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1 Korean J Gastroenterol Vol. 61 No. 5, pissn eissn ORIGINAL ARTICLE 단일기관에서경험한크론병에서 Infliximab 의치료효과 김연주, 김정욱, 이창균, 박현진, 심재준, 장재영, 동석호, 김효종, 김병호, 장영운 경희대학교의학전문대학원내과학교실 Clinical Outcome of Treatment with Infliximab in Crohn s Disease: A Single-Center Experience Yeon-Ju Kim, Jung-Wook Kim, Chang Kyun Lee, Hyun Jin Park, Jae-Jun Shim, Jae Young Jang, Suk Ho Dong, Hyo Jong Kim, Byung-Ho Kim and Young Woon Chang Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea Background/Aims: Our aim was to assess the long-term data regarding efficacy and safety of infliximab (IFX) treatment for refractory Crohn s disease (CD) patients in our tertiary teaching hospital. Methods: We have retrospectively analyzed the medical records of 89 CD patients who underwent IFX treatment between March 2003 and February 2011 at Kyung Hee University Hospital (Seoul, Korea). The primary outcome measurements were the rates of initial clinical response (CR) at 10 weeks after the 1st IFX infusion and sustained CR at the end of the follow-up. Overall adverse events related to IFX treatment were also evaluated. Results: The mean (SD) follow-up period of eligible 80 patients was 33.7 (21.9) months. A total of 77 patients (96%) showed initial clinical response, but 8 patients showed loss of response to IFX during the follow-up. Finally, 59 patients (59/77, 76.6%) showed sustained CR at the end of the study. Logistic regression analyses showed that an initial CR at 10 weeks was the independent predictor associated with sustained CR (OR , 95% CI , p=0.001). Overall adverse events reported in 18 patients (18/80, 23.3%), including 3 serious infection (pulmonary tuberculosis and herpes zoster). Conclusions: Treatment with IFX was efficacious and relatively safe for refractory CD patients in Korea. An initial CR at 10 weeks was significantly associated with sustained CR. (Korean J Gastroenterol 2013;61: ) Key Words: Inflammatory bowel disease; Crohn s disease; Infliximab; Safety 서론 크론병 (Crohn s disease, CD) 은호전과악화를반복하며진행하는대표적인만성염증성장질환으로, 국내의크론병유병률은아직서구에비해낮은편이지만꾸준히증가추세에있고궤양성대장염에대한크론병의비율도점차높아지고있는추세이다. 1 크론병은발병당시에는관내강염증만이대부분의환자에서관찰되지만, 시간이경과할수록대부분의환자들에서누공이나협착과같은합병증이발생하여누적수 술률이증가하는데, 이는전통적인크론병치료약제와방법이질병경과를호전시키지못하기때문으로생각되고있다. 2,3 하지만최초의생물학제재인 infliximab이처음크론병치료에도입된이후 10년간다양한항 tumor necrosis factor (TNF) 치료의경험과연구결과가축적되면서최근크론병치료의패러다임에큰변화가이루어지고있다. 