今日の臨床サポート

クローン病

著者: 長堀正和 東京医科歯科大学 消化器内科

著者: 渡辺守 東京医科歯科大学 消化器内科

監修: 上村直実 国立国際医療研究センター 国府台病院

著者校正/監修レビュー済:2021/02/24
参考ガイドライン:
  1. 日本消化器病学会:炎症性腸疾患(IBD)診療ガイドライン 2016 および 2020
患者向け説明資料

概要・推奨   

  1. 喫煙者には禁煙が強く勧められる(推奨度1)。
  1. クローン病患者の死亡率は健常人とほぼ同等か、やや高い傾向にある。
  1. 長期経過例では、大腸癌のサーベイランスのため、定期的な内視鏡検査が勧められる(推奨度2)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
長堀正和 : 講演料(ファイザー,武田薬品),研究費・助成金など(ファイザー,武田薬品)[2021年]
渡辺守 : 研究費・助成金など(アルフレッサファーマ(株)),奨学(奨励)寄付など(アッヴィ合同会社,EAファーマ(株),キッセイ薬品工業(株),杏林製薬(株),ゼリア新薬工業(株),田辺三菱製薬(株),武田薬品工業(株),日本化薬(株),持田製薬(株))[2021年]
監修:上村直実 : 未申告[2021年]

改訂のポイント:
  1. 定期レビューとして、「炎症性腸疾患診療ガイドライン 2020」を参考にし、治療指針のアップデートおよび便中カルプロテクチンや直腸肛門癌について加筆を行った

病態・疫学・診察

疾患情報(疫学・病態)  
  1. クローン病とは、原因不明の、口腔内から肛門周囲までの腸管のどの部位にでも発症する炎症性腸疾患の1つである。
  1. 診断には難治性炎症性腸管障害に関する調査研究班による「クローン病診断基準」が使用される。
  1. クローン病診断基準:<図表>
  1. クローン病は、指定難病であり、IOIBDスコア(<図表>)で2点以上の場合などは申請し認定されると保険料の自己負担分の一部が公費負担として助成される(平成27年1月施行)。
  1. 難病法に基づく医療費助成制度
 
 
  1. 家族歴は発病リスクを上げるため、遺伝的背景は発病の原因の1つと考えられている。
  1. 一卵性双生児での一致率は50%に満たないため、環境因子の関与が示唆される。
  1. 喫煙は発病リスクを上げ、喫煙者の予後は不良である。禁煙が強く勧められる。
  1. 大腸型および小腸型、それぞれにおいて、大腸癌および小腸癌のリスクが上昇する。
 
  1. クローン病の家族歴を持つことは、明らかに発病のリスクとなるが、絶対リスクは低率である。
  1. クローン病患者の家族におけるクローン病発病リスクは、必ずしも高くない。
  1. ベルギーの640人のクローン病患者の家族歴に関する調査研究[1]によると、一親等における年齢調整後のクローン病リスクは3.9%、兄弟では4.9%、親では1.9%、子どもでは7.4%であった。
  1. クローン病患者の家族がクローン病を発病することは多くはない。
  1. 絶対リスクは背景の有病率の影響を受けるため、日本人での数字はさらに低いものと思われる。
 
  1. 喫煙者には禁煙が強く勧められる(推奨度1)。
  1. 喫煙者は予後不良であり、その予後は、禁煙をすることで非喫煙者と同等になることが期待できる。
  1. 喫煙クローン病患者に対する禁煙指導を行った前向き介入試験[2]の結果からは、1年以上禁煙を継続できた患者の経過観察(1~54カ月:中央値29カ月)における増悪の頻度やステロイドや免疫抑制薬治療は、非喫煙者と同様であり、喫煙者より少なかった。また、622人のクローン病患者の前向きコホート研究[3]において、観察期間(12~18カ月)における増悪は、喫煙者、非喫煙者、かつての喫煙者において、それぞれ、46%、30%、23%であった。
  1. このことから、喫煙者では禁煙が強く推奨される。
問診・診察のポイント  
  1. 腹痛、下痢などの消化器症状について詳細に病歴を確認する。

