胃と腸46巻13号

2011年12月発行

今月の主題 難治性潰瘍性大腸炎─診療・治療の新たな展開 主題

難治性潰瘍性大腸炎に対するチオプリン製剤の寛解維持効果―再発関連因子の検討

著者： 河内修司¹ 江㟢幹宏¹ 藤岡審¹ 久保倉尚哉¹ 江頭一成¹ 池上幸治¹ 松本主之¹ 北園孝成¹

所属機関： ¹九州大学大学院病態機能内科学

ページ範囲：P.1992 - P.2001

要旨　潰瘍性大腸炎の臨床経過を遡及的に検討し，チオプリンによる寛解維持効果と再発関連因子を評価した．（1）チオプリン投与109例における6か月および12か月後の累積寛解維持率は77％と57％であった．（2）再発関連因子の検討では，ステロイド抵抗性（p＝0.0008）と喫煙（p＝0.003）が再発と有意に関連していた．しかし，再発例と非再発例でチオプリン維持投与に先行する寛解導入前の再発時大腸内視鏡所見に差はなかった．（3）チオプリン投与開始前に内視鏡を施行した48例において，チオプリンの寛解維持効果と有意に関連する内視鏡所見はなかった．以上より，潰瘍性大腸炎に対するチオプリンの寛解維持効果はステロイド反応性や喫煙習慣などの臨床像により異なることが明らかとなった．

参考文献

1）Gisbert JP, Linares PM, McNicholl AG, et al. Meta-analysis : the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 30 : 126-137, 2009

2）Andoh A, Tsujikawa T, Ban H, et al. Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 23 : 1373-1377, 2008

3）Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease : a 30 year review. Gut 50 : 485-489, 2002

4）Glas J, Török HP, Daczo J, et al. The leukocyte count predicts the efficacy of treatment with azathioprine in inflammatory bowel disease. Eur J Med Res 10 : 535-538, 2005

5）Glazier KD, Palance AL, Griffel LH, et al. The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease. J Clin Gastroenterol 39 : 21-26, 2005

6）Roblin X, Serre-Debeauvais F, Phelip JM, et al. 6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine. Aliment Pharmacol Ther 21 : 829-839, 2005

7）Cuffari C, Dassopoulos T, Turnbough L, et al. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2 : 410-417, 2004

8）Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 48 : 642-646, 2001

9）Cuffari C, Théorêt Y, Latour S, et al. 6-Mercaptopurine metabolism in Crohn's disease : correlation with efficacy and toxicity. Gut 39 : 401-406, 1996

10）Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 118 : 705-713, 2000

11）Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity : a meta-analysis. Gastroenterology 130 : 1047-1053, 2006

12）Hanai H, Iida T, Takeuchi K, et al. Thiopurine maintenance therapy for ulcerative colitis : the clinical significance of monitoring 6-thioguanine nucleotide. Inflamm Bowel Dis 16 : 1376-1381, 2010

13）Lopez-Sanroman A, Bermejo F, Carrera E, et al. Efficacy and safety of thiopurinic immunomodulators（azathioprine and mercaptopurine）in steroid-dependent ulcerative colitis. Aliment Pharmacol Ther 20 : 161-166, 2004

14）Kwan LY, Devlin SM, Mirocha JM, et al. Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease. Dig Liver Dis 40 : 425-432, 2008

15）潰瘍性大腸炎・クローン病 診断基準・治療指針．厚生労働科学研究費補助金 難治性疾患克服研究事業「難治性炎症性腸管障害に関する調査研究」（渡辺班）．平成22年度分担研究報告書 別冊 pp 1-3，2011

16）Sandborn WJ. Rational dosing of azathioprine and 6-mercaptopurine. Gut 48 : 591-592, 2001

17）Sandborn WJ, Hanauer SB. Systematic review : the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 17 : 29-42, 2003

18）Kudo T, Matsumoto T, Esaki M, et al. Mucosal vascular pattern in ulcerative colitis : observations using narrow band imaging colonoscopy with special reference to histologic inflammation. Int J Colorectal Dis 24 : 495-501, 2009

19）Seo M, Okada M, Yao T, et al. An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 87 : 971-976, 1992

20）Chebli LA, Chaves LD, Pimentel FF, et al. Azathioprine maintains long-term steroid-free remission through 3years in patients with steroid-dependent ulcerative colitis. Inflamm Bowel Dis 16 : 613-619, 2010

21）Ishioka S, Hiyama K, Sato H, et al. Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. Intern Med 38 : 944-947, 1999

22）Hibi T, Naganuma M, Kitahora T, et al. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol 38 : 740-746, 2003

23）Jewell DP, Truelove SC. Azathioprine in ulcerative colitis : final report on controlled therapeutic trial. Br Med J 4 : 627-630, 1974

24）Sood A, Kaushal V, Midha V, et al. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. J Gastroenterol 37 : 270-274, 2002

25）Sood A, Midha V, Sood N, et al. Role of azathioprine in severe ulcerative colitis : one-year, placebo-controlled, randomized trial. Indian J Gastroenterol 19 : 14-16, 2000

26）Lobo AJ, Foster PN, Burke DA, et al. The role of azathioprine in the management of ulcerative colitis. Dis Colon Rectum 33 : 374-377, 1990

27）Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 60 : 571-607, 2011

28）Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 34 : 1841-1854, 1989

29）Fraga XF, Vergara M, Medina C, et al. Effects of smoking on the presentation and clinical course of inflammatory bowel disease. Eur J Gastroenterol Hepatol 9 : 683-687, 1997

30）Szamosi T, Banai J, Lakatos L, et al. Early azathioprine/biological therapy is associated with decreased risk for first surgery and delays time to surgery but not reoperation in both smokers and nonsmokers with Crohn's disease, while smoking decreases the risk of colectomy in ulcerative colitis. Eur J Gastroenterol Hepatol 22 : 872-879, 2010

31）村野実之，平田一郎，年名謙，他．難治性潰瘍性大腸炎の内視鏡診断．胃と腸 40 : 1352-1360, 2005

32）Hirata I, Murano M. Endoscopic diagnosis of refractory ulcerative colitis. Inflammopharmacology 15 : 22-25, 2007

33）Rajwal SR, Puntis JW, McClean P, et al. Endoscopic rectal sparing in children with untreated ulcerative colitis. J Pediatr Gastroenterol Nutr 38 : 66-69, 2004

34）Oshitani N, Kitano A, Fukushima R, et al. Predictive factors for the response of ulcerative colitis patients during the acute-phase treatment. Digestion 46 : 107-113, 1990

35）辻川知之，佐々木雅也，安藤朗，他．内視鏡所見からみた重症潰瘍性大腸炎に対するステロイド治療効果の予測について．日本大腸肛門病会誌 55 : 436-440, 2002

36）勝又伴栄，横山薫，高橋裕之，他．潰瘍性大腸炎にみられる敷石様所見の臨床病理学的検討．胃と腸 33 : 1243-1253, 1998

37）Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 55 : 47-53, 2006

38）上野義隆，田中信治，鼻岡理恵，他．潰瘍性大腸炎の新しい治療による粘膜治癒と経過．胃と腸 42 : 1877-1884, 2007

39）Fujiya M, Saitoh Y, Nomura M, et al. Minute findings by magnifying colonoscopy are useful for the evaluation of ulcerative colitis. Gastrointest Endosc 56 : 535-542, 2002