4 Infliximab은염증성사이토카인인 TNF-α에대한단클론항체로, 이미여러전향적무작위대조연구에서스테로이드불응또는의존크론병과누공크론병에대해효과가입증되어 5-7 기존치료에 Received November 19, Revised February 19, Accepted March 4, 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 : 이창균, , 서울시동대문구경희대로 23, 경희대학교병원내과 Correspondence to: Chang Kyun Lee, Department of Internal Medicine, Kyung Hee University Hospital, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul , Korea. Tel: , Fax: , cklee92@paran.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 61 No. 5, May

2 Kim YJ, et al. Outcome of Infliximab Therapy in Crohn's Disease 271 반응이없는크론병환자에서관해유도와유지치료에중요한치료약물로자리매김하였다. 최근에는질병초기부터 infliximab과같은강력한항염증약물을투여하여단순한증상조절이아닌기저관내강염증을효과적으로치료하고, 완전한점막치유 (mucosal healing) 를유도하여질병의경과를변화시킴으로써궁극적으로는장기능을보존하는것이새로운치료목표가되고있다 하지만기존의연구들대부분이서구의크론병환자를대상으로시행된것이며, 생활양식과유전학적소인이상당한차이를보이는한국인환자에그대로적용하는것은적절하지않을수있다. 특히국내에는현재까지전향적무작위대조연구가없을뿐아니라, 많은수의환자를대상으로 1년이상장기추적한관찰연구도극히미비하여한국인크론병에서 infliximab 치료의장기효과와안전성을가늠하기어려운것이현실이다. 이번연구에서는단일기관에서난치성크론병으로진단하여 infliximab 치료를시행하고장기간추적관찰한환자들의치료성적을단면적으로분석하여, infliximab에대한치료효과와안전성을알아보고자한다. 대상및방법 1. 대상 2003년 3월부터 2011년 2월까지경희대학교병원소화기내과에서크론병으로진단되고, 기존치료에호전이없어난치성크론병으로진단한환자들중 infliximab으로치료받은 15세이상환자들의의무기록을후향분석하였으며, 2011년 8월을추적종료시점으로하였다. 크론병의질병분류는몬트리올분류 12 를사용하였으며, infliximab 투여의적응증은불응장관내질환 (refractory luminal CD) 또는누공크론병환자 (fistulizing CD) 를대상으로하였다. 불응장관내질환은스테로이드불응또는의존환자이면서면역조절제에반응이없는중등증이상환자로크론병질병활성도 (Crohn s disease activity index, CDAI) 점수가 220점이상 400점이하인경우로정의하였고, 스테로이드불응은최소 4주이상 prednisolone 40 mg/day 이상용량의치료에도반응이없는경우로, 스테로이드의존은스테로이드치료초기에반응을보였으나스테로이드감량도중또는중단 4주이내에증상악화를보인경우로각각정의하였다. 누공병변의환자의경우기존의항생제, 면역조절제등의약물치료에도불구하고누공의호전이없는경우를치료대상으로하였다. 2. Infliximab 치료방법과반응평가 Infliximab 투여시전처치로 hydrocortisone 100 mg을 정맥내투여하였고 5 mg/kg의용량으로 2시간동안정주하였다. Infliximab 치료를시작하면서기존에투여하던 5-aminosalicylic acid (5-ASA) 제제와면역조절제 (azathioprine, 6-mercaptopurine, methotrexate) 는용량변화없이병용투여하였고, 스테로이드제제는증상호전시감량하여중단하였다. 국내에서 infliximab의보험적용이이루어지기전증상의재발시관해유도만을위해단기간 infliximab를투여받다가중단하였거나, 불규칙적으로 infliximab을투여받다가이후에규칙적유지치료로전환한환자는간헐적투여군 (episodic treatment) 으로정의하였으며, 관해유도를위해 0, 2, 6주째 infliximab를투여받고 8주간격으로규칙적유지치료를시행받은환자들은규칙적투여군 (scheduled treatment) 으로정의하였다. 연구의일차목표인 infliximab 투여후치료반응평가는 CDAI 점수를이용하였으며전체연구대상환자중최초투여시점으로부터 10주째호전여부인초기임상반응률 (initial clinical response rate) 과연구종료시점에초기임상반응의유지여부인지속적임상반응률 (sustained clinical response rate) 로나누어알아보았다. 