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1 Korean J Gastroenterol Vol. 61 No. 1, pissn eissn CASE REPORT 크론병환자에서임신초기 Infliximab 투여후정상분만한 1 예 장영우, 박영숙, 김성환, 조윤주, 조영관, 안상봉, 서용수 1, 홍영옥 2 을지대학교의과대학을지병원내과학교실, 산부인과학교실 1, 병리학교실 2 A Case of Crohn s Disease Having Normal Delivery after Infliximab Treatment during Early Pregnancy Young Woo Jang, Young Sook Park, Seong Hwan Kim, Yun Ju Jo, Young Kwan Jo, Sang Bong Ahn, Yong Soo Seo 1 and Young Ok Hong 2 Departments of Internal Medicine, Obstetrics & Gynecology 1, and Pathology 2, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea Infliximab is a chimeric IgG1 monoclonal antibody to tumor necrosis factor (TNF)-α used in the treatment of steroid refractory or dependent Crohn s disease (CD). Patients with active CD are more likely to experience stillbirth, preterm labor, or small for gestational aged babies. The safety of administering infliximab in pregnant patients is not well documented. A 25-year-old woman, who was diagnosed with small bowel CD three years ago, was admitted to our hospital due to the aggravation of abdominal pain. She had been treated with mesalazine, azathioprine and intermittent steroid for three years. After admission, she did not respond to steroid therapy, we decided to try infliximab. After the administration of infliximab, epigastric pain was relived and Crohn s disease activity index score decreased significantly. However after the fourth infusion of infliximab, the patient became aware that she was ten gestational weeks old pregnancy state After then, infliximab was stopped and maintained by mesalazine. The patient gave birth to a healthy baby via normal vaginal delivery without the recurrence of CD. This case suggests that infliximab administration is safe during the early period of pregnancy. Thus, we report this case with a review of literature. (Korean J Gastroenterol 2013;61:37-41) Key Words: Crohn disease; Infliximab; Pregnancy 서론 크론병은식도에서항문까지전소화기관을침범하는만성염증성질환으로복통, 설사, 체중감소등의증상과장협착, 장누공, 복강농양및위장관출혈등의합병증을초래할수있다. 국내서도유병률이꾸준히늘고있으며특히 10대에서 20대에높은발병률을보이는크론병환자들은결혼, 임신, 출산등일련의과정을겪게된다. 1 크론병은 CD4+ T 세포활성화에의해 tumor necrosis factor (TNF)-α의증가가중요한병인으로알려지면서 2 TNF-α 의작용을차단하기위한약들이개발되었다. Infliximab은 TNF-α에높은특이도와친화도를가졌고 75% 는사람, 25% 는쥐의서열로이루어진단클론항체로, IgG1 이성접합체이다. 중증크론병의급성악화및누공성크론병에효과적이며관해유지에도중요한약물 3 로국내에서도보험인정으로처방이가능해졌고최근그처방이빠르게늘고있다. 그러나임신시에 infliximab의투약의안정성에대해서는제한적인보고가있을뿐이며 4,5 아직국내에서의보고는없는실정이다. 저자들은 25세크론병여자환자에서 infliximab 투약도중비계획임신이되었으나성공적인임신유지및 Received January 30, Revised April 20, Accepted April 21, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 박영숙, , 서울시노원구한글비석길 14번지, 을지대학교을지병원소화기내과 Correspondence to: Young Sook Park, Division of Gastroenterology, Eulji General Hospital, Eulji University School of Medicine, 14 Hangeulbiseok-gil, Nowon-gu, Seoul , Korea. Tel: , Fax: , pys1109@eulji.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 61 No. 1, January

38 장영우등. 크론병환자에서임신초기 Infliximab 투여후정상분만한 1 예 정상분만과출산이후 3년의추적관찰동안특별한문제가없는증례를경험하였기에문헌고찰과함께보고한다. 증례 크론병으로치료받던 25세여자가 2008년 8월복통이악화되어입원하였다.

대장내시경에서회맹판에다발성아프타궤양및반흔성변화가있었으며항문연상방 35 cm 구불결장에도다발성아프타궤양이있었다. 회맹판조직검사는급만성염증세포만이있었으나구불결장의조직생검결과육아종의소견이있었으며 (Fig.

