02 02 KJG (김지원)162.hwp

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1 Korean J Gastroenterol Vol. 70 No. 4, pissn eissn REVIEW ARTICLE 염증성장질환환자에서면역조절제와생물학적제제사용이암발생에미치는영향 김지현 1,2, 김지원 1,2 서울대학교의과대학내과학교실 1, 서울대학교병원운영서울특별시보라매병원내과 2 Effect of Immunomodulators and Biologic Agents on Malignancy in Patients with Inflammatory Bowel Disease Jee Hyun Kim 1,2 and Ji Won Kim 1,2 Department of Internal Medicine, Seoul National University College of Medicine 1, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center 2, Seoul, Korea Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD. (Korean J Gastroenterol 2017;70: ) Key Words: Inflammatory bowel disease; Malignancy; Azathioprine; 6-Mercaptopurine; Tumor necrosis factor-alpha 서론 크론병과궤양성대장염으로대표되는염증성장질환은재발과호전을반복하며위장관에염증을일으키는만성질환이다. 염증성장질환의발병기전은아직명확하게밝혀져있지않지만, 면역요인과함께유전적요인, 환경요인, 장내미생물요인이복합적으로작용할것으로여겨지고있다. 북미와서유럽등일찍이산업화가이루어진곳에유병률이높았으나최근우리나라를포함한아시아지역에서도그발병률과유병률이지속적으로증가하고있어이에대한관심이나날이높아지고있다. 1 염증성장질환은오랜기간동안만성적인장관의염증으로인하여장기적으로환자삶의질을떨어뜨리고, 장협착, 누공, 농양, 대장암과같은합병증이발생하게되는데, 염증성장질환의치료목표는점막치유를달성하여이러한질병경과를줄이는것이다. 면역조절제 (thiopurine, methotrexate) 와생물학적제제 (anti-tumor necrosis factor [TNF] agent) 는효과적인염증성장질환의치료제이지만, 종양발생의위험을증가시킬수있다는우려가있다. 이전연구를통해염증성장질환에서 thiopurine 사용은림프세포증식질환, 피부암등의위험을높일수있는것으로알려져있지만, 2,3 생물학적제제사용과암발생에대한대규모연구는많지않다. 최근면역억제제와생물학적제제에대한임상경험이축적되면서염증성장질환에서이들치료와관련된암에대한연구들이발표되고있다. 이에본종설에서는염증성장질환에서면역억제제, 생물 Received September 6, Revised September 25, Accepted October 17, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 김지원, 07061, 서울시동작구보라매로5길 20, 서울대학교병원운영서울특별시보라매병원소화기내과 Correspondence to: Ji Won Kim, Division of Gastroenterology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, Korea. Tel: , Fax: , kjwjor@snu.ac.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 70 No. 4, October

2 Kim JH and Kim JW. IBD Therapy and Malignancy 163 학적제제사용과연관된암발생에대해알아보고자한다. 본론 1. 대장암염증성장질환의유병기간이길어지고광범위한대장침범이있는경우대장암의발생위험이높아지는것으로알려져있다 년 Eaden 등이발표한 116개논문의메타분석에서궤양성대장염의경우대장암의연간발생률이 0.3%, 누적발생률이질병이환기간 10년에 1.6%, 20년에 8.3%, 30년에 18.4% 였으나, 년영국의전향적감시프로그램자료에서는누적발생률이 20년에 2.5%, 30년에 7.6%, 40년에 10.8% 로낮아졌다. 