대한내과학회지 : 제 76 권제 6 호 2009 특집 (Special Review) - 궤양성대장염 (Ulcerative colitis) 궤양성대장염의최신치료 고려대학교의과대학내과학교실 진윤태 김주형 Advances in ulcerative colitis therapy Yoon-Tae Jeen, M.D. and Juhyung Kim, M.D. Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Ulcerative colitis is an idiopathic inflammatory bowel disease characterized by colonic mucosal inflammation and chronic relapsing episodes. The initial therapeutic approach depends on both the extent of colonic involvement and the severity of the disease process at presentation. The mainstay of ulcerative colitis therapy is the administration of 5-aminosalicylic acid (5-ASA) or steroid. Additional medical therapy or colectomy should be considered if the patient remains symptomatic despite conventional therapy, regardless of the extent of colonic involvement. Cyclosporins are effective as a short-term rescue therapy for steroid-refractory ulcerative colitis. Recently, new 5-ASA and steroid formulations with altered delivery, dosing regimens, and less frequent administration have been introduced and demonstrated to be efficacious in active mild to moderate colitis. Infliximab is given to try to avoid the need for colectomy and has proven efficacious in ulcerative colitis. This review outlines the standard therapy for ulcerative colitis and discusses new insights into the recent trend focusing on new therapies, including biological agents and leukocytapheresis. (Korean J Med 76:654-660, 2009) Key Words: Ulcerative colitis; Therapy; Biologic agent 서론궤양성대장염은원인불명의대장염증을일으키며호전과악화를반복하는만성적인질환이다. 환자의 15% 정도는중증대장염의급성발병으로위중한경과를초래하며이경우약 30% 의환자는대장절제술을필요로한다. 또한오랜기간만성적인장관의염증으로인하여장기적으로환자삶의질을떨어뜨리고합병증으로대장암의발병가능성이높아진다 1,2). 국내에서는 1970년대부터궤양성대장염증례가보고되기시작하였고, 이후로도발병률과유병률이지속적으로증가됨에따라이에대한관심과연구도활발히이루어지고있다 3-5). 궤양성대장염의표준적인약물치료로 5-aminosalicylic acid (5-ASA) 제제, 스테로이드, 면역조절약물 (azathioprine, 6-mercaptopurine) 제제가있으며이들의효능에대한명확한근거는이미알려져있다 6). 하지만궤양성대장염환자의 20~40% 는통상적인약물치료에실패하거나부작용으로대장절제술을받게되며스테로이드에반응하지않는중증의환자에서 cyclosporin이사용되고있지만약제부작용과장기적인효능성에대해서는아직도연구자마다이견이있는실정이다. 따라서부작용이적으며장기적으로효능이입증된이상적인새로운치료법개발의필요성이대두되고있다 2,7). 최근들어궤양성대장염의기존치료법에대한몇가지새로운연구와크론병에서사용되고있는생물학적제제 (biologic agent) 가새로운치료법으로소개되고있다. 본고에서는기존의표준약제중에서새로운제형의개발 - 654 -
- Yoon-Tae Jeen, et al. Advance in therapy for ulcerative colitis - 을통한순응도를향상시키려는시도를소개하고생물학적제제와같은새로운약제와비약물성치료기술등과같은최신치료경향에관해살펴보고자한다. 본론 1. 새로운 5-ASA 제제과거부터궤양성대장염치료에사용되었던설파살라진은현재까지많은연구결과와 2007년 Cochrane Review 에서보고된바처럼효능과안정성이입증되어현재경증, 중등증궤양성대장염의초기관해유도및유지요법에있어서주요 1차선택약제로사용되고있다 8). 설파살라진은항염증작용을하는 5-ASA 와운반역할을하는설파피리딘으로이루어져있다. 설파살라진은효과적인치료제이지만설파피리딘에의한부작용발생으로인해사용에제한이있고, 5-ASA 는소장에서흡수되어국소적으로작용을보이기때문에대장점막까지 5-ASA 를이동시킬수있는많은기전들이개발되어왔다 9). 