5 g과경구스테로이드 40 mg 복용후증상이호전되어스테로이드용량감소후메살라진 3 g으로유지하였다.

, Seoul, Korea) 100 mg을 2006년 9월부터메살라진과함께투여하였다. 2008년 7월복통의악화로복부컴퓨터단층촬영및바륨소장조영술을시행하였다.

2 38 장영우등. 크론병환자에서임신초기 Infliximab 투여후정상분만한 1 예 정상분만과출산이후 3년의추적관찰동안특별한문제가없는증례를경험하였기에문헌고찰과함께보고한다. 증례 크론병으로치료받던 25세여자가 2008년 8월복통이악화되어입원하였다. 환자는 3년전 (2005년 7월 ) 반복되는상복부통증을주소로입원하여크론병으로진단받았다. 당시가족력이나사회력은없었으며위내시경검사에서역류성식도염이외에특이소견없었다. 대장내시경에서회맹판에다발성아프타궤양및반흔성변화가있었으며항문연상방 35 cm 구불결장에도다발성아프타궤양이있었다. 회맹판조직검사는급만성염증세포만이있었으나구불결장의조직생검결과육아종의소견이있었으며 (Fig. 1) 캡슐내시경에서공장 및회장에종주형궤양및협착이있어소장및대장을침범한크론병으로진단하였다 (Fig 2). 환자는메살라진 (Pentasa R ; Ferring Pharm. Korea Ltd., Seoul, Korea) 1.5 g과경구스테로이드 40 mg 복용후증상이호전되어스테로이드용량감소후메살라진 3 g으로유지하였다. 환자는 3개월후 2005년 10월항문주위농양이발생하여 metronidazole 투약후호전되었고이후크론병의악화에의한상복부통증으로간헐적인고용량의스테로이드를투약하였으며면역조절제인 azathioprine ( 아자프린 R ; Korea United Pharm. Inc., Seoul, Korea) 100 mg을 2006년 9월부터메살라진과함께투여하였다. 2008년 7월복통의악화로복부컴퓨터단층촬영및바륨소장조영술을시행하였다. 말단회장부위의부종과조영증가소견을보였고 erythrocyte sedimentation rate (ESR) 은 57 mm/hour, CRP 6.21 mg/dl Fig. 1. Colonoscopic and microscopic findings of sigmoid colon. (A) It showed aphthous ulceration 35 cm from anal verge. (B) Microscopically it showed chronic inflammation and granuloma (H&E, 400). Fig. 2. Capsule endoscopy. It showed segmental longitudinal ulcerations on the jejunum (A) and ileum (B). The Korean Journal of Gastroenterology