초기임상반응은불응장관내병변의경우 10주째완전히증상이호전되어 CDAI 점수가 150 이하로측정된경우를완전반응 (complete response), CDAI 점수가 70점이상감소하였으나 150점이하로호전되지않아증상이여전히남아있는경우를부분반응 (partial response), 증상의호전이없어 10주이내투여를중단한경우를무반응 (primary non-response) 으로정의하였다. 13 누공병변에대해서는누공으로부터배출이없고모든누공이막힌경우를완전반응, 누공이남아있으나그개수나크기혹은배출정도가감소한경우를부분반응, 그이외의경우를무반응으로정의하였다. 14 또한최초투여후 10주째 CRP를측정하여 50% 이상감소또는정상범주인경우 (normal <0.3 mg/dl), 생물학적반응 (biologic response) 이있는것으로정의하였다. 지속적인임상반응은초기임상반응을보인환자들가운데연구종료시점까지증상과질병활성도가모두호전된상태로유지된경우로정의하였다. 3. Infliximab 치료반응예측인자초기임상반응을보인환자들을추적관찰하여지속적인임상호전상태를보인환자들과그렇지못한환자들의임상적특징들, 즉성별, 흡연여부, 복부수술의기왕력, 장외증상, 진단당시나이, infliximab 첫투여시나이, 진단후첫투여까지기간 (48개월미만 ), 규칙적투여여부, 면역조절제병용투여여부, 첫투여후 10주째초기완전임상반응, white blood cell (WBC), CRP, CDAI 등을확인하여치료반응을예측할수있는인자를조사하였다. Vol. 61 No. 5, May 2013

3 272 김연주등. 단일기관에서경험한크론병에서 Infliximab 의치료효과 4. 안전성평가이번연구의 2차목표인 infliximab 치료의안전성을살펴보기위하여, 연구기간중 infliximab 투여와관련하여발생한모든부작용을평가하였다. 부작용이경미하고특별한치료없이회복되거나일시적인보존적치료로호전된경우를경증부작용 (minor adverse event) 으로정의하고, 입원및입원기간의연장이나심각한장애 (disability) 및사망에이른경우는중증부작용으로 (serious adverse event) 정의하였다. Infliximab 주입후 1시간이내발생한모든부작용은급성주입반응 (infusion reaction) 으로, 이후에발생한경우에는지연주입반응으로정의하였으며, 근육통, 관절통, 발열및발진등이나타나는경우를포함하였다. 5. 통계분석연속변수는 Student t-test, 범주형변수는 chi-square test 및 Fisher s exact test를시행하여분석하였고, 변수는비율 (%) 과평균 ( 표준편차 ) 으로제시하였다. Kaplan-Meier 분석을시행하여연구종료시점의지속적임상반응률을평가하였다. 이후로지스틱회귀분석 (logistic regression analysis) 을시행하여 infliximab 치료후지속적임상반응에영향을미치는독립적예측인자를알아보고자하였다. 통계프로그램은 PASW Statistics for Window 18.0 (IBM Co., Armonk, NY, USA) 를사용하였고통계적유의성은 p값이 0.05 미만일때로하였다. 결과 1. 대상환자의임상적특성총 89명의환자를대상으로연구가진행되었으며, 이중 9명은마지막추적기간까지자료가불충분하여연구에서배제되었고총 80명의환자를최종분석하였다 (Fig. 1). 남자가 55명 (68.8%) 이었고진단시와 infliximab 첫투여시평균연령은각각 27세 (27.0±8.9세) 와 28.5세 (28.5±10.3세) 였다 (Table 1). 최초 infliximab 투여시평균 CDAI 점수는 284점, 평균 CRP값은 3.37 mg/dl로모두활동성크론병이었다. Infliximab 투여의적응증은불응장관내질환이 35명 (43.8%), 누공질환이 45명 (56.2%) 이었으며투여방법으로는간헐적투여가 14명 (17.5%), 규칙적투여가 66명 (82.5%) 이었다. 크론병진단후 infliximab 투여까지유병기간의평균값은 55.6±52.6개월이었고처음 infliximab 투여후추적관찰기간의평균값은 33.7±21.9개월이었다 (Table 1). Infliximab 투여당시환자가복용하고있던약제는 63명 (78.8%) 이 5-ASA 제제, 15명 (18.8%) 이스테로이드제제였고, 67명 (83.8%) 은 azathiopurine이나 6-mercaptopurine (6-MP) 등의 thiopurine 제제를복용하고있었으며 1명 (1.3%) 은 methorexate를복용하고있었다 (Table 1). 모든환자는 infliximab 투여하기전에투베르쿨린반응검사 (tuberculin test) 를시행하였고 55명은결핵특이항원인 Fig. 1. Flow chart of the study population. CD, Crohn s disease; IFX, infliximab; TB, tuberculosis. The Korean Journal of Gastroenterology