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文献 

著者: M Peeters, H Nevens, F Baert, M Hiele, A M de Meyer, R Vlietinck, P Rutgeerts
雑誌名: Gastroenterology. 1996 Sep;111(3):597-603.
Abstract/Text BACKGROUND & AIMS: Because the mode of Crohn's disease inheritance is unknown, age-adjusted risk estimates and knowledge of disease characteristics will aid genetic counseling and modeling. The aim of this study is to determine the prevalence of familial occurrence of inflammatory bowel disease in first-degree relatives of patients with Crohn's disease and estimate their age-adjusted risks. It also evaluates agreement in disease characteristics between generations within families with a history of Crohn's disease.
METHODS: Six hundred forty patients with Crohn's disease and 800 control subjects were questioned about the occurrence of inflammatory bowel disease in their first-degree relatives. Agreement for age at diagnosis, initial disease location, disease behavior, and number of bowel resections was determined in 68 families with two or more members affected and compared with data in 100 unrelated patients with Crohn's disease.
RESULTS: Probands with Crohn's disease had a more frequent positive family history than controls. The age at diagnosis between probands with and without a positive family history was insignificant. Crude and age-adjusted risk elements were higher in relatives of patients, especially daughters, compared with those of controls. The age at diagnosis was older for parents than offspring but similar between siblings. Initial disease location was especially striking between siblings.
CONCLUSIONS: This study confirms familial aggregation and a high degree of disease concordance in Crohn's disease. The age at diagnosis and initial disease location was especially strong within generations.

PMID 8780562  Gastroenterology. 1996 Sep;111(3):597-603.
著者: J Cosnes, L Beaugerie, F Carbonnel, J P Gendre
雑誌名: Gastroenterology. 2001 Apr;120(5):1093-9. doi: 10.1053/gast.2001.23231.
Abstract/Text BACKGROUND AND AIMS: To evaluate the benefit of smoking cessation in individuals with Crohn's disease, we performed an intervention study in a large cohort of smokers with the disease.
METHODS: Repeated counseling to stop smoking, with easy access to a smoking cessation program, was given to 474 consecutive smokers with Crohn's disease. Patients who stopped smoking for more than 1 year (quitters) were included in a prospective follow-up study, which compared disease course and therapeutic needs with 2 control groups, continuing smokers and nonsmokers, paired for age, gender, disease location, and activity.
RESULTS: There were 59 quitters (12%). Predictors of quitting were the physician, previous intestinal surgery, high socioeconomic status, and in women, oral contraceptive use. During a median follow-up of 29 months (1-54 months), the risk of flare-up in quitters did not differ from that in nonsmokers and was less than in continuing smokers (P < 0.001). Need for steroids and for introduction or reinforcement of immunosuppressive therapy, respectively, were similar in quitters and nonsmokers and increased in continuing smokers. The risk of surgery was not significantly different in the 3 groups.
CONCLUSIONS: Patients with Crohn's disease who stop smoking for more than 1 year have a more benign disease course than if they had never smoked.

PMID 11266373  Gastroenterology. 2001 Apr;120(5):1093-9. doi: 10.1053/・・・
著者: J Cosnes, F Carbonnel, F Carrat, L Beaugerie, S Cattan, J Gendre
雑誌名: Aliment Pharmacol Ther. 1999 Nov;13(11):1403-11.
Abstract/Text BACKGROUND: Cigarette smoking is associated with a more severe course of Crohn's disease, but individual factors determining this effect are poorly known and it is not clear whether smoking cessation is associated with an improvement in the disease activity.
AIM: To assess the factors determining the harmful effect of smoking in individuals with Crohn's disease.
METHODS: A total of 622 consecutive patients with Crohn's disease and Crohn's disease activity index <200 were enrolled in a prospective 12-18 month cohort study. Patients were classified as current smokers, former smokers, or non-smokers. Alcohol consumption, oral contraceptive use, body mass index, and blood lipid levels were also recorded. The main outcome measure was the rate of flare-up.
RESULTS: A total of 139 current smokers (46%) developed a flare-up, vs. 79 non-smokers (30%) and 13 former smokers (23%). The relative risk of flare-up adjusted for confounding factors was 1.35 (1.03-1.76) in current smokers. This risk was increased in patients with previously inactive disease and in those who had no colonic lesions. It became significant above a threshold of 15 cigarettes per day. Former smokers behaved like non-smokers. Obesity, dyslipidaemia, and alcohol consumption had no significant effect.
CONCLUSIONS: Current smoking, particularly heavy smoking, markedly increases the risk of flare-up in Crohn's disease. Former smokers have a risk similar to that of non-smokers.