3 Jang YW, et al. A Case of Crohn s Disease Normal Delivery after Infliximab Medication During Pregnancy 39 로상승되어있어스테로이드정주치료를시작하였다. 이후환자의증상이호전되어경구스테로이드를당분간유지하기로하고퇴원하였으나 7일후상복부통증의악화로재입원하였다. 발열은없었으나상복부압통이있었고말초혈액검사에서백혈구 5,440/mm 3, 혈색소 9.5 g/dl로수개월전에비해빈혈이악화되었으며 CRP는 6.51 mg/dl로상승되어있었고 Crohn s disease activity index (CDAI) 302점이었다. 당시 B형간염의항원, 항체는음성이었고결핵의과거력은없었다. 2005년크론병으로진단받고증상의악화로간헐적으로고용량의스테로이드를투여하였으며, 면역억제제및메살라진을유지하는상태에서 2008년 7월스테로이드정주요법을시도하였으나일시적인반응후다시통증이악화되었기에생물학적제제인 infliximab 5 mg/kg을투여하기로결정하였다. 2008년 8월첫번째주사후증상의호전을보여 2주째및 6주째주사하였다 (Fig. 3). 2008년 12월 4차 infliximab 주사하였으며더이상의복통은호소하지않았고 CDAI는 126점으로감소하였다. 환자는 2008년 11월 1일마지막생리를하였으며 12월 4 차 infliximab 투여당시임신 7주상태였으나임신사실을알지못하였다. 이후임신 10주에임신사실을알았으며비계획임신이었으나강력히임신유지를원하였다. 환자와의상의후더이상의 infliximab은투약하지않았으며메살라진만매일 3 g을복용하였고임신기간중복통의재발없이 CDAI 는 150 이하로유지되었다. 임신 41주에 3 kg의건강한여아를질식분만하였으며모유 Fig. 3. Crohn s disease activity index (CDAI) score and infliximab treatment. LNMP, last normal menstrual period; NSVD, normal spontaneous vaginal delivery. 수유를시작하였다. 신생아에게 bacillus calmette-guérin (BCG), measles, mumps, rubella (MMR), oral polio vaccine (OPV) 의생백신을포함한예방접종을지침에맞추어진행하였다. 분만 5개월후복통이다시악화되고설사가동반되었는데, 복부컴퓨터단층촬영에서 2008년 8월에비하여회맹판과회장의부종과염증이더진행된소견이있었으며 CDAI도 370점으로다시상승하여모유수유중 5번째 infliximab 투여를시작하였고이후수유는 4개월간지속하였다. 환자는 infliximab 재투여후관해유지되어 8주간격으로 infliximab을투여하고있으며 3년후추적관찰에서아이는특별한문제없이건강하게자라고있다. 고찰 크론병이임신도중악화되는비율은 1/3 정도이다. 6 임신도중질병의임상경과는임신당시질병의활성도에의해좌우된다. 즉, 임신전비활동성인경우대부분비활동성인상태를유지하지만임신전활동성인경우에는약 70% 에서임신기간중에질병활동성이지속되거나악화될수있다. 7 일반적으로급성악화시기에임신이되었을경우조산, 유산, 사산, 저체중아출산등임신합병증이발생할확률이 2-3배높아진다. 하지만관해기에서임신유지및출산은정상인에비해뒤지지않는다. 8,9 따라서임신에나쁜영향을미치는것은약제가아니라질병의활성도이므로임신을유지하기위해서는크론병의조절이중요하다. 메살라진은임신및수유에안정성이인정되어있다. 그러나급성악화기에사용하는고용량의스테로이드, 항생제, 사이클로스포린등은기형아의위험성은높지않지만조산및저체중아의위험은높아지므로, 임신기간중크론병의악화와임신및태아의합병증을예방하기위해서는계획적인임신에대한교육이절실히필요하다 년미국 Food and Drug Administration (FDA) 에서승인된 infliximab은세포에결합되기전의 TNF-α의차단과대식세포나활성화된 T-림프구의표면에있는 TNF-α의과도한항진을차단하여 11 크론병, 궤양성대장염, 건선, 류마티스관절염, 강직성척추염등의질환의치료에사용된다. Infliximab은 FDA에서 B등급 12 으로분류하였다. 이는동물실험에서태아에해가없는것을의미하며인체를대상으로시행한대조임상연구는없기에임상에서처방을주저하는경우가많다. 외국의연구를보면크론병환자를대상으로전향적인연구를시행한 TREAT registry에서 66명의임산부가있었고이중 36명에게 infliximab을투여하였다. 기형아의출산은 infliximab 투여군에서없었으며조산 (11.1% vs. 7.1%; p=0.53) 이나신생아합병증 (8.3% vs. 7.1%; p=0.78) 은투여하지않은군과큰차이가없었다. 13 또한 131명의임산부에게 Vol. 61 No. 1, January 2013