4 Kim YJ, et al. Outcome of Infliximab Therapy in Crohn's Disease 273 Table 1. Patients Baseline Characteristics Characteristic Data (n=80) 16/58/6 (20.0/72.5/7.5) Male/female 55/25 (68.8/31.2) Age (yr) At diagnosis 27.0±8.9 At the first infusion of IFX 28.5±10.3 Smoker 14 (17.5) BMI (kg/m 2 ) 19.8±3.4 Previous abdominal surgery 17 (21.3) CDAI 284±79 CRP (mg/dl) 3.37±3.67 Montreal classification Age at diagnosis (A1/A2/A3) a Location (L1/L2/L3/L4) b 12/18/49/1 (15.0/22.5/61.3/1.2) Behavior (B1/B2/B3) c 63/13/4 (78.8/16.2/5.0) Indication for IFX treatment Luminal CD 35 (43.8) Fistulising CD 45 (56.2) Treatment schedule Episodic treatment 14 (17.5) Scheduled treatment 66 (82.5) Duration of disease prior to 55.6±52.6 1st IFX infusion (mo) Follow up period after 1st IFX 33.7±21.9 infusion (mo) Number of infusion of IFX 13.8±8.4 (3-37) Concomitant medication at 1st IFX Aminosalicylates 63 (78.8) Steroids 15 (18.8) AZA/6-MP 67 (83.8) MTX 1 (1.3) QuantiFERON-TB Gold test 48/7/25 (60.0/8.8/31.2) (negative/positive/no test) Values are presented as n (%), mean±sd, or mean±sd (range). CDAI, Crohn s disease activity index; CD, Crohn s disease; IFX, infliximab; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate. a A1, 16; A2, 17-40; A3, 40. b L1, ileitis; L2, colitis; L3, ileocolitis; L4, upper gastrointestinal. c B1, inflammatory or nonstricturing; B2, stricturing; B3, penetrating. 터페론-감마분비검사 (interferon-gamma release assay) 로 QuantiFERON-TB Gold (QFT-G; Cellestis, Carnegy, Australia) test도함께시행하였다. 이두가지검사중최소한가지검사에서양성소견을보인 7명 (8.8%) 의환자에게 infliximab 투여전 isoniazid 300 mg을 3주간투여하였고, 이후 9개월간유지요법을시행하였다. 2. 초기임상반응 (Initial clinical response) Infliximab 첫투여후 10주째평가에서임상반응을보인경우는 77명 (96%) 이었으며증상의호전이없어 10주이내투여를중단한경우인무반응 (primary non-responder) 환자가 3명 (4%) 이었다 (Fig. 1). 임상반응을보인환자중완전반응을보인환자는장관내질환의경우 27명 (77.1%), 누공크론병환자에서는 33명 (73.3%) 으로의미있는차이는없었다 (p=0.637). 또한생물학적반응을보인경우도각각 28명 (85.0%), 37명 (82.2%) 으로두군사이에의미있는차이는없었다 (p=0.801) (Fig. 2). 3. 지속적인임상반응 (Sustained clinical response) 초기임상반응을보인 77명의환자중추적종료시점인 2011년 8월까지지속적인임상호전상태를유지한환자는 59명 (76.6%) 이었다. 초기반응을보인환자중에서 infliximab 을중단한환자는모두 18명 (23.4%) 이었으며, 원인으로는추적관찰기간중증상의악화를보인경우 (loss of response) 8명 (10.4%), 폐결핵 2명 (2.6%), 기타 8명 (10.4%) 이었다. 기타의원인으로는추적관찰실패 (5명), 임신 (2명), 경제적문제 (1 명 ) 였다 (Fig. 1). 장관내병변과누공병변을가진환자들에대해증상호전과생물학적반응을살펴보았을때증상의완전한소실을보인환자는각각 21명 (87.5%) 과 29명 (82.9%) 으로두군간에는통계적으로의미있는차이는없었고 (p=0.749), 생물학적반응에서도각각 19명 (79.2%) 과 33명 (94.2) 으로두군간에차이는없었다 (p=0.161) (Fig. 3). 