PMID 10571595  Aliment Pharmacol Ther. 1999 Nov;13(11):1403-11.
著者: Laurent Beaugerie, Philippe Seksik, Isabelle Nion-Larmurier, Jean-Pierre Gendre, Jacques Cosnes
雑誌名: Gastroenterology. 2006 Mar;130(3):650-6. doi: 10.1053/j.gastro.2005.12.019.
Abstract/Text BACKGROUND & AIMS: Early intensive therapy in Crohn's disease should be considered only in patients with disabling disease. The aim of our study was to identify at diagnosis factors predictive of a subsequent 5-year disabling course.
METHODS: Among the 1526 patients seen at our unit with Crohn's disease diagnosed between 1985 and 1998, we excluded patients operated on within the first month of the disease, patients with inadequate data, and patients with severe chronic nondigestive disease. In the 1188 remaining patients, Crohn's disease course within the first 5 years of the disease was categorized as disabling when at least 1 of the criteria of clinical severity, conventionally predefined, was present.
RESULTS: Among the 1123 patients with follow-up data allowing full 5-year course classification, the rate of disabling disease was 85.2%. Independent factors present at diagnosis and significantly associated with subsequent 5-year disabling were the initial requirement for steroid use (OR 3.1 [95% CI: 2.2-4.4]), an age below 40 years (OR 2.1 [95% CI: 1.3-3.6]), and the presence of perianal disease (OR 1.8 [95% CI: 1.2-2.8]). The positive predictive value of disabling disease in patients with 2 and 3 predictive factors of disabling disease was 0.91 and 0.93, respectively. These values were 0.84 and 0.91, respectively, when tested prospectively in an independent group of 302 consecutive patients seen at our institution from 1998.
CONCLUSIONS: At diagnosis of Crohn's disease in a referral center, factors predictive of subsequent 5-year disabling course are an age below 40 years, the presence of perianal disease, and the initial requirement for steroids.

PMID 16530505  Gastroenterology. 2006 Mar;130(3):650-6. doi: 10.1053/j・・・
著者: F L Wolters, M G V M Russel, R W Stockbrügger
雑誌名: Aliment Pharmacol Ther. 2004 Sep 1;20(5):483-96. doi: 10.1111/j.1365-2036.2004.02123.x.
Abstract/Text BACKGROUND: Disease outcome in Crohn's disease might have changed during the last four decades. Disease outcome measurement in Crohn's disease has methodological difficulties because of patient selection and lack of proper definition of diagnostic and outcome measurement criteria.
AIM: To assess possible changes in disease outcome in Crohn's disease during the last four decades.
METHODS: A systematic literature search was performed using the MEDLINE search engine and major international conference libraries. Articles and abstracts were selected according to stringent inclusion criteria.
RESULTS: Forty articles and nine abstracts complied with the inclusion criteria. Seven studies with a median follow-up time between 11.1 and 17 years showed standard mortality ratios in Crohn's disease ranging between 2.16 and 0.72 with a tendency of decline during the last four decades. One study with 11.4 years mean follow-up time showed a statistically significant increased relative risk for colorectal cancer that was not confirmed by three others. Sixteen publications applied in the disease recurrence category. Probability of first resective surgery ranged between 38 and 96% during the first 15 years after diagnosis. The overall recurrence and surgical recurrence rates after first resective surgery ranged between 50 and 60, and 28 and 45% respectively during the following 15 years without an apparent time trend.
CONCLUSION: This structured literature review provides no hard evidence for change in disease outcome in Crohn's disease during the last four decades.