설파살라진의부작용을줄이면서항염증의주된작용물인 5-ASA 의운반과치료효과를유지하기위해 Asacol, Pentasa, Claversal/Mesasal/ Salofalk 등과같은다양한새로운약물들이개발되었고 10-12), 각약물들은 5-ASA 의전달방식차이로인해제형들간에는다양한효능과내약성을보이게되었다 ( 표 1) 13,14). 궤양성대장염은지속적으로오랜기간약물을복용하게되므로환자들의약물순응도가중요한데일부보고에의하면환자의최대 60% 가처방된약을복용하지않는다고알려 져있고이와같은순응도의감소는재발율의증가와밀접한관련이있다 15). 따라서최근에는환자의순응도를높이기위해약물투여횟수를줄이거나일회투여용량을증가시키는시도들이이루어지고있다. 새로개발된 MMX mesalazine 제형은 mesalazine 1.2 g에 ph의존적중합체필름 (polymer film) 으로코팅시키는 Multiple Matrix System (MMX) 기술을이용한것으로활동성약물이전체대장을통과하면서 24시간이상골고루전달되도록하였다. 활동성궤양성대장염환자에서 MMX mesalazine 제제의효능성에대한최근임상연구를보면경증, 중등증궤양성대장염환자 343명을대상으로시행한연구결과 MMX mesalazine 2.4 g과 4.8 g을하루 1회투여한군모두에서위약군보다유의하게임상적관해와내시경관해에도달하였다고보고하였다 16). 경증, 중등증궤양성대장염환자 280명을대상으로시행한또다른연구에서도 MMX mesalazine 2.4 g (1.2 g씩하루 2회 ) 과 4.8 g을하루 1회투여한군모두에서위약군보다유의하게효능면에서낫다고보고하고있다 17). 또한 MMX mesalazine 의관해유지효과에대한무작위비교연구에서도 MMX mesalazine 2.4 g을하루 1회투여한군과 1.2 g을하루 2회투여한군이비슷한효능을보여고용량 mesalazine의하루 1회요법이관해유도및유지를위한효능및순응도면에서임상에서유용할것으로제시되고있다 20-22). 최근또다른시도로 Pentasa 와 Salofalk 과립제와같은미세환약 (micropellet) 제제를사용해지속적방출이가능하도록하여기존알약제제보다투여횟수를줄이려는연구도 Table 1. 5-ASA formulations, doses and delivery Generic name 5-ASA Dose per tablet/capsule/sachet Mesalazine Pentasa 500, 1,000, or 2,000 mg - 655 - Formulation Ethylcellulose-coated microgranules (sustained release) Delivery Duodenum to rectum Mesalazine Asacol 400 or 800 mg Eudragit-S-coated tablets Terminal ileum, colon (released at ph > 7) Mesalazine Mezavant/Lialda 1,200 mg Eudragit-S-coated multimatrix system Terminal ileum, colon Mesalazine Salofalk 250 mg Eudragit-L-coated tablets Mid to distal ileum, colon Mesalazine Ipocol 400 mg Enteric coated with Eudragit-S Terminal ileum, colon Sulphasalazine Salazopyrin 500 mg 5-ASA linked to sulfapyridine by an Colon azo-bond Balsalazide Colazide 750 mg 5-ASA linked to 4-aminobenzoyl-b-alanine Colon by an azo-bond Olsalazine Dipentum 250 mg 5-ASA dimer linked by an azo-bond Colon
- 대한내과학회지 : 제 76 권제 6 호통권제 586 호 2009 - 있다. 362명의환자를대상으로한무작위이중맹검연구에서 Pentasa 과립제제를하루 1회 2 g 투여한군이 1 g씩하루 2회투여한군보다 1년후관해율이 12% 정도더우월한것으로보고되었다. 이와같이기존 5-ASA 제제를고용량으로투여하거나지속적방출이가능한미세환약 (micropellet) 과립제제와같은신기술로변형된형태로투여할경우환자의약제개수와복용빈도를줄여순응도를향상시키고나아가치료효능과재발률감소에기여할것으로기대되고있다 18). 2. 스테로이드제제스테로이드제제가사용되면서중증궤양성대장염환자의사망률이급격히감소하였고, 현재도스테로이드는 5- ASA 제제에반응하지않는활동성궤양성대장염치료에중요한역할을담당하고있다. 그러나빠른증상호전을보이지만지속적으로사용시전신적부작용발생과연관되어있어약물의존성과과다체액, 복부선조, 고혈당, 골다공증, 부신기능장애, 무혈성괴사, 백내장, 정서장애등이발생할수있어주의가요망된다. 또한장기적관해유지에는효능이없으므로일단임상적인관해유도에성공하면용량을단계적으로줄여나가면서관해유지단계에들어갈경우스테로이드를중단해야한다 19). 최근에는스테로이드의효능을유지하면서전신적부작용을줄이고자새로운대장방출스테로이드제형이개발되어시도되고있다. Beclomethasone dipropionate (BDP) 는위산저항성이있는 Eudragit-L100/55으로코팅되어있어 ph 6 미만에서용해되고소장원위부와대장에서방출되어전신적영향이최소화된주로국소적효능을나타내는 2세대스테로이드이다. 현재까지진행된연구에서 BDP 단독혹은 5-ASA 제제와병행투여시효능면에서 5-ASA 단독투여보다떨어지지않았고국소치료에서도 mesalazine 관장과비교시효능과순응도에있어비슷하다고보고하고있다 20-22). 