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Outcome Predictors for Thiopurine Maintenance Therapy in Patients with Crohn’s Disease

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Abstract

Background

Little is known about the factors that predict clinical relapse in Crohn’s disease patients receiving thiopurine therapy to maintain remission. The objective of this study was, therefore, to investigate these factors.

Methods

A total of 82 Crohn’s disease patients who received their first course of azathioprine or 6-mercaptopurine treatment at Severance Hospital between June 1996 and July 2007 were recruited to the study. During the follow-up period (25.5 ± 16.6 months) 19 patients (23.2%) discontinued the medication because of significant adverse effects. Forty-five patients who continued to receive thiopurines to maintain medically or surgically induced remission were enrolled in the study. After adjusting the maintenance dose, patients in remission were followed at 2–3 month intervals. Relapse was defined as a Crohn’s disease activity index ≥150.

Results

The male-to-female ratio was 1.5:1 and the mean age was 26.3 ± 7.1 years. Cumulative relapse was 18.0% after one year and 49.2% after three years. According to multivariate Cox regression analysis, younger age (<30 years) at thiopurine therapy and increased C-reactive protein level (≥0.5 mg/dL) at remission were independent predictors of relapse (hazard ratio 19.751, 95%-confidence interval (CI) 1.996–195.402, P = 0.011 and hazard ratio 9.001, 95% CI 1.583–51.181, P = 0.013, respectively).

Conclusions

Younger age (<30 years) and increased C-reactive protein level at remission were independent predictors of relapse in Crohn’s disease patients receiving thiopurines to maintain remission. These high-risk groups warrant closer observation and possibly early introduction of biological agents.

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References

  1. Munkholm P, Langholz E, Davidsen M, et al. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand J Gastroenterol. 1995;30:699–706.

    Article  PubMed  CAS  Google Scholar 

  2. Loftus EV Jr, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:1–20.

    Article  PubMed  Google Scholar 

  3. Munkholm P, Langholz E, Nielsen OH, et al. Incidence and prevalence of Crohn’s disease in the county of Copenhagen, 1962–1987: a sixfold increase in incidence. Scand J Gastroenterol. 1992;27:609–614.

    Article  PubMed  CAS  Google Scholar 

  4. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986–2005: a KASID study. Inflamm Bowel Dis. 2008;14:542–549.

    Article  PubMed  Google Scholar 

  5. Kim ES, Kim WH. Inflammatory bowel disease in Korea: epidemiological, genomic, clinical, and therapeutic characteristics. Gut Liver. 2010;4:1–14.

    Article  PubMed  Google Scholar 

  6. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002;8:244–250.

    Article  PubMed  Google Scholar 

  7. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev. 2000;2:CD000067.

    Google Scholar 

  8. Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2009;104:2089–2096.

    Article  PubMed  CAS  Google Scholar 

  9. Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37:674–678.

    Article  PubMed  CAS  Google Scholar 

  10. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6; discussion 16–19.

    Google Scholar 

  11. Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002;122:512–530.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Kim PS, Zlatanic J, Korelitz BI, et al. Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol. 1999;94:3254–3257.

    Article  PubMed  CAS  Google Scholar 

  14. Murakami Y, Matsui T, Hirai F, et al. Efficacy of azathioprine in mild or moderate relapse in Crohn’s disease: clinical and endoscopic evaluation. Dig Endosc. 2010;22:25–32.

    Article  PubMed  Google Scholar 

  15. Thia KT, Loftus EV Jr, Sandborn WJ, et al. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008;103:3167–3182.

    Article  PubMed  Google Scholar 

  16. Sahmoud T, Hoctin-Boes G, Modigliani R, et al. Identifying patients with a high risk of relapse in quiescent Crohn’s disease. The GETAID group. The groupe d’Etudes Therapeutiques des affections inflammatoires digestives. Gut. 1995;37:811–818.

    Article  PubMed  CAS  Google Scholar 

  17. Consigny Y, Modigliani R, Colombel JF, et al. A simple biological score for predicting low risk of short-term relapse in Crohn’s disease. Inflamm Bowel Dis. 2006;12:551–557.

    Article  PubMed  Google Scholar 

  18. Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology. 1996;110:424–431.

    Article  PubMed  CAS  Google Scholar 

  19. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–533.

    Article  PubMed  CAS  Google Scholar 

  20. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005;307:1920–1925.

    Article  PubMed  CAS  Google Scholar 

  21. Ginaldi L, De Martinis M, D’Ostilio A, et al. The immune system in the elderly: II. Specific cellular immunity. Immunol Res. 1999;20:109–115.

    Article  PubMed  CAS  Google Scholar 

  22. D’Inca R, Bertomoro P, Mazzocco K, et al. Risk factors for non-adherence to medication in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2008;27:166–172.

    Article  PubMed  Google Scholar 

  23. Horne R, Parham R, Driscoll R, et al. Patients’ attitudes to medicines and adherence to maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis. 2009;15:837–844.

    Article  PubMed  Google Scholar 

  24. Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:661–665.

    Article  PubMed  Google Scholar 

  25. Desai D, Faubion WA, Sandborn WJ. Review article: biological activity markers in inflammatory bowel disease. Aliment Pharmacol Ther. 2007;25:247–255.

    Article  PubMed  CAS  Google Scholar 

  26. Boirivant M, Leoni M, Tariciotti D, et al. The clinical significance of serum C reactive protein levels in Crohn’s disease. Results of a prospective longitudinal study. J Clin Gastroenterol. 1988;10:401–405.

