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1 Essentials of Primary Care: 소화기 염증성장질환종류에따른치료전략 가톨릭대학교의과대학내과학교실 이강문 서론염증성장질환은장관에원인미상의만성염증을일으키는질환으로악화와호전을반복하면서진행하는임상경과를보이며궤양성대장염과크론병이대표적인질환이다. 두질환은복통, 설사등유사한위장관증상을나타내고스테로이드나면역억제제같은치료에반응한다는공통점이있으나, 유전적배경및병태생리에차이가있고침범부위, 합병증등특징적임상양상이다르며 [1,2] 일부치료옵션에차이를보인다. 따라서두질환의감별진단이중요하며이에따른차별화된치료적접근이필요하다. 본고에서는궤양성대장염과크론병의감별진단및이에따른각각의치료전략에대해간단히살펴보고자한다. 궤양성대장염과크론병의감별진단어느한가지검사만으로염증성장질환을진단할수는없으며, 임상증상, 검사실소견, 내시경검사및조직검사, 영상검사소견을종합하여진단을내리게된다 [3,4]. 궤양성대장염은대장의점막및점막하층에국한된염증을특징으로하며대부분직장을침범하고근위부로진행하는연속적인병변을보인다. 내시경소견으로는점막의발적, 부종, 혈관상의소실, 과립상, 미란, 출혈및궤양등이질병의중증도에따라다양하게관찰되며정상부위와염증부위의경계가명확하게구분되는것이특징이다. 반면크론병은구강부터항문까지위장관전체를침범할수있으며장벽의전층을침범하므로협착이나누공등합병증발생이흔하다. 특징적인내시경소견은종주궤양, 조약돌점막모양또는종주로배열된아프타궤양이비연속적으로나타나는것이며주로회맹부를침범하고항문병변을흔히동반한다. 그러나궤양 성대장염환자에서비전형적인분포를보이는경우가드물지않고 [5] 내시경소견이애매한경우도적지않아임상에서두질환의감별이항상쉬운것은아니다. 두질환의감별이어려운경우, 일단공통적인치료를하면서누공, 협착, 항문병변발생여부등임상경과를주의깊게관찰하고추적내시경검사및조직검사를시행하는것이도움이된다. 궤양성대장염의치료전략궤양성대장염의치료는급성기증상을개선하고점막의염증을호전시켜관해에이르게하는관해유도치료와질병의재발없이관해를장기간유지하기위한관해유지치료로이루어지며, 이를통해환자의건강과삶의질을높이는것이치료의최종목표이다. 궤양성대장염의병변범위와임상중증도가치료방법의선택에영향을미치므로이에대한평가가중요하다 [6,7]. 1. 침범부위평가궤양성대장염의병변범위는대장내시경검사소견에의한 Montreal classification에따라직장염 ( 염증이직장구불결장접합부하방에국한 ), 좌측대장염 ( 직장에서비만곡부까지침범 ), 그리고광범위대장염 ( 비만곡부근위부까지침범 ) 으로분류한다 [8]. 중증환자의경우진단초기에구불결장경검사만을시행하는경우가많은데, 추후에라도대장내시경검사및조직검사를통해정확환병변의범위를평가하여야한다. 2. 임상중증도평가궤양성대장염의임상중증도를평가하기위한여러지표가개발되었으나, 현재는 Truelove-Witts score [9] 와 Mayo score

2 년대한내과학회추계학술대회 - Table 1. Truelove-Witt s Score for Clinical Severity of Ulcerative Colitis [9] 경도 * 중등도 중증 ** 배변횟수 4회이하 중증과경증사이 6회이상 혈변 - or 발열 없음 37.5 이상 빈맥 없음 90회 / 분이상 빈혈 없음 헤모글로빈 75% 이하 ESR 정상 30 mm/h 이상 * 경도는위의 6가지조건을모두만족 ** 중증은 6회 / 일이상의설사와육안적혈변을항상동반 Table 2. Mayo Score; Ulcerative Colitis Disease Activity Index (Range 0-12) [10] Variables Score Criteria Stool frequency 0 Normal number of stool stools more than normal stools more than normal 3 5 stools more than normal Rectal bleeding 0 No blood seen 1 Streaks of blood with stool less than half the time 2 Ovid blood with stool most of the time 3 Blood alone passed Endoscopic findings 0 Normal or inactive disease 1 Mild (erythema, decreased vascular pattern, mild friability) 2 Moderate (marked erythema, absent vascular pattern, friability, erosions) 3 Severe (spontaneous bleeding, ulcerations) Physician s global assessment 0 Normal 1 Mild 2 Moderate 3 Severe [10] 가가장널리사용되고있다 (Table 1 & 2). Truelove-Witts score는임상증상, 활력지수, ESR 등에따라중증도를관해, 경도, 중등도, 중증, 전격성 (fulminant) 으로분류하며실제임상에서간편히적용할수있는방법이다. 경도, 중등도, 중증은표 1에기술된바와같으며, 관해는증상이완전히호전되어혈변이없고배변횟수가하루 3회이하이며내시경검사에서점막이정상, 혹은치유된경우로정의한다. 