느리게흡수되는제형으로개발된 prednisolone metasulfobenzoate (predocol) 를하루 40 mg씩투여한경우, prednisolone 을단계적감량을하는기존방식과비교하였을때부작용이유의하게감소한다는보고가있었고 23), MMX 기술을도입한 budesonide MMX 9 mg을투여하여위약군과비교한다른연구에서는장염활성지수 (colitis activity index) 에서더좋은반응을보였고, 유의할만한부신피질기능억제는없다고보고하였다. 따라서향후많은연구와개발을통해기존약물의효능을그대로유지하면서부작용을줄일수있 는보다향상된스테로이드제형들이임상치료에등장할것으로기대된다. 3. Azathioprine/6-Mercaptopurine 퓨린유사체인 azathioprine 과 6-mercaptopurine (6-MP) 은스테로이드를중단할수없는환자에서스테로이드용량을줄여주거나끊을수있게하는효과가있지만아직까지무작위맹검연구로검증이부족하고약효가나타나기까지 3~6개월이소요되므로관해유도에는효과가없다고알려져있고현재는관해유지요법으로주로사용되고있다 24,25). 대부분의환자들이큰부작용없이잘적응하지만급성췌장염, 간수치상승, 골수기능억제및림프종발병률이일반인보다 4배정도증가한다는보고가있어투여시주의가요망된다. 관해유지치료에서는 5-ASA 제제에부작용이있거나스테로이드의존성이발생할경우선택적으로투여한다면효과적인치료제로사용이가능하다 26,27). 4. Cyclosporin 중증궤양성대장염환자에서정주스테로이드치료를투여하여도 30~40% 에서는관해를보이지않는데 28) 이를스테로이드불응성중증궤양성대장염이라간주한다. 스테로이드나면역억제약물에반응이없는경우에는종종거대세포바이러스 (cytomegalovirus) 감염이동반된경우가있기때문에반드시이를감별하는노력이필요하다 29,30). 스테로이드에반응하지않는궤양성대장염은과거대장절제술을시행하였으나술후발생하는낭염 (pouchitis) 등의합병증과신뢰할만한수술예후인자부족으로수술을대체할만한다양한약물치료에대해연구가진행되어왔다. 1971년에면역억제제로 cyclosporin이장기이식후거부반응을예방하기위해사용되어오다가 31) 궤양성대장염에서 interleukin (IL)-2와 IL-3의생성과백혈구의 chemotaxis를억제하고 T세포의세포사멸 (apoptosis) 을유도하는것이 32,33) 알려지면서새로운치료제로사용되기시작했다 34). Cyclosporin 은 azathioprine/6-mp 과같은다른면역억제제와는달리작용시간이빠른장점이있고, 최근 Cochrane review 에서는대상환자의 82% 에서효과가있었다고보고하고있어 35) 현재수술적치료가고려되는환자들에게대체치료로가장우선적으로고려되고있다. 하지만관해유도효능에대한연구마다이견이많으며부작용으로골수억제기능은없지만신독성, 고혈압, 간질, 전해질불균형, 기회감염등의위험이있어치료결정에신중해야한다. Cyclosporin이기존의스테로이드 - 656 -
- 진윤태외 1 인. 궤양성대장염의최신치료 - 치료보다더효과적인지, 대장절제술을유의하게줄일수있는지에대한근거가아직까지부족하므로최근에도약제에대한논란의여지가있는상황이다 7,35). 5. 생물학적제제 (Biologic agent) 1) Infliximab 장관의염증에있어 Tumor necrosis factor (TNF)-α가가장중요한사이토카인 (cytokine) 이자매개체로염증성장질환에서발현이증가되는것으로알려졌고, 이에대한단클론항체 (monoclonal antibody) 로가장처음개발된생물학적제제가 infliximab 이다. 대표적인 TNF-α 길항체인이약제가기존의스테로이드나면역억제제에비해우수한증상호전과점막치유효과를나타내어최근들어염증성장질환의치료에새로운장을열고있다 36). 초기에는주로크론병에초점이맞혀져연구가진행되었는데국내에서도스테로이드, 항생제, 면역억제제등기존치료에반응하지않는중증또는누공성크론병환자에서 infliximab 에대한보험급여가인정되고있으나궤양성대장염에서는적응증에포함은되지만아직까지보험급여대상으로는인정받지못하고있다. 크론병과마찬가지로궤양성대장염에서도 TNF-α가발병기전에중요한역할을하는것으로밝혀져 37,38) 궤양성대장염에서의 infliximab 의치료효능에대한임상적연구가활발히진행되었다. 2005년에 Rutgeerts 등 39) 이중등도이상의궤양성대장염환자 700명이상이포함된두개의다기관무작위비교임상연구인 Active ulcerative Colitis Trial (ACT)-1, ACT -2의결과를발표하였다. 두연구모두위약, infliximab 5 mg/kg/iv, 10 mg/kg/iv군으로나누어 0, 2, 6주에투여한후 8주간격으로지속투여하였다. 두연구모두위약군에비해 infliximab 투여군이유의한관해유도효과를보였을뿐만아니라점막병변치유와스테로이드감량에서도우월한효과를보였고, 대장절제술감소와연관성이있었다 40). 하지만장기적인투여시효능과대장절제술을얼마나감소시켜줄지에대한근거들은아직까지충분하지않아앞으로좀더대규모환자를대상으로한지속적인연구가필요할것으로생각된다. 현재미국및유럽에서는기존의약제 (5-ASA, 스테로이드, 면역억제제 ) 사용으로관해나호전을보이지않는중등도이상의궤양성대장염환자에서관해유도나유지와및스테로이드감량을목적으로 infliximab 사용을권장하고있다. 국내에서도스테로이드나 6-mercaptoprine 또는 azathioprine 등보편적인기존치료약제에대한적정한반응을나 타내지않거나내약성이없는경우또는이러한약제가금기인중등도- 중증의궤양성대장염환자에한해보험급여대상은아니지만투여는가능하다. ACT trials에서는 484명의환자중 17명에서심각한부작용이관찰되었으며 8명이폐렴, 결핵, 히스토프라스모시스증, 4명의암발생, 3명이신경병증 (2명은시신경염, 1명은다발성운동질환 ) 을보였다. Infliximab에대해현재까지급성주입반응, 중증혈청병, 감염 ( 특히잠복결핵재활성화 ) 및림프종과드물게탈수초질환, 시신경염등이부작용으로발생할수있다고알려져있고결핵의유병률이아직까지높은국내에서는사용시결핵의선별검사가선행되야하는등주의가요망된다. 그러나현재까지등록된안전성프로파일의검토에서는암의발생률이다른치료에비해증가하지않았고심각한감염과사망률도다른치료와유사한것으로보고되어비교적안전한약물로임상에서사용이가능하다. 2) 새로운생물학적제제최근크론병과마찬가지로궤양성대장염환자에서도 infliximab 외에 adalimumab, certolizumab, natalizumab, visilizumab, basiliximab, daclizumab 등과같은새로운생물학제제의효능에대한연구가진행되고있다. Humanized anti TNF antibody 제제인 adalimumab과 T세포사멸을유도하는 anti-cd3 antibody인 visilizumab 을사용한궤양성대장염환자를대상으로한소규모연구에서임상적인효능이확인되었고경미한부작용이외심각한감염은없다고보고되었다. 현재병인에대한면역학적기전을규명해가면서면역조절에관여하는 TNF, adhesion molecule, T-cell activation, NF- Кb 등에대한다양한생물학적제제가연구되고있으나아직까지연구결과가부족하고장기적효능과안정성에대해서극복해야될점들이많으므로현재까지궤양성대장염환자에서 infliximab 이주된생물학적제제로사용되고있는실정이다. 국내에서도간헐적으로임상에서사용이증가추세에있으므로향후대규모환자를대상으로다기관연구등이진행되면국내에서의관해유도및유지효과에대한좋은근거를제시해줄것으로생각된다. 6. Leukocytapheresis 염증성장질환의병태생리에있어 TNF-α, IL-1β, IL-6, IL-8, IL-23과같은염증매개물질의분비가중요한역할을하고있는데주로말초혈액내의활성화된과립구 (granulocyte), 단핵구 (monocyte) 와같은백혈구와대식세포 (macro- - 657 -
- The Korean Journal of Medicine: Vol. 76, No. 6, 2009 - phage) 에의해분비되는것으로알려져있다. 혈액내의활성화된백혈구가장점막내로이동하여침윤하게되고수적인증가와동시에생존기간도증가하여결국장점막에만성적인염증을유발시킨다. 또한염증이진행되면장내피세포내케모카인 (chemokine) 수용체를상향조절하게되어염증부위로면역세포가동원되면서염증이더욱악화되게된다 41,42). 최근염증성장질환과백혈구간의상관관계에대한연구가활발히진행되면서백혈구가염증성장질환의치료목표대상이되고있다. 이에 α4β7-integrin에대한단일클론항체 (monoclonal antibody), 표피세포성장인자 (epidermal growth factor) 43), 백혈구제거요법 (leukocytapheresis) 44) 등이활성화된백혈구의기능차단을목표로치료에이용되고있다. 이중 leukocytapheresis (LCAP) 는주로일본에서연구된방법으로백혈구제거시스템인 Adacolumn (Jimro Co., Gumma, Japan) 45) 와 Cellsorba (Asahi Medical Co., Tokyo, Japan) 46) 를이용하여체외순환방식으로활성화된말초과립구, 단핵구등의백혈구를흡착방식에의해선택적으로제거함으로염증을조절하는것으로알려져있다. 일반적으로중등도궤양성대장염환자에서치료시약 60~80% 의치료반응이보고되고있으며사용시중대한부작용은거의없는것으로보고되고있다. 400명이상의환자들이포함된기존연구결과를살펴보면약 10% 미만에서만부작용이보고되었는데오심, 일시적인경미한두통과발열, 요로계감염과피로감만을호소하였고, 이외에심각한부작용은없어현재까지는매우안전한치료법으로여겨지고있다 47). 국내에서도기존약물치료에불응하는중등증이상의활동성궤양성대장염환자 27명을대상으로 Adacolumn 을이용하여 leukocytapheresis 시행한다기관연구를발표한바있다. 연속 5주간매주 1회 60분간시행한결과 70.4% 에서개선이상을보였고, 임상활성도가현저히호전되고, 내시경활성도와삶의질이유의하게호전되었다. 131회의시술중단 3건의경미한부작용만발생하였고, 치료를중단한예는없어기존연구에서와같이효과적이고안전한치료법으로보고하였다 48). 최근까지의대부분연구가 leukocytapheresis 의효능과안정성에대해긍정적인결과들을보고하고있지만대규모전향적무작위비교연구에대한자료부족이구미를중심으로지적되고있어향후더많은연구가필요할것으로사료된다. 결 궤양성대장염은원인불명의재발이빈번한만성적인경과를밞는질환으로환자의삶의질감소및장기적인합병증과생명의위협까지초래할수있다. 따라서환자의증상과병변의범위, 중등도에따라적절한약물을선택하여치료하는것이예후를향상시키는데중요하다. 그동안많은연구를통해궤양성대장염에대한다양한치료법들이개발사용되고있지만아직도효능과부작용면에서제한이있고극복되어야할점들이많다. 최근에는기존 5-ASA 제제와스테로이드제제에대한새로운제형의개발과용량및투여횟수조절을통해환자의약물복용순응도와치료효능을향상시키려는시도들이새롭게조명되고있다. 또한염증을비특이적으로억제하는기존의약물과는달리주요병인기전에선택적으로작용하는 infliximab 을포함한생물학적제제와 leukocytapheresis 같은새로운치료법이최신치료의중요한흐름으로자리매김하고있다. 앞으로궤양성대장염의병태생리와약물학에대한연구의진전이가속화된다면보다우수한효능과지속적반응을보이면서부작용이최소화된이상적인치료들이개발될수있을것으로기대해본다. 론 중심단어 : 궤양성대장염 ; 치료 ; 생물학적제제 REFERENCES 1) Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis: III. complications. Gut 5:1-22, 1964 2) Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 53(Suppl 5):V1-V16, 2004 3) Kim SJ, Cho YK, Rhee JE, Yoon CM. Two cases of ulcerative colitis. Korean J Gastroenterol 2:29-34, 1970 4) Yang SK, Hong WS, Min YI, Kim HY, Yoo JY, Rhee PL, Rhee JC, Chang DK, Song IS, Jung SA, Park EB, Yoo HM, Lee DK, Kim YK. Incidence and prevalence of ulcerative colitis in the Songpa-Kangdong District, Seoul, Korea, 1986-1997. J Gastroenterol Hepatol 15:1037-1042, 2000 5) Yang SK, Yun S, Kim JH, Park JY, Kim HY, Kim YH, Chang DK, Kim JS, Song IS, Park JB, Park ER, Kim KJ, Moon G, Yang SH. Epidemiology of inflammatory bowel disease in the Songpa- Kangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis 14:542-549, 2008 6) Stange EF, Travis SP. The European consensus on ulcerative colitis: new horizons? Gut 57:1029-1031, 2008-658 -
- Yoon-Tae Jeen, et al. Advance in therapy for ulcerative colitis - 7) Caprilli R, Viscido A, Latella G. Current management of severe ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 4:92-101, 2007 8) Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev:CD000544, 2006 9) Myers B, Evans DN, Rhodes J, Evans BK, Hughes BR, Lee MG, Richens A, Richards D. Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut 28:196-200, 1987 10) Dew MJ, Hughes PJ, Lee MG, Evans BK, Rhodes J. An oral preparation to release drugs in the human colon. Br J Clin Pharmacol 14:405-408, 1982 11) Hardy JG, Healey JN, Reynolds JR. Evaluation of an entericcoated delayed-release 5-aminosalicylic acid tablet in patients with inflammatory bowel disease. Aliment Pharmacol Ther 1:273-280, 1987 12) Rasmussen SN, Bondesen S, Hvidberg EF, Hansen SH, Binder V, Halskov S, Flachs H. 5-aminosalicylic acid in a slow-release preparation: bioavailability, plasma level, and excretion in humans. Gastroenterology 83:1062-1070, 1982 13) Green JR, Lobo AJ, Holdsworth CD, Leicester RJ, Gibson JA, Kerr GD, Hodgson HJ, Parkins KJ, Taylor MD. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. Gastroenterology 114:15-22, 1998 14) Pruitt R, Hanson J, Safdi M, Wruble L, Hardi R, Johanson J, Koval G, Riff D, Winston B, Cross A, Doty P, Johnson LK. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis. Am J Gastroenterol 97:3078-3086, 2002 15) Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 96:2929-2933, 2001 16) Kamm MA, Sandborn WJ, Gassull M, Schreiber S, Jackowski L, Butler T, Lyne A, Stephenson D, Palmen M, Joseph RE. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 132:66-75, quiz 432-433, 2007 17) Lichtenstein GR, Kamm MA, Boddu P, Gubergrits N, Lyne A, Butler T, Lees K, Joseph RE, Sandborn WJ. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 5:95-102, 2007 18) Ng SC, Kamm MA. Review article: new drug formulations, chemical entities and therapeutic approaches for the management of ulcerative colitis. Aliment Pharmacol Ther 28:815-829, 2008 19) Lennard-Jones JE, Misiewicz JJ, Connell AM, Baron JH, Jones FA. Prednisone as maintenance treatment for ulcerative colitis in remission. Lancet 1:188-189, 1965 20) Campieri M, Adamo S, Valpiani D, D Arienzo A, D'Albasio G, Pitzalis M, Cesari P, Casetti T, Castiglione GN, Rizzello F, Manguso F, Varoli G, Gionchetti P. Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study. Aliment Pharmacol Ther 17:1471-1480, 2003 21) Rizzello F, Gionchetti P, D'Arienzo A, Manguso F, Di Matteo G, Annese V, Valpiani D, Casetti T, Adamo S, Prada A, Castiglione GN, Varoli G, Campieri M. Oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study. Aliment Pharmacol Ther 16:1109-1116, 2002 22) Biancone L, Gionchetti P, Blanco Gdel V, Orlando A, Annese V, Papi C, Sostegni R, D'Inca R, Petruzziello C, Casa A, Sica G, Calabrese E, Campieri M, Pallone F. Beclomethasone dipropionate versus mesalazine in distal ulcerative colitis: a multicenter, randomized, double-blind study. Dig Liver Dis 39:329-337, 2007 23) Rhodes JM, Robinson R, Beales I, Pugh S, Dickinson R, Dronfield M, Speirs CJ, Wilkinson P, Wilkinson SP. Clinical trial: oral prednisolone metasulfobenzoate (Predocol) vs. oral prednisolone for active ulcerative colitis. Aliment Pharmacol Ther 27:228-240, 2008 24) Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 4:627-630, 1974 25) Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 91:423-433, 1996 26) Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6- mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev:CD000478, 2007 27) Herrlinger K, Stange EF. Azathioprine in chronic inflammatory bowel diseases: evidence base. Med Klin (Munich) 95:201-206, 2000 28) Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 121:255-260, 2001 29) Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, Orlando A, Rosselli M, Rizzo A, Pagliaro L. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis. Am J Gastroenterol 96:773-775, 2001 30) Papadakis KA, Tung JK, Binder SW, Kam LY, Abreu MT, Targan SR, Vasiliauskas EA. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol 96:2137-2142, 2001 31) Borel JF, Kis ZL. The discovery and development of cyclosporine (Sandimmune). Transplant Proc 23:1867-1874, 1991 32) Kountouras J, Zavos C, Chatzopoulos D. Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease. J Cell Mol - 659 -