    Article  PubMed  CAS  Google Scholar 

  27. Papi C, Festa V, Leandro G, et al. Long-term outcome of Crohn’s disease following corticosteroid-induced remission. Am J Gastroenterol. 2007;102:814–819.

    Article  PubMed  CAS  Google Scholar 

  28. Solem CA, Loftus EV Jr, Tremaine WJ, et al. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:707–712.

    Article  PubMed  Google Scholar 

  29. Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–1301.

    Article  PubMed  Google Scholar 

  30. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–468; quiz e410–e461.

    Google Scholar 

  31. Devlin SM, Panaccione R. Evolving inflammatory bowel disease treatment paradigms: top-down versus step-up. Gastroenterol Clin North Am. 2009;38:577–594.

    Article  PubMed  Google Scholar 

  32. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–1395.

    Article  PubMed  CAS  Google Scholar 

  33. Lautenbach E, Berlin JA, Lichtenstein GR. Risk factors for early postoperative recurrence of Crohn’s disease. Gastroenterology. 1998;115:259–267.

    Article  PubMed  CAS  Google Scholar 

  34. Bitton A, Dobkin PL, Edwardes MD, et al. Predicting relapse in Crohn’s disease: a biopsychosocial model. Gut. 2008;57:1386–1392.

    Article  PubMed  CAS  Google Scholar 

  35. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010;6:CD000545.

    Google Scholar 

  36. Kim JH, Cheon JH, Hong SS, et al. Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol. 2010;44:242–248.

    Article  Google Scholar 

  37. Hindorf U, Lindqvist M, Peterson C, et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut. 2006;55:1423–1431.

    Article  PubMed  CAS  Google Scholar 

  38. Gisbert JP, Nino P, Rodrigo L, et al. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol. 2006;101:2769–2776.

    Article  PubMed  CAS  Google Scholar 

  39. Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4:44–49.

    Article  PubMed  CAS  Google Scholar 

  40. Lowry PW, Franklin CL, Weaver AL, et al. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut. 2001;49:656–664.

    Article  PubMed  CAS  Google Scholar 

  41. Gilissen LP, Bierau J, Derijks LJ, et al. The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2005;22:605–611.

    Article  PubMed  CAS  Google Scholar 

  42. Hande S, Wilson-Rich N, Bousvaros A, et al. 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis. 2006;12:251–257.

    Article  PubMed  Google Scholar 

  43. Shah JA, Edwards CM, Probert CS. Should azathioprine and 5-aminosalicylates be coprescribed in inflammatory bowel disease?: an audit of adverse events and outcome. Eur J Gastroenterol Hepatol. 2008;20:169–173.

    Article  PubMed  CAS  Google Scholar 

  44. Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol. 1995;39:456–459.

    PubMed  CAS  Google Scholar 

  45. Kim JH, Cheon JH, Kim WH. The frequency and the course of the adverse effects of azathioprine/6-mercaptopurine treatment in patients with inflammatory bowel disease. Korean J Gastroenterol. 2008;51:291–297.

    PubMed  Google Scholar 

  46. Lee HJ, Yang SK, Kim KJ, et al. The safety and efficacy of azathioprine and 6-mercaptopurine in the treatment of Korean patients with Crohn’s disease. Intest Res. 2009;7:22–31.

    Google Scholar 

  47. Cheon JH, Kim JH, Kim BY, et al. Allele frequency of thiopurine methyltransferase and inosine triphosphate pyrophosphatase gene polymorphisms in Korean patients with inflammatory bowel diseases. Hepatogastroenterology. 2009;56:421–423.

    PubMed  CAS  Google Scholar 

  48. Jung YS, Cheon JH, Park JJ, et al. Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs. J Hum Genet. 2010;55:121–123.

    Article  PubMed  CAS  Google Scholar 

  49. Kim DU, Kim YH, Kim BJ, et al. The efficacy of low dose azathioprine/6-mercaptopurine in patients with inflammatory bowel disease. Hepatogastroenterology. 2009;56:1395–1402.

    PubMed  CAS  Google Scholar 

  50. 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. 2003;38:740–746.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Thia KT, Li M, Ling KL, et al. Azathioprine is effective in corticosteroid-dependent Asian inflammatory bowel disease patients. Inflamm Bowel Dis. 2011;17:809–815.

    Article  PubMed  Google Scholar 

  53. Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn’s disease. Dig Dis Sci. 1985;30:58–64.

    Article  PubMed  CAS  Google Scholar 

  54. Ha C, Dassopoulos T. Thiopurine therapy in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4:575–588.

    Article  PubMed  CAS  Google Scholar 

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Author notes

  1. Jae Jun Park

    Present address: Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Korea

Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea

    Jae Jun Park, Jae Hee Cheon, Sung Pil Hong, Tae Il Kim & Won Ho Kim

  2. Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea

    Jae Jun Park, Jae Hee Cheon, Sung Pil Hong, Tae Il Kim & Won Ho Kim

  3. Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea

    Jae Hee Cheon & Won Ho Kim

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  1. Jae Jun Park
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Correspondence to Won Ho Kim.

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Park, J.J., Cheon, J.H., Hong, S.P. et al. Outcome Predictors for Thiopurine Maintenance Therapy in Patients with Crohn’s Disease. Dig Dis Sci 57, 133–141 (2012). https://doi.org/10.1007/s10620-011-1955-9

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  • DOI: https://doi.org/10.1007/s10620-011-1955-9

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