5 대규모코호트연구결과에따르면염증성장질환환자에서대장암의표준화발생비 (standardized incidence ratio, SIR) 는 1990년 5.7배에서 2000년이후의연구에서는 배로과거보고에비해상대적으로발생위험이낮았다. 7-9 심지어미국 Olmsted count 지역에서시행한코호트연구는궤양성대장염환자에서일반인구집단과비교하여대장암의발생률이높지않다는결과를보고하기도하였으나, 10 최근의메타분석에의하면궤양성대장염환자에서는대장암발생위험이일반인구에비해약 2.4배높았다. 11 이렇게과거에비해대장암발생위험이줄어드는이유로는초기연구에서의선택비뚤림, 향상된염증조절약물효과, 적절한시기에시행된대장절제술, 감시프로그램도입등을들수있다. 국내다기관연구에서궤양성대장염관련대장암의누적발생률은 10년, 20년, 30년에각각 0.7%, 7.9%, 33.2% 로서양과비교하여크게다르지않았다. 12 Thiopurine은염증성장질환에서이러한대장암의위험을감소시키는것으로보인다. 염증성장질환에서발생하는대장암은장상피층의만성염증에기인하고, 관련되는유적적기전은산발성대장암과는다른것으로알려져있다. 13 만성염증은염증세포에서분비되는과도한 cytokine, chemokine 들이상피세포의사멸을억제, 과성장을유도하고, 13 이과정에서 DNA 변화가빈번히발생하여억제유전자의변이가유도되며, 이는암을유발하게된다. 14 Thiopurine은다른특정항암기전이아닌, 이와같은점막염증을감소시킴으로써염증성대장암을예방하는것으로이해된다. 장기이식환자와같이염증성장질환이아닌다른질환에서는 thiopurine 사용이대장암위험을감소시키지않았다 년네덜란드에서발표된연구에서 2,578명을대상으로전향적연구를시행하였고, azathioprine을적어도 6개월간유지하였을경우대장암의예방에유의한효과를보였다 (high-grade dysplasia or/and cancer, adjusted hazard ratio [HR] 0.10, 95% confidence interval [CI] ). 16 Gong 등이시행한메타분석에서도 thiopurine 사용은대장에서신생물 ( 이형성과암 ) 발생을유의하게감소시켰는데 (relative risk [RR] 0.71, 95% CI ), thiopurine군에서진행신생물의 RR은 0.72 (95% CI ), 암의 RR은 0.70 (95% CI , p=0.111) 이었다. 17 하지만다른메타분석에서는염증성장질환환자에서신생물의위험에대한 thiopurine의유의한효과가없음을보고하기도하였다 (odds ratio [OR] 0.87, 95% CI ) ,484명의염증성장질환환자를대상으로프랑스에서시행된 Cancers Et Surrisque Associéaux Maladies inflammatoires intestinales En France (CESAME) 연구에서도현재 thiopurine 사용은일반인에비해대장암의위험을높이지않았지만, 장기간에걸친광범위한대장염을앓고있는환자를대상으로한하위분석에서는진행성대장신생물의발생위험을유의하게감소시켰다 (HR 0.28, 95% CI ). 19 항 TNF 제제와같은생물학적치료에서대장암위험에대해평가한연구는지금까지거의없었는데, 염증성장질환과관련된대장암의위험인자를확인한네덜란드연구에서항 TNF 제제사용이대장암발생의예방인자 (OR 0.09, 95% CI ) 였으나, 20 덴마크지역기반코호트연구에서항 TNF 제제는대장암발생에영향을미치지않았다 (adjusted RR 1.06, 95% CI ). 21 TNF-α는암세포의세포사멸 (cellular apoptosis) 을유도하여항암효과를보이기도하지만, 암세포의증식, 침습, 전이를자극하여암을촉진시키기도한다. 3,22 최근동물실험연구결과는 TNF-α가염증-매개성암발생을유발한다는것을보여주었다. 대장염연관성대장암 (colitis-associated colon cancer) 동물모델에서 TNF-α와림프구가대장점막고유판 (lamina propria) 에서증가하고, 항 TNF 제제를처리하였을때, 상피세포에서 NF-κB의불활성화와관련하여종양의수와크기가감소하는것을확인하였다. 23 이러한기전을통해항 TNF 제제가염증성장질환에서대장암발생을억제할가능성이있겠으나, 앞서언급한 TNFα의이중효과를고려하여향후더많은연구가필요하다. 2. 소장암소장암은발생기전이명확하게밝혀지지않았으나, 일반인과비교하여크론병에서현저하게증가하는것으로알려져있다. 미국 Olmsted count 지역에서시행한코호트연구에서크론병환자의소장암발생률은일반인에비해 40배이상높았으며, 10 세개의메타분석에따르면크론병환자에서소장암 SIR은 27.1 (95% CI ), 33.2 (95% CI ) 및 28.4 (95% CI ) 였다 또 13,756명의크론병환자를 30년간관찰한최근연구에서는 SIR이 8.4 (95 % CI ) 였다. 27 크론병에서발생한소장암은복통, 장폐색그리고 Vol. 70 No. 4, October 2017