한편전격성은중증기준을모두만족하면서, 하루 15회이상의설사, 지속적인출혈, 수혈이필요한정도의빈혈, 38.0 이상의고열, 백혈구증다증, 심한복통과복부압통을동반한경우이다. 임상연구에서많이이용되던 Mayo score 는생물학제제의 치료대상선정및반응평가를위해임상에서도흔히쓰이고있다. 배변횟수, 항문출혈, 의사의전반적평가와더불어내시경소견을평가에포함하고있으며, 4가지항목의점수를합하여 0-2점을관해, 3-5점을경도, 6-10 점을중등도, 점을중증으로평가한다. 3. 치료방법의선택앞서기술한병변의범위및중증도에따라적절한치료방법을선택할수있다. 증상이심하지않은직장염의경우에좌약등국소치료제가 1차치료로권유되며, 좌측대장염이나광범위대장염의경우엔경구제제단독혹은국속제제와의병용요법이권유된다. 중증혹은전격성대장염은입

3 이강문. 염증성장질환종류에따른치료전략 Figure 1. Treatment algorithm of active ulcerative colitis. 원및스테로이드정주치료의대상이며, 불량한예후를보일수있으므로치료에대한반응을주의깊게평가하여다음치료전략을세워야한다. 거대세포바이러스감염이치료반응에영향을미치는인자중하나이므로 [11,12], 특히중증궤양성환자에서스테로이드정주치료나생물학제제치료에반응이없는경우거대세포바이러스감염여부를확인해야한다. 대한장연구학회 IBD연구회에서는실제진료를담당하는의사가궤양성대장염환자의치료방법을결정하는데도움을주고자 2012년궤양성대장염치료가이드라인를발표하였다 [6]. 이에따른활동성궤양성대장염치료를정리한알고리즘을그림 1에소개하였다. 크론병의치료전략크론병의치료목표는관해를유도하고유지함으로써궁극적으로합병증을예방하고환자의삶의질을향상시키는것이다. 궤양성대장염과마찬가지로, 질병의침범부위및행태, 임상중증도를고려하여적절한치료전략을세우는것이중요하다 [13,14]. 1. 침범부위및질병행태평가크론병은위장관의어느부위라도침범할수있으므로대 장내시경외에도소장침범을평가하기위해영상의학검사를시행한다. 과거엔소장조영술이주로이용되었으나최근엔전산화단층촬영이나자기공명영상을이용한소장촬영법 (CT or MR enterography) 이표준화된검사법으로인정받고있다 [15]. 원인불명의만성복통을호소하는환자에서대장내시경및영상의학검사에서특이소견이없는경우캡슐내시경이고려될수있다 [16]. 상부위장관내시경은상부위장관증상이있는경우에만추천된다. 누공, 농양등장관외합병증이의심될때에는초음파, 전산화단층촬영또는자기공명영상이적절한검사방법이다. 최근우리나라에서도크론병환자에서자기공명영상, 캡슐내시경, 초음파검사가보험급여인정을받아크론병진료에많은도움이되고있다. 2005년제안된 Montreal classification은진단시나이, 침범부위및질병행태에따라크론병의표현형 (phenotype) 을분류하고있다 (Table 3) [8]. 예를들어 18세에진단된소장 ( 회장 ) 의협착형크론병은 A2, L1, B2로표기한다. 만일이환자에서공장에도병변이있고항문주위누공이동반되었다면 A2, L1+L4, B2p로표기하면된다. 2. 임상중증도의평가현재임상에서크론병의중증도를평가하는데 Crohn s disease activity index (CDAI) [17] 가가장널리이용되고있다 (Table 4). 일반적으로 CDAI 150 미만은관해, 150이상

4 년대한내과학회추계학술대회 - Table 3. Montreal Classification of Crohn s Disease [8] Age at diagnosis A1 16 years A years A3 > 40 years Location L1 Terminal ileum (the lower third of the small bowel with or without spill over into cecum) L2 Colon L3 Ileocolon (terminal ileum + any location between ascending colon and rectum) L4 Isolated upper disease (a modifier that can be added to L1-L3 when concomitant upper gastrointestinal disease is present) Behavior B1 Nonstricturing nonpenetrating B2 Strincturing B3 Penetrating p Perianal disease modifier (added to B1-B3 when concomitant perianal disease in present) Table 4. Crohn s Disease Activity Index [17] Items Factor 1. Number of liquid or very soft stools * X 2 2. Abdominal pain * (0 = none, 1 = mild, 2 = moderate, 3 = severe) X 5 3. General well-being * (0 = generally well, 1 = slightly under par, 2 = poor, 3 = very poor, 4 = terrible) X 7 4. Number of 6 listed categories patients now has: X 20 1) Arthritis/arthralgia 