지속적인임상반응을보인환자 59명중연구종료시점에 infliximab 투여를유지하고있던환자는 48명 (62.3%) 이었으며, 나머지 11명 (14.3%) 의환자는완전관해를보여투여를중단하였다. 이 11명의환자들의투여형태는규칙적으로투여했던경우가 9명으로간헐적으로투여한 2명보다많았고, 중단후에도모든환자가평균 35.4개월동안관해를유지하였다. 또한 11명의환자중 8명은 infliximab 투여중단후면역조절제를유지하였으며 7명은 azathiopurine을, 1명은 methotrexate를복용하였다. 4. 지속적인임상반응에대한예측인자분석초기반응을보인 77명환자중최종추적기간까지지속적인임상반응을보인환자 59명과추적관찰기간중증상의악화를보여 infliximab을중단한환자 8명의두군으로나누어각각의임상적특징들에대해단변량분석과다변량분석을시행하였다. 지속적인임상반응에대한다변량분석에서첫투여후 10주째초기완전임상반응 (OR , 95% CI , p=0.001) 을보인경우만이통계적으로의미있는결과를보였다 (Table 2, Fig. 4). 5. 이상반응이상반응은총 18명 (23.3%) 에서보고되었다. 이중 13명 (16.9%) 의환자는경도의근육통이나유사감기증상등을경 Vol. 61 No. 5, May 2013

5 274 김연주등. 단일기관에서경험한크론병에서 Infliximab 의치료효과 Fig. 2. Clinical response at 10 weeks after the initiation of the infliximab treatment. CD, Crohn s disease. Fig. 3. The sustained clinical and biologic response in patients with Crohn s disease (CD) at the end of follow-up. Table 2. Factors Predicting Sustained Clinical Response to Infliximab Therapy by Multiple Regression Analysis OR 95% CI p-value Presence of fistula Smoking Age at diagnosis (>20 yr) Age at the 1st infusion (>25 yr) Duration prior to 1st IFX (<48 mo) Concomitant medication Aminosalicylates Steroid Clinical CR at 10 weeks IFX, infliximab; AZA, azathioprine; 6-MP, 6-mercaptopurine; CR, complete response. 험하였고나머지 5명 (6.4%) 이임상적으로의미있는이상반응을경험하였다 (Table 3). 이 5명중 2명 (2.6%) 의환자는 infliximab 투여당일경도의발진과소양감을호소하였으나문제없이투약을종료할수있었다. 1명 (1.3%) 의환자에서대상포진이발생하였으며항바이러스치료후호전되었고, 2명 (2.5%) 의환자는폐결핵이발생하였다. 폐결핵이발생한두명모두 infliximab 투여전투베르쿨린반응검사는음성이었으며 QuantiFERON-TB Gold test는시행하지않았다. 이중한명은폐결핵진단후외래추척관찰이중단되었고, 나머지한명은 6개월간항결핵제복용후완치되었다. The Korean Journal of Gastroenterology

6 Kim YJ, et al. Outcome of Infliximab Therapy in Crohn's Disease 275 Fig. 4. The sustained clinical response in patients with Crohn s disease at the end of follow-up stratified by of the disease prior to the infliximab (IFX) treatment (A) and clinical complete response at 10 weeks (B) via Kaplan Meier survival plots. CR, complete response; PR, partial response. Table 3. Adverse Events after Infliximab Treatment Types of adverse events Data Minor and transient side effects a 13 (16.9) Acute infusion reaction 2 (2.6) Serious adverse events 3 (3.9) Herpes zoster 1 (1.3) Pulmonary tuberculosis 2 (2.6) Total 18 (23.3) Values are presented as n (%). a Myalgia, flu-like symptom or arthralgia. 