3 164 김지현, 김지원. 염증성장질환치료와종양 체중감소가매우흔하였으며, 대부분이회장에위치하였다. 28 크론병에서스테로이드, 면역조절제및항 TNF 제제사용은소장암발생의잠재적인위험요인으로여겨지고있다. 이전연구에서원위부공장 / 직장질환, 협착및만성누공성질환, 긴질병이환기간, 진단시낮은연령, 남성과더불어스테로이드및면역조절제치료가소장암의위험인자로보고되었다 Lashner 31 가발표한환자-대조군연구에서는할로겐화방향족화합물, 지방족아민및석면에노출된직업력과 6-mercaptopurine 사용 (OR 10.8, 95% CI ) 이크론병에서소장암의발생과연관이있었다. 염증성장질환에서면역조절제및항 TNF 제제사용은소장암발생과연관성이제안되고있으나, 아직연구가충분치않은상황으로더많은연구가필요할것으로생각된다. 3. 림프증식질환 1) Thiopurine 제제염증성장질환환자에서 thiopurine과림프증식질환 (lymphoproliferative disorder) 관련성에대한다수의연구가있다. 염증성장질환에서 thiopurine 사용은림프종발생을증가시키며, 환자의연령, 유병기간, 약제사용기간등이그발생과연관이있었다. 영국에서시행된대규모지역기반환자-대조군연구에서한번이라도 azathioprine을사용한환자는사용한적이없는환자에비해림프종발생의위험이유의하게증가하였다 (OR 3.22, 95% CI ). 32 CESAME 전향적연구는 thiopurine을사용한염증성장질환환자에서림프종발생위험이사용하지않은환자에비해 5배증가하였을뿐만아니라, 항 TNF 제제와병용하여사용하였을경우그위험성이 10배로증가함을보여주었다. 33 이연구에서 65세이상, 남성및긴유병기간이림프종발생위험증가와연관이있었으며, thiopurine을사용하다가중단한경우에는사용하지않은환자와유사하게림프종의위험성이감소하였다. 또최근독일에서진행된지역기반코호트연구에서도비슷한결과를보여주었는데, 염증성장질환환자에서 thiopurine으로치료하였을때, 항 TNF 제제를투여하는경우 (thiopurine과병합또는단독투여 ) 와비교하여악성종양의발생위험이증가하였고 (HR 4.15, 95% CI ), 50세이상, 4년이상의 thiopurine 치료기간이피부암과림프종과관련이있었다. 2 5개의단일기관연구와 1개의인구기반연구를종합한메타분석을보면, SIR은 4.2 (95% CI ) 로 thiopurine 사용과림프증식질환이연관성을보였다. 34 하지만이후다른메타분석에서는 thiopurine과림프증식질환은연관성을보이지않았는데, 이는메타분석에포함된연구들의차이에기인하는것으로보인다. 35 국내다기관연구에서는총 6,585명 의염증성장질환환자를분석하였고, 이중림프종 7예 (0.1%) 가확인되었다. 염증성장질환환자에서림프종의 SIR 은 2.03 (95% CI, ), 크론병환자에서 SIR은 9.31 (95% CI, ) 이었으며, thiopurine에노출된환자에서림프종의 SIR은 5.93 (95% CI, ) 이었다. 36 장기이식환자에서 thiopurine 투여는 Epstein-Barr 바이러스 (Epstein-Barr virus, EBV) 와상당한연관성을가진림프세포증식질환의발생위험을증가시키는것으로알려져있다. 37 염증성장질환환자에서도 thiopurine 투여후발생하는림프증식질환은 EBV 감염과밀접한관계가있다. 1985년부터 2000년까지 Mayo 병원에서진료받은염증성장질환환자중에서림프종이발생한 18명을분석하였을때, thiopurine 치료를받은 6명중에서 5명이 EBV 양성인반면, thiopurine 치료를받지않았던 12명중에서 2명만이 EBV 양성이었다. 38 CESAME 연구에서확인된림프증식질환증례들중, EBV 활성화상태가확인된 19예중 12예 (63.2%) 에서 EBV 양성을보였다. 33 최근 17,384명의환자를대상으로한네덜란드연구에서는 44명의림프종환자중 33명에서 EBV 활성화상태를확인할수있었는데, 단 19% (4/21) 의 EBV 음성림프종환자에서 thiopurine을투약하였던반면, EBV 양성림프종환자의 92% (11/12) 가 thiopurine 치료를받았다. 