2) Iritis/uveitis 3) Erythema nodosum/pyoderma gangrenosum/aphthous stomatitis 4) Anal fissure, fistula, or abscess 5) Other fistula 6) Fever over 100 F (37.8 C) during past weak 5. Taking lomotil/opiates for diarrhea (0 = no, 1 = yes) X Abdominal mass (0 = none, 1 = questionalble, 5 = definite) X Hematocrit [Males: (47-Hct), Females: (42-Hct)] X 6 8. Body weight [1-(observed/ideal)] 100 X 1 미만은경도, 220 이상 450 미만은중등도, 450 이상은중증질환으로분류된다. 그러나 CDAI는평가자에따라점수가다를수있고, 복통의정도나전반적인안녕감등주관적인평가요소가존재하며, 평가전 7일동안의증상점수의합을구해야하고, 누공형이나협착형크론병환자또는장루를갖고있는경우에적합하지않은제한점이있다 [18]. 따라서내시경소견이나생화학표지자 (CRP, 대변칼프로텍틴등 ) 와같이보다객관적으로질병의중증도및치료에대한반응을평가할수있는지표의유용성에대한연구가진행되고있다. 3. 치료방법의선택대한장연구학회 IBD연구회에서는실제진료를담당하는의사가크론병환자의치료방법을결정하는데도움을주고자 2012년크론병치료가이드라인를발표하였다 [6]. 이에따른활동성크론병치료를정리한알고리즘은그림 2와같다. 경도- 중등도크론병의 1차치료로 budesonide 1일 9 mg 투여가선호되나현재국내에서는사용이불가능하다. 이전메타분석에서 5-aminosalicylate의치료효과는크지않은것으로보고되었으나 [19] 보다최근의연구에서는경도- 중등도크론병환자에서고용량메살라민 ( 하루 4.5 g) 을 8주간투여한결과 62.1% 에서관해가유도되어 budesonide의치료효과

5 이강문. 염증성장질환종류에따른치료전략 Figure 2. Treatment Algorithm of Active Crohn s Disease (69.5%) 에필적한만한결과를보였다 [20]. 누공이나감염의증거가없는경우항생제치료는권고되지않는다. 중등도-중증크론병의경우스테로이드치료가 1차적인치료이며조기에면역조절제를병용하는것이추천된다. 치료에반응이없거나재발하는경우, 또는약제부작용으로더이상의투여가힘든경우항TNF(tumor necrosis factor) 제제등생물학제제치료가권고된다. 염증성장질환치료전략의최신경향대규모코호트연구에의하면상당수의염증성장질환환자들이치료에도불구하고질병이진행하여합병증이발생하고이로인해결국수술을받게된다 [21,22]. 이는단순히증상의소실을목표로하는과거의치료전략에문제가있음을시사해준다. 최근점막치유 ( 내시경적관해 ) 가재발이나수술률의감소등양호한장기임상경과의예측인자임이밝혀지고 [23-25] 강력한항염증작용을갖는항TNF제제가도입되면서염증성장질환의치료목표가변화하고있다. 즉, 증상이소실되는임상적관해를넘어내시경검사에서점막의치유소견을보이는내시경적관해나조직학적관해, 생화학표지자가정상화되는생물학적관해까지를목표로해야한다는주장이설득력을얻고있다. 이를위해서질병중증도가높은고위험군환자에서는보다조기에적극적인치료를도 입하는방향으로치료의패러다임이진화하고있다 [26,27]. 결론 최근우리나라에서염증성장질환의발생이꾸준히증가하면서임상현장에서드물지않게염증성장질환환자를만날수있게되었다. 하지만아직도급성장염이나장결핵등과의감별이어려운경우가흔하고궤양성대장염과크론병의구분이힘든경우도있으므로, 임상의들은각질환의특징적인임상양상및내시경소견을숙지하고적절한검사법을이용하여정확한진단을하도록노력해야한다. 또한질환의침범부위나병변의범위, 임상중증도에따라치료방법을선택하게되므로널리이용되는분류법이나중증도지표를숙지하고있어야한다. 일단치료를시작하면치료에대한반응을주의깊게평가하고, 호전된후엔철저한모니터링을통해적절한시기에적절한치료가이루어지도록해야할것이다. REFERENCES 1. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:

6 년대한내과학회추계학술대회 - 2. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347: Choi CH, Chung SA, Lee BI, et al. Diagnostic guideline of ulcerative colitis, Korean J Gastroenterol 2009;53: Ye BD, Jang BI, Jeen YT, et al. Diagnostic guideline of Crohn s disease. Korean J Gastroenterol 2009;53: Park SH, Yang SK, Park SK, et al. Atypical distribution of inflammation in newly diagnosed ulcerative colitis is not rare. Can J Gastroenterol Hepatol 2014;28: Choi CH, Kim YH, Kim YS, et al. Guidelines for the management of ulcerative colitis. Intest Res 2012;10: Travis SP, Stange EF, Lémann M, et al. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis 2008;2: Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut 2006;55: Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317: Kim YS, Kim YH, Kim JS, et al. The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: a prospective multicenter study. J Clin Gastroenterol 2012;46: Park SH, Yang SK, Hong SM, et al. Severe disease activity and cytomegalovirus colitis are predictive of a nonresponse to infliximab in patients with ulcerative colitis. Dig Dis Sci 2013;58: Ye BD, Yang SK, Shin SJ, et al. Guidelines for the management of Crohn s disease. Intest Res 2012;10: Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis 2010;4: Dambha F, Tanner J, Carroll N. Diagnostic imaging in Crohn's disease: what is the new gold standard? Best Pract Res Clin Gastroenterol 2014;28: Triester SL, Leighton JA, Leontiadis GI, et al. Meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn's disease. Am J Gastroenterol 2006;101: Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70: Sostegni R, Daperno A, Scaglione N, et al. Review article: Crohn's disease: monitoring disease activity. Aliment Pharmacol Ther 2003;17(Suppl 2): Hanauer SB, Strömberg U. Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials. Clin Gastroenterol Hepatol 2004;2: Tromm A, Bunganic I, Tomsova E, et al. Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn's disease. Gastroenterology 2011;140: Jess T, Riis L, Vind I, et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis 2007;13: Solberg IC, Vatn MH, Høie O, et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol 2007;5: Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011;141: Lee KM, Jeen YT, Cho JY, et al. Efficacy, safety, and predictors of response to infliximab therapy for ulcerative colitis: A Korean multicenter retrospective study. J Gastroenterol Hepatol 2013;28: Colombel JF, Rutgeerts PJ, Sandborn WJ, et al. Adalimumab induces deep remission in patients with Crohn's disease. Clin Gastroenterol Hepatol 2014;12: 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: Sandborn WJ, Hanauer S, Van Assche G, et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J Crohns Colitis 2014;8:

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( )Kju269.hwp 만성세균성전립선염모델흰쥐에서 의항염효과 Anti-inflammatory Effect of Lycopene on Chronic Bacterial Prostatitis Rat Model Cho Hwan Yang, Dong Wan Sohn, Yong-Hyun Cho From the Department of Urology, The Catholic University