고 찰 Infliximab은여러전향적대조군연구에서기존의치료에반응하지않는장관내크론병이나누공크론병의치료에있어관해유도와유지에효과적임이입증되었다. 5,6,13 이연구들에서단기적으로 80% 이상의환자들이증상호전을경험하였고 50% 이상에서는완전관해에이르렀다. 6,13 또한국내에서 infliximab의치료효과를보고한연구들에서도 80% 전후의단기치료반응률과다양한임상소견들에훌륭한치료효과를보였다. 15,16 하지만실제임상에서 infliximab의장기적인효과에대한결과는아직확립되지않았으며현재몇몇의서양연구들이 17,18 보고되어있고국내에서는현재진행되고있는대규모코호트연구를통해 infliximab 치료의장기적인예후에대한결과를알수있을것으로기대하고있다. 이번연구에서 infliximab의단기효과를본 10주째임상반응률이 96% 로, 이중완전반응을보인환자는장관내병변에서는 77.1%, 누공병변에서는 73.3% 로조사되었다. 이는이전연구들과 6,13,15,16 유사한결과이나, 일반적으로장관내병변에비해치료가힘들 고경과가좋지않은누공형병변에대해서도유의한차이없이높은조기반응을보였다. 또한이번연구에서초기임상반응을보였던 77명의환자를평균 33.2개월간추적관찰하였을때지속적임상반응률은 76.6% 로이전서양연구들에서 11,17,18 보고한약 65% 와비교하여비교적높은반응률을보였다. 서양연구에 11,17 비해추적관찰기간이짧아직접적으로비교하긴어렵고이전국내보고가없어단정하긴어렵지만, 국내크론병환자에서지속적인임상반응률이서양환자에비해높을가능성을생각해볼수있겠다. 이러한가정은향후국내대규모코호트연구를통한장기간추적관찰로확인이필요하겠다. Infliximab은크론병치료의중요한목표중의하나인점막치유에도효과적임이보고되고있다. 10,19,20 Infliximab은단기요법을통해점막치유를유도하고 19 정기유지요법으로점막치유와함께크론병관련입원율 20 및수술률을 10 줄여주는것으로알려져있다. 최근 infliximab을투여받은 214명의크론병환자의점막치유를통한장기예후를예측한대규모코호트연구에서, 초기반응을보인 183명의환자중약 68% 가점막치유를보였고정기요법이 45.4% 로 22.4% 의간헐적투여보다유의하게높은점막치유율을보였다. 10 좀더장기간관찰을통해점막치유효과를본다른연구에서 infliximab 유지치료환자의약 50% 가투여 54주후에점막치유를보였다고보고하였다. 20 결과에서언급하지않았지만이번연구에서 infliximab 투여전후로대장내시경을시행한 47명의환자중 31명 (65.9%) 이마지막추적관찰시점막의완전치유를보였다. 또한이들의투여형태에따라살펴보았을때정기유지요법이간헐적투여보다더높은점막치유율을보여 (55.3%:4.2%, p<0.001) 이전서양연구들과유사한결과를 Vol. 61 No. 5, May 2013

7 276 김연주등. 단일기관에서경험한크론병에서 Infliximab 의치료효과 보였다. 이번연구에서 68명 (85%) 의환자가 infliximab 투여기간중 thiopurine 혹은 methotrexate와같은면역조절제를병용투여하였다. 면역조절제병용투여의효과에대해서는아직까지확립된지침은없다. 초기연구들에서 21,22 간헐적투여군에있어면역조절제가 infliximab에대한항체생성을감소시켜부작용을감소시키고치료효과를높인다고보고하였지만현재일반적으로규칙적인유지치료가권고되고있는상황에서이를그대로적용하기에는무리가있다. 또한 infliximab 유지치료시면역조절제병용투여효과에대해연구마다차이를보이고있다. 9,23-25 국내연구들도보고마다차이가있는데투여당시면역억제제를 3개월이상복용한군에서유의하게낮은조기재발을보고한연구가 15 있고다른보고에서는 26 azathioprine 병합투여한장관내크론병환자에서큰이득이없다고보고하였다. 더욱이면역조절제의병용투여가악성종양과같은심각한부작용을높인다는보고들도 있어현재국내가이드라인에서는환자의임상양상에따라병용투여를고려할것을권고하고있다. 30 이번연구에서는 85% 의환자에서면역조절제를병용투여하여병합투여환자의비율이높아직접적으로 infliximab 단독투여군과비교하기어려웠다. 따라서향후추가적인연구들을통하여이에대한확인이필요하겠다. 추가적으로본연구에서 infliximab 초기투여시최종추적기간까지지속적인임상반응을예측할수있는인자를조사하였다. 그중에서 10주째초기임상반응을보인경우가지속적인임상반응예측인자로서의미가있었다 (Table 3, Fig. 4). 반면연령, 흡연여부, 면역조절제병용투여여부, 진단후 infliximab 투여시까지기간및질병행태 ( 장관내질환혹은누공형 ) 등은예측인자로서의미는없었다 (Table 3, Fig. 4). 이는과거서양연구에서흡연유무, 면역조절제병용투여 18,24 및질병행태 18 등이의미있는예측인자로제시되었고국내연구에서질병행태와 16 면역조절제병용투여가 15 치료반응과관련이있다는보고들과차이가있었다. 하지만 infliximab 투여전질병이환기간은다른연구결과와 11,18 마찬가지로의미가없었다. 