39 Thiopurine은 EBV에감염된 B세포의증식을억제하는자연살해세포 (natural killer cell) 와세포독성 T세포 (cytotoxic T cell) 에독성을나타내어림프증식질환을발생시킬수있을것으로생각된다. 40 염증성장질환에서 thiopurine 사용은림프증식질환위험을증가시킬수있으며, 환자의연령, 유병기간, thiopurine 약제사용기간등이그발생에영향을미치는것으로보인다. 따라서 thiopurine을사용하는염증성장질환환자에서원인불명의두통, 피로또는발열, 장염증에기인하지않는림프절종대, 비장또는간장의크기증가, 혈구탐식성림프조직구증 (hemophagocytic lymphohystiocytosis) 이있을때에는림프세포증식질환을의심하고, EBV 부하를포함한검사수행및혈액학전문의의의견을구하는것이좋겠다. 41 2) 생물학적제제 Infliximab과 adalimumab 같은항 TNF 제제는염증성장질환의대표적인생물학적치료제로, 우리나라에서도그사용이급증하고있다. 항 TNF-α 제제도면역억제효과가있으므로림프증식질환발생과연관이있을것으로생각된다. 하지만면역조절제노출없이항 TNF 제제를쓰는환자가극히드물어항 TNF 치료와악성종양의연관성을평가하기는쉽지않다. 6,273명의크론병환자들을대상으로 5년간추적관찰한 Crohn s Therapy, Resource, Evaluation and Assessment The Korean Journal of Gastroenterology

4 Kim JH and Kim JW. IBD Therapy and Malignancy 165 Tool (TREAT) 연구에서 infliximab 사용에따른림프종의위험은증가하지않았으나 (RR 0.80, 95% CI ), 42 유지요법의유용성을알아본 A Crohn s disease Clinical trial Evaluating infliximab in a New long-term Treatment regimen (ACCENT) 1 연구에서는 1예의림프종이보고되었다. 43 이후의여러연구들에서도비록소수이지만림프종발생이보고되었는데, 대부분의림프종환자들이이전에 thiopurine을사용한병력이있었다. 44,45 크론병에서항 TNF 치료의효과와안전성을알아본메타분석에서항 TNF 치료군과대조군에서악성종양발생빈도에는차이가없었으며 (0.24% vs %, 95 % CI ), 46 Lichtenstein 등이시행한대규모연구에서도크론병환자에서 infliximab 사용과암발생사이의유의한연관성은없었다. 47 하지만최근 26개의연구, 8,905명의성인크론병환자들을대상으로한메타분석결과, 항 TNF 제제를면역조절제와함께사용하였을때비호치킨림프종 (non-hodgkin lymphoma) 발생위험이증가하였다 (SIR 3.23, 95% CI ). 48 다른연구에서도 thiopurine 단독치료군 (SIR 1.4, 95% CI ) 에비해항 TNF 치료군 (SIR 4.4, 95% CI ) 에서림프종발생의위험이높았지만, 생물학적제제치료를받은대부분의환자가 thiopurine으로치료받은병력이있거나병합치료를받고있어그해석에주의할필요가있겠다. 49 CESAME 연구에서도일부환자가생물학적제제를투여받았으나, 그중대부분은 thiopurine과병용투약하여림프종발생에대해확실한결론을이끌어낼수는없었다. 33 현재까지연구를종합하면, 염증성장질환환자에서항 TNF 제제사용은림프증식질환의위험증가와관련가능성이있으나, 면역억제제와함께사용하는경우가많아그영향을배제하기어렵고, 실제발생률은매우낮았다. 따라서림프종발생의위험성은치료약제를사용하여얻은이득과비교하여잘따져보아야한다. 50 다른생물학적제제로인테그린 α4에대한항체 (natalizumab, vedolizumab, etrolizumab) 가있는데, 염증성장질환에서이들약물의암발생위험에대한연구는많지않다. 최근메타분석에따르면항-인테그린치료를한염증성장질환환자에서일반인에비해장관외암발생위험도는증가하지않았다 (RR 1.57, 95% CI ). 51 하지만아직연구가충분치않아새로운생물학적제제와암발생에대한향후잘고안된연구가필요하다. 3) 간비장 T세포림프종간비장 T세포림프종 (Hepatosplenic T cell lymphoma, HSTCL) 은주로 35세이하의젊은남자에서발생하는드문형태의공격적인림프종으로, 발열, 체중감소, 복통, 전신쇠약감, 간과비장종대, 골수침범으로인해백혈구및혈소판 감소, 빈혈등의소견을보인다. 염증성장질환환자에서장기간의 thiopurine 치료는간비장 T세포림프종위험이높이는것으로보인다 년부터 2011년까지염증성장질환에서발생한 HSTCL 36예를분석한연구에서 HSTCL 발생위험도는 thiopurine 단독치료에서약 1:45,000, 53 thiopurine과생물학적제제병합치료를받을경우 1:22,000이었는데, 35세미만의젊은남성환자에서그위험이증가하였다. 52 또크론병에서확인된 HSTCL 28예를분석한연구결과, 모든환자들은 thiopurine 치료를받은적이있고, 이중 22명의환자들은 infliximab과병합치료를받았다. 54 CESAME 연구에서는연구기간이끝난후에 HSTCL 한건의발생이보고된바있다. 55 염증성장질환에서 HSTCL의발생기전은잘알려져있지않지만, 젊은남성에서 thiopurine과항 TNF 제제를병합사용하였을때그위험이증가하는것으로보인다. 따라서젊은염증성장질환환자에게는 HTPCL 발생위험을고려하여 thiopurine과생물학적제제의장기적조합을피하는것이권고되고있다. 41,56 4. 피부암염증성장질환환자에서현재또는과거에 thiopurine를투약한경우비흑색종피부암의위험이유의하게증가하였다 염증성장질환환자는편평상피세포암 (SIR 2.2, 95% CI ) 의위험이증가하였고, 특히크론병환자 (SIR 5.5, 95% CI ) 에서그위험이높았다. 61 Long 등이보고한코호트연구에서염증성장질환환자의비흑색종피부암발병률이대조군에비해높았으며 (incidence RR 1.64, 95% CI ), 크론병환자에서 1년이상지속적으로 thiopurine 사용 (adjusted OR 4.27, 95% CI ) 하거나최근사용 (adjusted OR 3.56, 95% CI ) 한경우에비흑색종피부암발생이증가하였다. 62 CESAME 연구에서도 thiopurine 치료력이없는환자는일반대조군과비교하여비흑색종피부암의위험이증가하지않았지만, thiopurine 제제를현재사용 (HR 5.9, 95% CI ) 하거나과거에사용 (HR 3.9, 95% CI ) 한경우에비흑색종피부암발생위험도가증가하였다. 57 하지만 methotrexate (MTX), calcineurin inhibitor 같은면역억제제사용은비흑색종피부암의위험도를증가시키지않았다. 항 TNF 제제도비흑색종피부암과연관이있는데, 특히 thiopurine과함께사용할때그위험이증가되었다. 크론병환자에서 1년이상생물학적제제를사용 (adjusted OR 2.18, 95% CI ) 하거나최근에사용 (adjusted OR 2.07, 95% CI ) 하였을경우비흑색종피부암발생이증가하였고, 62 면역조절제를병합하여사용할때그위험은 6.75배로, 단독으로사용할경우에비해더증가하는것을볼수있었다. 국내에서는 azathioprine 치료중 Vol. 70 No. 4, October 2017

5 166 김지현, 김지원. 염증성장질환치료와종양 유방편평세포암종이발생한크론병 1예를보고한바있다. 63 염증성장질환환자에서흑색종발생은 thiopurine 제제사용에서위험이증가하지않았지만, 생물학적치료와상관관계가있었다. 59,64 크론병환자에서생물학적제제를 1년이상사용할경우흑색종발생은 1.88배증가하였다. 59 또염증성장질환환자 172,837명을포함한메타분석결과, 총 179건의흑색종사례가보고되어일반인의예상위험보다 37% 높은위험을보였다. 64 이러한결과를통해모든염증성장질환환자에서 1차예방으로자외선차단제를바르고, 면역조절제또는항 TNF 제제로치료를받는염증성장질환환자에서는정기적인피부과검진이권장된다 자궁경부암염증성장질환환자에서면역조절제의사용이자궁경부암발생을증가시키는지에대해서는명확히밝혀져있지않지만, 일부연구에서이형성 (dysplasia) 의발생을증가시킨다고보고하고있다. 염증성장질환환자 116명을대상으로한후향적코호트연구에서염증성장질환환자는대조군과비교하여비정상자궁경부세포진검사를보이는경우가더많았지만 (18% vs. 5%, p=0.004), 치료약물사용과유의한연관성은없었다. 65 또 Kane 등이보고한후속연구에서도염증성장질환환자는비정상자궁경부세포진검사 (42.5% vs. 7%, p=0.001) 와고등급병변 (OR 3.1, p=0.001) 위험이더높았다. 66 이연구에서는이전연구와는달리, 면역억제제 (predisone, thiopurine, infliximab) 를 6개월이상사용한여성에서비정상자궁경부세포진검사를보일위험이거의 2배증가하였고, 면역억제제에노출된환자에서고등급병변발생위험또한더높았다 (OR 6.5, 95% CI ). 