Copyright 2004 Blackwell Publishing Ltd
PMID 15339320  Aliment Pharmacol Ther. 2004 Sep 1;20(5):483-96. doi: 1・・・
著者: F Casellas, J López-Vivancos, X Badia, J Vilaseca, J R Malagelada
雑誌名: Am J Gastroenterol. 2000 Jan;95(1):177-82. doi: 10.1111/j.1572-0241.2000.01681.x.
Abstract/Text OBJECTIVE: When patients with Crohn's disease (CD) express concerns about their disease, they emphasize worries about surgery. However, most studies about the impact of surgery in CD on health-related quality of life (HRQOL) have compared postsurgical changes on HRQOL relative to HRQOL before surgery, not taking into account the influence of CD activity on HRQOL. Our aim was to assess whether surgical treatment of CD modifies HRQOL, compared with inactive CD, active CD, or healthy controls.
METHODS: Outcomes of 29 CD patients in remission with a previous bowel resection were compared with those from 42 clinically active CD patients and 48 patients with medically induced remission. A reference control group of 63 healthy individuals was also studied. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well Being Index (PGWBI), and the EuroQol.
RESULTS: Active CD patients scored the lowest on the IBDQ. Both operated and nonoperated inactive CD patients had lower HRQOL scores than controls in overall IBDQ and in all five domains. However, neither global score, digestive, systemic, emotional, social, or functional dimensions differed significantly between operated and nonoperated inactive CD patients. PGWBI and the visual analog scale of the EuroQol were also similar in both groups of inactive CD patients (103 [range, 94-107] vs. 103 [97-106] and 90 [73-87] vs. 82 [76-84]), but significantly higher than in active CD.
CONCLUSIONS: HRQOL is impaired in active CD, and improves during remission irrespective of whether it had been achieved medically or surgically. Our results suggest that to improve HRQOL it is more important to achieve remission than the approach, drugs or surgery, chosen.

PMID 10638579  Am J Gastroenterol. 2000 Jan;95(1):177-82. doi: 10.1111・・・
著者: D C Broering, C F Eisenberger, A Koch, C Bloechle, W T Knoefel, J R Izbicki
雑誌名: Dig Surg. 2001;18(2):124-30. doi: 50112.
Abstract/Text BACKGROUND: Improvement in quality of life is one of the important determinants in the treatment of Crohn's disease. Since there is no cure with radical resection of inflamed bowel, strictureplasty has become a useful surgical technique in the treatment of small bowel obstruction. The scope of this study was to define the results of strictureplasty and resection in terms of quality of life, surgical recurrence and postoperative complications.
METHODS: The charts of 67 patients with Crohn's disease of the small bowel were analyzed retrospectively. Patients were treated either by strictureplasty (group A) or resection (group B). Quality of life was evaluated in follow-up examinations using the Inflammatory Bowel Disease Questionnaire (IBDQ).
RESULTS: Postoperative morbidity was 14.8% after strictureplasty and 17% after resection (p = 0.8). 50% of the patients treated by strictureplasty and 37% treated by resection developed recurrent disease (p = 0.40). Quality-of-life measurement revealed no significant difference between patients treated by strictureplasty or resection.
CONCLUSION: Results after strictureplasty are comparable to those after resection in terms of complications, recurrence and quality of life in the treatment of small bowel strictures in Crohn's disease. In the long run there might be an advantage for strictureplasty because it prevents complications caused by resectional therapy such as short bowel syndrome.

Copyright 2001 S. Karger AG, Basel
PMID 11351157  Dig Surg. 2001;18(2):124-30. doi: 50112.
著者: Jean Frédéric Colombel, William J Sandborn, Walter Reinisch, Gerassimos J Mantzaris, Asher Kornbluth, Daniel Rachmilewitz, Simon Lichtiger, Geert D'Haens, Robert H Diamond, Delma L Broussard, Kezhen L Tang, C Janneke van der Woude, Paul Rutgeerts, SONIC Study Group
雑誌名: N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492.
Abstract/Text BACKGROUND: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown.
METHODS: In this randomized, double-blind trial, we evaluated the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50.
RESULTS: Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P=0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.
CONCLUSIONS: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy. (ClinicalTrials.gov number, NCT00094458.)

2010 Massachusetts Medical Society
PMID 20393175  N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056・・・
著者: Brian G Feagan, William J Sandborn, Christopher Gasink, Douglas Jacobstein, Yinghua Lang, Joshua R Friedman, Marion A Blank, Jewel Johanns, Long-Long Gao, Ye Miao, Omoniyi J Adedokun, Bruce E Sands, Stephen B Hanauer, Severine Vermeire, Stephan Targan, Subrata Ghosh, Willem J de Villiers, Jean-Frédéric Colombel, Zsolt Tulassay, Ursula Seidler, Bruce A Salzberg, Pierre Desreumaux, Scott D Lee, Edward V Loftus, Levinus A Dieleman, Seymour Katz, Paul Rutgeerts, UNITI–IM-UNITI Study Group
雑誌名: N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.1056/NEJMoa1602773.
Abstract/Text BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.
METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).
RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.
CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

