쿨린피부검사 ) 를시행할것을권유하고있다 (3). 하지만그외에다른기회감염에대해서는적절한예방방법이없다. TNF-α억제제의적응증과사용빈도가현재급격히증가하고있으며, 그로인한감염의증가가예측된다. 국내에종양괴사인자억제제사용과관련되어발생한진균감염증에대한보고가아직없어저자들은류마티스관절염의치료로 etanercept를사용하던중 Candida parapsilosis에의한엉덩이윤활낭염이발생된환자를경험하였기에문헌고찰과함께증례를보고하는바이다. 증례환자 : 58세여자주소 : 입원 1개월전부터발생된좌측엉덩이종괴과거력 : 25년전에류마티스관절염, 10년전에당뇨병을진단받고인슐린으로치료중이다. 9개월전좌측의대퇴골경부골절로고관절반치환술을받았다. 고혈압, 간염, 결핵, 기타질환의과거력은없었다. Fig. 1. non-tender 6 5 cm left buttock soft tissue mass was found. 가족력 : 특이병력없음. 사회력 : 전업주부로술과담배는하지않았다. 현병력 : 류마티스관절염으로 hydroxychloroquine, 스테로이드, methotrexate 등으로치료받다가 1년전시행한혈액검사에서혈색소 6.6 g/dl, 백혈구 6,400/ mm 3, 혈소판 284,000/mm 3 으로빈혈관찰되어 methotrexate는중지하였다. 그후 5개월전부터양측무릎과손목, 손가락등에다발성관절통이악화되어 etanercept를투여하기시작하였다. 투여당시진찰소견상급성감염의소견이나단순흉부 X선촬영에서특이소견관찰되지않았으며투베르쿨린검사는음성으로확인되었다. 그후관절통은호전되었으나, 입원 1개월전부터왼쪽엉덩이에통증과압통을동반하지않은 6 5 cm 크기의덩이가발생하였다 ( 그림 1). 류마티스관절염에의한엉덩이윤활낭염 (ischial bursitis) 이의심되어외래에서윤활액을뽑은후병변안에스테로이드를주사하였으나일주일후덩이가재발하여입원하였다. 뽑은윤활액검사에서적혈구 8,750/mm 3, 백혈구 6,750/mm 3 ( 다핵구 95%, 림프구 5%) 이었으며, 그람염색에서소수의효모가관찰되었고, 배양검사에서 Candida parapsilosis가동정되었다. 입원시혈액검사에서백혈구 5,400/mm 3 이었고, 적혈구침강속도 26 mm/hr, C반응단백은 mg/l로증가되어있었으며, 골반단순 X선검사는정상이었지만자기공명영상에서왼쪽엉덩이부위에윤활낭염의소견이관찰되었다 ( 그림 2). 환자는칸디다윤활낭염으로진단되어 etanercept 투여를중단하 176

이광선외 : Candida Bursitis and Etanercept Treatment in a Patient with RA Fig. 2.

enhancement was showed on T1 weighted image (B). Fig. 3.

수술당시육안으로는윤활낭염에의한활막의비후소견이관찰되었고, 윤활낭은점성을가진불투명한회백색의액체로충전되어있었다. 수술부위윤활낭에대한조직학적검사에서만성염증및섬유화가관찰되었다 ( 그림 3).

3 이광선외 : Candida Bursitis and Etanercept Treatment in a Patient with RA Fig. 2. Left ischial bursal mass (arrow) was detected on T2 weighted image of enhanced pelvis MRI (A) and capsular enhancement was showed on T1 weighted image (B). Fig. 3. Left ischial bursal biopsy shows degeneration of synovium (A) (H&E, 100) and chronic inflammation with fibrosis (B) (H&E, 400). 고그외에 hydroxychloroquine, 스테로이드등기존류마티스관절염약은유지하고, amphotericin B 1 mg/kg을하루한번정맥투여하였으며, 정형외과에서전신마취하에병소내절제및생검을시행하였다. 수술당시육안으로는윤활낭염에의한활막의비후소견이관찰되었고, 윤활낭은점성을가진불투명한회백색의액체로충전되어있었다. 수술부위윤활낭에대한조직학적검사에서만성염증및섬유화가관찰되었다 ( 그림 3). Amphotericin B 투여 8 일후항진균제감수성결과에서배양된 Candida parapsilosis가 fluconazole에감수성을보여 amphotericin B 투여를중지하고 fluconazole 200 mg을하루한번총 6일간정맥주사후 fluconazole 300 mg 경구투여로유지하고퇴원하였다. 2주후에수술부위에발진관찰되고 Pseudomonas aeroginosa가 2차감염되어이미사용하고있던 fluconazole에 ceftazidime을추가한후재수술시행하였다. fluconazole은총 4주, ceftazidime은총 2주간사용하였으며재수술후덩이가재발되지않고발진은사라졌으며수술부위상처가치유되어퇴원후외래에서추적관찰중이다. 177