4 40 장영우등. 크론병환자에서임신초기 Infliximab 투여후정상분만한 1 예 infliximab을투여한보고가있는데결과를확인할수있는 96 명중 82명이크론병환자였다. 정상분만이 67% (64/96) 였으며유산 15% (14/96), 치료적유산 19% (18/96) 로 infliximab 을투여하지않은크론병임신환자의결과와비슷하였다. 14 다른보고에서는 10명의임신중인크론병환자를대상으로 infliximab을질병의악화방지를위해투여한바있으며, 이중 8명의환자에게관해유지를위해서임신기간동안 2개월에한번씩지속적으로 infliximab을투여하였고 2명의환자는임신중크론병이악화되어임신초기및후기에각각 1회투여하였다. 10명의신생아모두에서선천성기형이나자궁내성장지연은없었으나 3명의조산, 1명의저체중아출산이있었다. 15 Infliximab은이론적으로는인간의정상부 (constant region) 의 IgG1를포함하고있는데 1분기에소량이태반을통과하고주로 2, 3분기에태반을통과한다고알려져있으며, 분만시그통과가최대치에이르기때문에임신 3분기이후에는 infliximab의투여를금한다는의견도있었다. 16 따라서임신 2, 3분기투여에대한연구도추후에이루어져야하겠다. 이번증례에서는 infliximab을임신전 3회및임신 7주에 1 회투여하였다. 이후환자가복통없이임신을유지하여더이상의 infliximab을주사하지는않았으며, 정상여아를 41주에질식분만하여임신초기 infliximab이태아에게안전하였고오히려임신전에질병의활성도를안정시켜더좋은임신결과를얻었던것으로생각된다. Vasiliauskas 등 17 은임신기간중 8주간격으로 infliximab을투여받은난치성크론병환자의유아에서 infliximab의농도를측정하였다. 분만 6주후혈청에서성인의치료농도에해당되는수치로 infliximab이검출되었지만모유에서는검출되지않았기에모유를통해서는유아에게전달되지않는것으로판단된다. 따라서이번증례와같이 infliximab 투여중모유수유도안전하다고본다. 하지만크론병조절을위해임신중 infliximab을 8주간격으로 10 mg/kg로투여한후출산한유아에서 BCG 접종후파종성감염으로사망한증례 18 가있으며, infliximab의반감기가 8-10일로길기때문에장기적으로유아의면역계에어떤영향을미치는지는지속적인관찰및추적이필요할것으로생각된다. 결론적으로크론병환자는의사와상담후임신과출산을계획하는것이중요하며활성기에는임신을피하는것이이상적이다. 불가피하게 infliximab 투여중임신이되었다면환자의증상이회복되기까지, 적어도임신중반부까지는안전하게사용할수있으므로불필요한임신중절을피하고, 의사와환자모두분만시기까지두려움없이질병의활성도를낮추는일에최선을다하면될것으로생각된다. 또한임신을원하는활동성크론병환자에서는조기에생물학적제제를사용하 여질병의관해를유도함으로써더좋은임신결과를얻을수도있을것으로제안한다. REFERENCES 1. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, : a KASID study. Inflamm Bowel Dis 2008;14: Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 1998;115: Hanauer SB, Feagan BG, Lichtenstein GR, et al.; ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359: Lee SH. Use of TNF inhibitor in particular clinical settings. J Korean Rheum Assoc 2009;16: Papa A, Mocci G, Bonizzi M, et al. Use of infliximab in particular clinical settings: management based on current evidence. Am J Gastroenterol 2009;104: Habal FM, Ravindran NC. Management of inflammatory bowel disease in the pregnant patient. World J Gastroenterol 2008;14: Kim WH. Inflammatory bowel disease and pregnancy. Intes Res 2003;2: Alstead EM, Nelson-Piercy C. Inflammatory bowel disease in pregnancy. Gut 2003;52: Hudson M, Flett G, Sinclair TS, Brunt PW, Templeton A, Mowat NA. Fertility and pregnancy in inflammatory bowel disease. Int J Gynaecol Obstet 1997;58: Park YS. Support good quality of life. Intes Res 2010;8(Suppl 2): Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-tnf-alpha monoclonal antibody ca2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7: Kwan LY, Mahadevan U. Inflammatory bowel disease and pregnancy: an update. Expert Rev Clin Immunol 2010;6: Lichtenstein G, Cohen RD, Fegan BG, et al. Safety of infliximab in Crohn s disease: data from 5000-patients TREAT registry. Gasteroenterology 2004;126(Suppl 2):A Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn's disease and rheumatoid arthritis. Am J Gastroenterol 2004;99: Mahadevan U, Kane S, Sandborn WJ, et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease. Aliment Pharmacol Ther 2005; 21: Schnitzler F, Fidder H, Ferrante M, et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy. Inflamm Bowel Dis 2011;17: Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental transfer The Korean Journal of Gastroenterology

5 Jang YW, et al. A Case of Crohn s Disease Normal Delivery after Infliximab Medication During Pregnancy 41 of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006;4: Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J. Case Report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn's disease. J Crohns Colitis 2010;4: Vol. 61 No. 1, January 2013

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar