胃と腸39巻2号

2004年02月発行

今月の主題 Crohn病経過例における新しい治療の位置づけ 主題

Crohn病経過例における免疫抑制剤の効果

著者： 岩男泰¹² 諸星雄一¹ 松岡克善¹ 久松理一¹ 岩上祐子¹ 泉谷幹子¹ 桜庭篤¹ 芳沢茂雄¹ 佐藤俊朗¹ 一松収¹ 岡本晋¹ 高石官均¹ 井上詠¹ 緒方晴彦¹ 日比紀文¹² 杉野吉則³

所属機関： ¹慶應義塾大学医学部消化器内科 ²慶應義塾大学医学部包括先進医療センター ³慶應義塾大学放射線診断科

ページ範囲：P.185 - P.199

要旨　Crohn病に対する少量の免疫抑制剤の治療効果を検討した．対象は当院において免疫抑制剤を投与したCrohn病患者の109例であり，治療効果の判定は長期経過が追跡可能な76例で行った．治療目的別では緩解維持37.3％，ステロイド減量・離脱目的では63.6％の有効率を示した．さらに，腸切除術後に緩解維持療法を目的に免疫抑制剤を投与した症例19例と非投与症例32例の比較では，再手術率，1年以内・2年以内の早期再燃率はともに免疫抑制剤投与群で低かった．投与量は6-mercaptopurine30mg/日，azathioprine50mg/日の少量投与であるが，有効性は欧米からの報告と遜色はないと思われた．副作用は109例中14例(12.8％)にみられた．内訳は骨髄抑制7例，消化器症状3例，脱毛3例，頭痛1例であり，いずれも投与中止により症状の改善，検査値の正常化が得られ，重篤なものはなかった．免疫抑制剤の少量投与の緩解維持およびステロイド減量・離脱における有用性と安全性が確認された．

参考文献

1）樋渡信夫，今野保敏，小林和人．経腸栄養法の実際─炎症性腸疾患．臨床外科 40 : 73-80, 1985

2）Matsui T, Ueki M, Yamada M, et al. Indication and options of nutritional treatment for Crohn's disease. A comparison of elemental and polymeric diets. J Gastroenterol 30 (Suppl 8) : 95-97, 1995

3）Lochs H, Mayer M, Fleig WE, et al. Prophylaxis of postoprative relapse in Crohn's disease with mesalamine : European Cooperative Crohn's Disease Study VI. Gastroenterology 118 : 264-273, 2000

4）O'Donoghue DP, Dawson AM, Powell-Tuck J, et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet II : 955-957, 1978

5）Willoughby JM, Beckett J, Kumar PJ, et al. Controlled trial of azathioprine in Crohn's disease. Lancet II : 944-947, 1971

6）Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn's disease with 6-mercaptopurine : A long-term, randomized, double-blind study. N Engl J Med 302 : 981-987, 1980

7）Ewe K, Press A, Singe C, et al. Azathioprine combined with prednisolone in active Crohn's disease. Gastroenterology 105 : 367-372, 1993

8）Candy S, Wright JP, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 37 : 674-678, 1995

9）Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine with Crohn's disease : A metaanalysis. Ann Intern Med 122 : 132-142, 1995

10）Matsueda K, Shoda R, Takazoe M, et al. Therapeutic efficacy of cyclic home elemental enteral alimentation in Crohn's disease : Japanese cooperative Crohn's disease study. J Gastroenterol 30 (suppl 8) : 91-94, 1995

11）Bouhnik Y, Lemann M, Mary JY, et al. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 347 : 215-219, 1996

12）Present DH, Melzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease : Short and long-term toxicity. Ann Intern Med 111 : 641-649, 1989

13）Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease : 27years of experience. Gut 34 : 1081-1085, 1993

14）Marion JF. Toxicity of 6-mercaptopurine/azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 4 : 116-117, 1998

15）Warman JI, Korelitz BI, Fleisher MR, et al. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatement of Crohn's disease and ulcerative colitis. J Clin Gastroenterol 37 : 220-225, 2003

16）Connell WR, Kamm MA, Dickson M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 343 : 1249-1252, 1994

17）Fraser AG, Orchard TR, Robinson EM, et al. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 16 : 1225-1232, 2000

18）Lewis JD, Schwartz JS, Linchtenstein GR. Azathioprine for maintenance of remission in Crohn's disease : Benefits outweigh the risk of lymphoma. Gastroenterology 118 : 1018-1024, 2000

19）Alstead EM, Richie JK, Lennard-Jones JE, et al. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 99 : 443-446, 1990

20）Francella A, Dyan A, Boddian C, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease : A retrospective cohort study. Gastroenterology 124 : 9-17, 2003

21）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

22）Hibi T, Iwao Y, Yajima T, et al. Immunosuppressive agents in the treatment of Crohn's disease and ulcerative colitis. J Gastroenterol 30 : 121-123, 1995

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

24）Lowry PW, Frankin CL, Weaver AL, et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut 49 : 665-670, 2001

25）Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 118 : 1025-1030, 2000

26）Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 340 : 1398-405, 1997

27）日比紀文，下山孝，金城福則，他．潰瘍性大腸炎およびクローン病緩解維持に対するアザチオプリンの有効性に関する臨床研究．平成10～12年度創薬等ヒューマンサイエンス研究総合研究報告書（第4分野：気象疾病治療薬等の開発に関する研究）．pp 8-13, 2001

28）Hibi T, Naganuma N, 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