4 대한류마티스학회지제 15 권제 2 호 2008 고찰윤활낭염은국소적손상혹은류마티스관절염, 통풍, 패혈증같은전신질환과동반되어발생한다. 류마티스관절염환자에서비교적흔히동반되며, 대부분의경우는감염과관련없이질환자체의활성화에의한윤활막에자가면역기전에의해발생한다. 본증례의경우도처음윤활낭염진단당시통증이나압통, 윤활낭주위로홍반이나국소적발열같은감염소견이보이지않아류마티스관절염자체에의한윤활낭염으로생각하여흡입한윤활액에대한세균학적검사를시행하지않았다. 감염성윤활낭염중표재성의경우는대부분상재피부의침술이나연조직염이퍼져발생한다 (4). 또한숙주의윤활액과윤활조직이증가하거나, 면역력이감소되어있으면감염성윤활낭염이더흔히발생하는것으로알려져있다 (5,6). 윤활액검사는감염성윤활낭염과다른질환에의한윤활낭염의감별진단에가장중요하며감염성관절염이아닌경우백혈구가 50,000/mm 3 이하인경우가흔하다 (5). 또한확진을위해서는그람염색과배양검사가매우중요하다. TNF-α는활성화된대식세포와 T 세포에서주로합성되어분비된다. 분비된 TNF-α는삼합체를형성하여그수용체와결합하여각종염증성시토카인을분비시키고, 내피부착분자와케모카인을발현하며, 목적장기로의백혈구이동과통합에주요역할을한다 (7). 감염에대한방어인자로서의역할은 Mycobacterium tuberculosis, M. avium, M. bovis, BCG, Listeria monocytogenes, Aspergillus fumigatus, Histoplasma capsulatum, Toxoplasma gondii, Cryptococcus neoformans, Candida albicans와같이육아종형성에의해제거되는병원균방어에중요역할을하는것으로알려져있다 (8-11). TNF-α억제제는중증감염과기회감염을증가시키는것으로알려져있으며, 결핵과같은육아종성질환뿐아니라각종세균, 진균, 바이러스에의한감염이증가한다. 이러한감염은 infliximab과 etanercept 가다른양상으로나타나는데, etanercept가 infliximab 에비해결핵위험이낮으며, 치료기간내내일정한비율로발생한다. 하지만 infliximab은대부분 90일 이내에발생한다. 하지만이러한이유의원인은명확하지않다 (12). TNF-α억제제사용중발생한진균감염에대한외국의증례보고를보면미국의경우오하이오강이나미시시피강주위에서의파종성히스토플라스마증이보고되고있으며, 그외에파종성으로발생하는크립토콕쿠스증, 콕시디오이데스진균증, 칸디다증, 아스페르길루스증등이다양하게보고되고있다 (12). 국내에는아직까지진균감염증의보고는없으나 etanercept 사용중발생한아데노바이러스폐렴과, infliximab 사용중발생한결핵성뇌수막염의보고가있다 (13,14). TNF-α억제제를사용하는경우결핵을제외하고는현재까지적절한예방법이없다. 따라서감염의가능성을항상의심해야하며, 증상이발생하면빠른평가를해야한다. 또한 TNF-α억제제로인해드문감염원에의한감염이발생할수있으므로조직검사와배양같은적극적인검사가반드시이루어져야한다. 본증례의환자와같이장기간류마티스관절염과당뇨병을앓아와이미면역력이저하된상태에서 TNF-α억제제를사용하는류마티스관절염환자에게서는세균또는진균에의한기회감염의가능성의증가하므로이에대한조기의적극적검사와치료를시행하여야한다. 요 국내에종양괴사인자억제제사용중발생한진균감염증에대한보고가아직없어저자들은류마티스관절염의치료로 etanercept를사용하던중 Candida parapsilosis에의한엉덩이윤활낭염이발생된환자를경험하였기에문헌고찰과함께보고하는바이다. 약 참고문헌 1) Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-fc fusion protein. N Engl J Med 1997;337:

5 이광선외 : Candida Bursitis and Etanercept Treatment in a Patient with RA 2)Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38: ) Hamilton CD. Infectious complications of treatment with biologic agents. Curr Opin Rheumatol 2004;16: ) Zimmermann B 3rd, Mikolich DJ, Ho G Jr. Septic bursitis. Semin Arthritis Rheum 1995;24: ) Canoso JJ, Yood RA. Reaction of superficial bursae in response to specific disease stimuli. Arthritis Rheum 1979;22: ) Ho G Jr, Tice AD, Kaplan SR. Septic bursitis in the prepatellar and olecranon bursae: an analysis of 25 cases. Ann Intern Med 1978;89: ) Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168: ) Allendoerfer R, Deepe GS Jr. Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol 1998;160: ) Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2: ) Huffnagle GB, Toews GB, Burdick MD, Boyd MB, McAllister KS, McDonald RA, et al. Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans. J Immunol 1996;157: ) Mehrad B, Strieter RM, Standiford TJ. Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis. J Immunol 1999;162: ) Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 2004;19: ) Kang MJ, Kim MS, Choi EH, Lee KE, Kim YK, Choi HJ. Adenoviral pneumonia during etanercept treatment in a patient with rheumatoid arthritis. Korean J Intern Med 2007;22: ) Kim YH, Lee BJ, Park JJ, Lee WW, Han WS, Oh SN, et al. Tuberculous meningitis in a patient with Crohn's disease, which was treated with infliximab. Korean J Gastrointest Endosc 2007;34:

歯채민병.PDF

歯채민병.PDF Patient number Sex Age Animal contact 1 F 36 No 2 F 31 Cat scratch Result of biopsy/aspiration cytology of lymph nodes Chronic granulomatous inflammation with caseation necrosis, compatible with tuberculous