PMID 27959607  N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.10・・・
著者: Jessica Coelho, Laurent Beaugerie, Jean Frédéric Colombel, Xavier Hébuterne, Eric Lerebours, Marc Lémann, Philippe Baumer, Jacques Cosnes, Arnaud Bourreille, Jean Pierre Gendre, Philippe Seksik, Antoine Blain, Etienne H Metman, Andrée Nisard, Guillaume Cadiot, Michel Veyrac, Benoît Coffin, Xavier Dray, Fabrice Carrat, Philippe Marteau, CESAME Pregnancy Study Group (France)
雑誌名: Gut. 2011 Feb;60(2):198-203. doi: 10.1136/gut.2010.222893. Epub 2010 Nov 29.
Abstract/Text BACKGROUND AND AIMS: Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines.
METHODS: 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C).
RESULTS: Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome.
CONCLUSIONS: The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.

PMID 21115547  Gut. 2011 Feb;60(2):198-203. doi: 10.1136/gut.2010.2228・・・
著者: Fabian Schnitzler, Herma Fidder, Marc Ferrante, Vera Ballet, Maja Noman, Gert Van Assche, Bernard Spitz, Ilse Hoffman, Kristel Van Steen, Séverine Vermeire, Paul Rutgeerts
雑誌名: Inflamm Bowel Dis. 2011 Sep;17(9):1846-54. doi: 10.1002/ibd.21583. Epub 2011 Jan 6.
Abstract/Text BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy.
METHODS: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women.
RESULTS: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis.
CONCLUSIONS: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.

Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
PMID 21830263  Inflamm Bowel Dis. 2011 Sep;17(9):1846-54. doi: 10.1002・・・
著者: Stephen B Hanauer, Brian G Feagan, Gary R Lichtenstein, Lloyd F Mayer, S Schreiber, Jean Frederic Colombel, Daniel Rachmilewitz, Douglas C Wolf, Allan Olson, Weihang Bao, Paul Rutgeerts, ACCENT I Study Group
雑誌名: Lancet. 2002 May 4;359(9317):1541-9. doi: 10.1016/S0140-6736(02)08512-4.
Abstract/Text BACKGROUND: We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.
METHODS: 573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.
FINDINGS: 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.
INTERPRETATION: Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

PMID 12047962  Lancet. 2002 May 4;359(9317):1541-9. doi: 10.1016/S0140・・・
著者: A H Steinhart, K Ewe, A M Griffiths, R Modigliani, O O Thomsen
雑誌名: Cochrane Database Syst Rev. 2003;(4):CD000301. doi: 10.1002/14651858.CD000301.
Abstract/Text BACKGROUND: The efficacy of corticosteroids in the setting of maintenance therapy for Crohn's disease has never been clearly demonstrated. It would be important to determine, based upon the currently available data from controlled trials, if the use of chronic corticosteroid therapy is of benefit in patients with quiescent Crohn's disease or if there is an identifiable subgroup of Crohn's disease patients, such as those in whom therapy cannot be successfully tapered, who might benefit from such treatment.
OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease.
SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and July, 2003. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 2003 in order to identify unpublished studies. The Cochrane Central Register of Controlled Trials and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched.
SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest.
DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data.
MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months.
REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up. This review updates the existing review of corticosteroids for maintaining remission of Crohn's disease which was published in the Cochrane Library (Issue 2, 2003).