예측인자로의미가다른연구들의결과와는일치하였다. 서양에서도현재까지지속적인임상반응을예측할수있는인자들이확립되어있지않고국내연구들도서로결과가달라명확한결론을내리기는힘든상황이지만향후대규모코호트연구를통해의미있는예측인자를도출해낸다면이를이용하여 infliximab 투여의비용및부작용을고려한맞춤치료를기대할수있을것이다. Infliximab의적응증이확대되어사용이증가하면서이의부작용에대한관심도증가하고있는데현재까지 infliximab 투여와관련한심각한부작용이 6-20% 까지보고되고있 다. 5,14,31,32 비교적경미한부작용중하나인급성주입반응은과거서양보고에따르면 5-19% 정도이며 14,33,34 국내에서는 % 로보고되고있다. 15,16 이번연구에서이상반응을보인 5명 (6.3%) 의환자중 2명 (2.5%) 이급성주입반응을보여약간낮은발생률을보였다. 이는면역조절제 (85.0%) 및스테로이드투여 (78.8%) 환자들의비율이비교적높아기존연구들에서 5,31 보인면역조절제혹은스테로이드병용투여가주입반응을감소시킨다는보고에부합한결과로생각된다. 다른주요한부작용인감염이 3명 (3.8%) 의환자에서발생하였고 1명의환자에서대상포진이발생하여항바이러스제치료후호전되었고나머지 2명의환자는폐결핵에감염되었다. Infliximab의투여는감염의위험을증가시키는것으로알려져왔으며 14,31,32 특히우리나라에서유병률이높은결핵의발생을약 8배까지증가시키는것으로알려져있다. 35 따라서 infliximab 투여전현증결핵및활동결핵으로진행할가능성이높은잠복결핵에대한철저한평가가필요할것으로생각된다. 이전에보고되었던악성종양, 자가면역질환및사망등과같은심각한합병증은 31 과거국내보고와 15,16,26 마찬가지로이번연구에서도관찰되지않았다. Infliximab 투여와관련된대부분의합병증은비교적경미하고보존치료에잘반응하지만치명적인감염이발생할수있으므로주의깊은감시가필요하다. 이번연구는과거 13명 15 과 40명 16 의크론병환자를분석한국내후향연구들과비교하여가장많은수의크론병환자를대상으로하였으며, 추적기간의중앙값도 33.7개월로길어국내환자들의 infliximab 투여반응효과및부작용을평가하는데의미있는연구로생각된다. 하지만유병률이높은서양의연구들과비교하면환자수가적어치료효과, 안전성및예측인자등을비교평가하는데제한점이있다. 따라서향후국내에서다기관코호트연구를통한대규모의연구를통해이러한문제를해결하여의미있는결과가나올수있을것으로기대한다. 결론으로이번연구를통해한국인크론병의치료에있어서도 infliximab의투여는효과적이고부작용도적어비교적안전하게사용할수있으며진단후조기에투여하고초기에임상반응이좋다면훌륭한장기적인효과를기대할수있을것이다. 요약 목적 : Infiximab은기존의치료에반응하지않는장관내병변과누공성병변의치료에서효과적이며비교적안전한치료이다. 이번연구는국내단일기관에서 infliximab으로치료받은크론병환자를대상으로장기간에걸쳐 infliximab의효과와 The Korean Journal of Gastroenterology

8 Kim YJ, et al. Outcome of Infliximab Therapy in Crohn's Disease 277 안전성에대하여분석하고자하였다. 대상및방법 : 2003년 3월부터 2011년 2월까지경희대학교병원소화기내과에서 infliximab으로치료받은 80명의크론병환자들을후향분석하였다. 임상반응은초기임상반응과지속적인임상반응으로분류하였다. 결과 : Infliximab 첫투여후추적기간의중앙값은 33.7개월이었다. Infliximab 투여후 10주째초기임상반응을보인경우는 77명 (96%) 이었으며불응장관내질환의경우 27명 (81.8%), 누공질환의경우는 33명 (75%) 으로유의한차이는없었다 (p=0.475). 또한초기반응을보인 77명의환자중최종추적기간까지지속적인임상호전을유지한환자는 59명 (76.6%) 이었다. 이중 11명의환자들은완전관해를보여 infliximab 투여를중단하였고, 중단후에도평균 35.4개월동안관해를유지하였다. 지속적인임상반응에대한예측인자분석에서는오직첫투여후 10주째초기완전임상반응 (OR , 95% CI , p=0.001) 을보인경우만이통계적으로의미있는결과를보였다. 총 18명의환자에서이상반응이관찰되었고, 1명의환자에서대상포진이, 2명에서폐결핵이발생하였다. 결론 : 한국인크론병의치료에있어서 infliximab의투여는효과적이고부작용도적어비교적안전하게사용할수있으며투여후 10주째초기완전임상반응만이지속적인임상반응의예측인자로서의미가있었다. 