최근메타분석에서도면역억제제를사용하는염증성장질환환자에서자궁경부이형성과자궁경부암의위험이증가하는것을확인할수있었다 (OR 1.34, 95% CI ). 67 하지만, 염증성장질환환자 525명을대상으로한연구에서궤양성대장염환자에서의자궁경부검사이상이건강한대조군에비교하여차이가없음을보고하기도하였다. 68 자궁경부암조직의 90% 이상에서인유두종바이러스 (human papilloma virus, HPV) 가발견된다. 염증성장질환환자에서현재또는과거의 HPV 감염은광범위한피부사마귀및 / 또는림프종이있는경우에는면역조절제의중단을고려해야하겠지만, 일반적으로면역조절제치료에대한금기는아니다. 또사용하는 HPV 백신은생백신이아니므로면역억제환자에게안전하게투여할수있으며, 고위험형 HPV 16 및 18 에대한보호기능을제공한다. 4가 HPV 백신 (Gardasil) 은 HPV 6, 11, 16 및 18을대상으로하며, 2가 HPV 백신 (Cervarix) 은 HPV 16 및 18을대상으로한다. 따라서염증성 장질환여성환자에서특히면역억제제치료를받는경우에는 정기적인부인과검진을권장하고있으며, 적절한경우 HPV 예 방접종을받는것이좋겠다. 69 결 론 본고에서는염증성장질환에서생물학적제제를포함한 면역억제제사용과관련된암에대해알아보았다. 염증성장 질환환자에서 thiopurine 과항 TNF 제제의사용은림프증 식질환발생위험을증가시킬수있으며, 특히젊은남성에서 thiopurine 과항 TNF 제제병합치료는간비장 T 세포림프 종발생과연관성이높아보인다. Thiopurine 과항 TNF 제제 는염증성장질환환자에서비흑색종피부암발생과관련이 있고, 특히항 TNF 제제는흑색종의발생위험과도연관이 있다. 또염증성장질환여성환자에서면역억제제를사용함 으로써자궁경부질환의위험이증가할수있다. 결론적으로, 염증성장질환에서면역조절제및생물학적치료는림프종, 피부암등의암발생을증가시키는것으로보이지만, 그실제 적인발생률은매우낮다. 따라서환자와의사는각치료제의 실제적인효과와잠재적인위험도를고려하여치료전략을세 워야하겠다. REFERENCES 1. Ng WK, Wong SH, Ng SC. Changing epidemiological trends of inflammatory bowel disease in Asia. Intest Res 2016;14: Beigel F, Steinborn A, Schnitzler F, et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti TNF alpha antibodies. Pharmacoepidemiol Drug Saf 2014;23: Beaugerie L. Inflammatory bowel disease therapies and cancer risk: where are we and where are we going? Gut 2012;61: Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48: Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130: Zhiqin W, Palaniappan S, Raja Ali RA. Inflammatory bowel disease-related colorectal cancer in the Asia-Pacific region: past, present, and future. Intest Res 2014;12: Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990; 323: Söderlund S, Brandt L, Lapidus A, et al. Decreasing time-trends of colorectal cancer in a large cohort of patients with inflammatory bowel disease. Gastroenterology 2009;136: ; quiz Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91: The Korean Journal of Gastroenterology

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