- 대한내과학회지 : 제 76 권제 6 호통권제 586 호 2009 - Med 8:317-328, 2004 33) Ina K, Kusugami K, Shimada M, Tsuzuki T, Nishio Y, Binion DG, Imada A, Ando T. Suppressive effects of cyclosporine A on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant ulcerative colitis. Inflamm Bowel Dis 8:1-9, 2002 34) Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330:1841-1845, 1994 35) Shibolet O, Regushevskaya E, Brezis M, Soares-Weiser K. Cyclosporine A for induction of remission in severe ulcerative colitis. Cochrane Database Syst Rev:CD004277, 2005 36) Gisbert JP, Gonzalez-Lama Y, Mate J. Systematic review: infliximab therapy in ulcerative colitis. Aliment Pharmacol Ther 25:19-37, 2007 37) Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339:89-91, 1992 38) Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 34:1705-1709, 1993 39) Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353:2462-2476, 2005 40) Sandborn WJ, Rutgeerts P, Feagan BG. Infliximab reduces colectomy in patients with moderate-to-severe-uc: colectomy analysis from ACT 1 and ACT 2. Gut 56(Suppl III):A26, 2007 41) McCarthy DA, Rampton DS, Liu YC. Peripheral blood neutrophils in inflammatory bowel disease: morphological evidence of in vivo activation in active disease. Clin Exp Immunol 86:489-493, 1991 42) Meuret G, Bitzi A, Hammer B. Macrophage turnover in Crohn s disease and ulcerative colitis. Gastroenterology 74:501-503, 1978 43) Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 349:350-357, 2003 44) Sawada K, Ohnishi K, Fukunaga K, Chikano S, Egashira A, Satomi M, Shimoyama T. Mechanism of leukocytapheresis effect in the treatment of ulcerative colitis. Nihon Rinsho Meneki Gakkai Kaishi 22:469-474, 1999 45) Saniabadi AR, Hanai H, Suzuki Y, Ohmori T, Sawada K, Yoshimura N, Saito Y, Takeda Y, Umemura K, Kondo K, Ikeda Y, Fukunaga K, Nakashima M, Beretta A, Bjarnason I, Lofberg R. Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? J Clin Apher 20:171-184, 2005 46) Sawada K, Muto T, Shimoyama T, Satomi M, Sawada T, Nagawa H, Hiwatashi N, Asakura H, Hibi T. Multicenter randomized controlled trial for the treatment of ulcerative colitis with a leukocytapheresis column. Curr Pharm Des 9:307-321, 2003 47) Sigurbjornsson FT, Bjarnason I. Leukocytapheresis for the treatment of IBD. Nat Clin Pract Gastroenterol Hepatol 5:509-516, 2008 48) Kim HJ, Kim JS, Han DS, Yang SK, Hahm KB, Lee WI, Kwon SW, Choi JH, Kim WH, Choi KY, Song IS. Granulocyte and monocyte adsorption apheresis in Korean conventional treatment-refractory patients with active ulcerative colitis: a prospective open-label multicenter study. Korean J Gastroenterol 45:34-44, 2005-660 -