색인단어 : 염증성장질환 ; 크론병 ; Infliximab; 효과 ; 안전성 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: Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn's disease. Inflamm Bowel Dis 2002;8: Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology 2008;135: Danese S, Colombel JF, Reinisch W, Rutgeerts PJ. Review article: infliximab for Crohn's disease treatment--shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther 2011;33: 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: Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340: Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350: D'Haens G, Baert F, van Assche G, et al; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet 2008;371: Colombel JF, Sandborn WJ, Reinisch W, et al; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362: Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn's disease. Inflamm Bowel Dis 2009;15: Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort. Gut 2009;58: Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006;55: Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease ca2 Study Group. N Engl J Med 1997;337: Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Infliximab for Crohn's disease in clinical practice at the Mayo Clinic: the first 100 patients. Am J Gastroenterol 2001;96: Choi KD, Song HJ, Kim JS, Jung HC, Song IS. Efficacy and safety of treatment with infliximab in Crohn's disease-the experience of single center in Korea. Korean J Gastroenterol 2005;46: Kim SH, Yang S, Kim KJ, et al. Efficacy of infliximab in the treatment of korean patients with crohns disease. Korean J Gastroenterol 2009;54: Rudolph SJ, Weinberg DI, McCabe RP. Long-term durability of Crohn's disease treatment with infliximab. Dig Dis Sci 2008;53: Sprakes MB, Ford AC, Warren L, Greer D, Hamlin J. Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: a large single centre experience. J Crohns Colitis 2012;6: D'haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. Gastroenterology 1999;116: Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc 2006;63: Vermeire S, Noman M, Van Assche G, Baert F, D'Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut 2007;56: Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348: Lichtenstein GR, Diamond RH, Wagner CL, et al. Clinical trial: Vol. 61 No. 5, May 2013

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untitled 대한소화기학회지 2009;54:108-116 DOI: 10.4166/kjg.2009.54.2.108 한국인크론병에대한 Infliximab 의효과 울산대학교의과대학서울아산병원내과학교실 김세희ㆍ양석균ㆍ김경조ㆍ김은희ㆍ윤순만ㆍ예병덕ㆍ변정식ㆍ명승재ㆍ김진호 Efficacy of Infliximab in the Treatment of Korean Patients with