PMID 14583917  Cochrane Database Syst Rev. 2003;(4):CD000301. doi: 10.・・・
著者: Bruce E Sands, Frank H Anderson, Charles N Bernstein, William Y Chey, Brian G Feagan, Richard N Fedorak, Michael A Kamm, Joshua R Korzenik, Bret A Lashner, Jane E Onken, Daniel Rachmilewitz, Paul Rutgeerts, Gary Wild, Douglas C Wolf, Paul A Marsters, Suzanne B Travers, Marion A Blank, Sander J van Deventer
雑誌名: N Engl J Med. 2004 Feb 26;350(9):876-85. doi: 10.1056/NEJMoa030815.
Abstract/Text BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas.
METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization.
RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009).
CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Copyright 2004 Massachusetts Medical Society
PMID 14985485  N Engl J Med. 2004 Feb 26;350(9):876-85. doi: 10.1056/N・・・
著者: William J Sandborn, Paul Rutgeerts, Robert Enns, Stephen B Hanauer, Jean-Frédéric Colombel, Remo Panaccione, Geert D'Haens, Ju Li, Marie R Rosenfeld, Jeffrey D Kent, Paul F Pollack
雑誌名: Ann Intern Med. 2007 Jun 19;146(12):829-38. Epub 2007 Apr 30.
Abstract/Text BACKGROUND: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent.
OBJECTIVE: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events.
DESIGN: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).
SETTING: 52 sites in the United States, Canada, and Europe.
PATIENTS: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points).
INTERVENTION: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.
MEASUREMENTS: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured.
RESULTS: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.
LIMITATIONS: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.
CONCLUSION: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. For more information on adalimumab in Crohn disease, click here. ClinicalTrials.gov registration number: NCT00105300.

PMID 17470824  Ann Intern Med. 2007 Jun 19;146(12):829-38. Epub 2007 A・・・
著者: C Canavan, K R Abrams, J Mayberry
雑誌名: Aliment Pharmacol Ther. 2006 Apr 15;23(8):1097-104. doi: 10.1111/j.1365-2036.2006.02854.x.
Abstract/Text BACKGROUND: Crohn's disease is associated with small bowel cancer whilst risk of colorectal cancer is less clear.
AIM: To ascertain the combined estimates of relative risk of these cancers in Crohn's disease.
METHODS: MEDLINE was searched to identify relevant papers. Exploding references identified additional publications. When two papers reviewed the same cohort, the later study was used.
RESULTS: Meta-analysis showed overall colorectal cancer relative risk in Crohn's disease as 2.5 (1.3-4.7), 4.5 (1.3-14.9) for patients with colonic disease and 1.1 (0.8-1.5) in ileal disease. Meta-regression showed reduction in relative risk over the past 30 years. Subgroup analysis showed Scandinavia had significantly lower colorectal cancer relative risk than the UK and North America. Cumulative risk analysis showed 10 years following diagnosis of Crohn's disease relative risk of colorectal cancer is 2.9% (1.5%-5.3%). Meta-analysis showed small bowel cancer relative risk in Crohn's disease is 33.2 (15.9-60.9). Small bowel cancer relative risk has not significantly reduced over the last 30 years.
CONCLUSION: Relative risk of colorectal and small bowel cancers are significantly raised in Crohn's disease. Cumulative risk of colorectal cancer of 2.9% at 10 years suggests a potential benefit from routine screening. However, the value of screening requires rigorous appraisal.

PMID 16611269  Aliment Pharmacol Ther. 2006 Apr 15;23(8):1097-104. doi・・・
著者: A M Griffiths, A Ohlsson, P M Sherman, L R Sutherland
雑誌名: Gastroenterology. 1995 Apr;108(4):1056-67.
Abstract/Text BACKGROUND/AIMS: The efficacy of enteral nutrition as primary therapy of active Crohn's disease is controversial. The aim of the study was to compare by meta-analysis the likelihood of clinical response to liquid diet therapy vs. corticosteroids and to assess the importance of formula composition to efficacy.
METHODS: Randomized controlled trials comparing exclusive enteral nutrition with corticosteroids and elemental with nonelemental formulas were identified through a combination of computerized and hand-searching techniques. Rates of clinical remission of active Crohn's disease, based on the intention-to-treat principle, were extracted from the studies by two independent reviewers. Odds ratios for likelihood of clinical response were calculated.
RESULTS: In eight trials comprising 413 patients, enteral nutrition was inferior to corticosteroids (pooled odds ratio, 0.35; 95% confidence interval, 0.23-0.53). In five trials comprising 134 patients, there was no difference in the efficacy of elemental versus nonelemental formulas (pooled odds ratio, 0.87; 95% confidence interval, 0.41-1.83).
CONCLUSIONS: Corticosteroids are more effective than enteral nutrition in the treatment of active Crohn's disease. Limited sample size precludes definitive conclusions about the importance of formula composition in the efficacy of enteral nutrition; however, data analyzed in this study do not support an advantage to elemental feedings compared with a polymeric formulation.

PMID 7698572  Gastroenterology. 1995 Apr;108(4):1056-67.

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