Skip to main content
Top
Published in: Digestive Diseases and Sciences 1/2015

01-01-2015 | Original Article

Leukopenia Predicts Remission in Patients with Inflammatory Bowel Disease and Behcet’s Disease on Thiopurine Maintenance

Authors: Mi Sung Park, Dong Hyun Kim, Duk Hwan Kim, Soo Jung Park, Sung Pil Hong, Tae Il Kim, Won Ho Kim, Jae Hee Cheon

Published in: Digestive Diseases and Sciences | Issue 1/2015

Login to get access

Abstract

Backgrounds

The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD.

Methods

We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn’s disease (CD), and 83 with intestinal Behçet’s disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/μL) and nonleukopenic (n = 76, WBC count ≥4,000/μL) patients.

Results

The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan–Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively).

Conclusion

Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet’s disease.
Literature
1.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
2.
go back to reference Kobayashi K, Ueno F, Bito S, et al. Development of consensus statements for the diagnosis and management of intestinal Behcet’s disease using a modified Delphi approach. J Gastroenterol. 2007;42:737–745.PubMedCrossRef Kobayashi K, Ueno F, Bito S, et al. Development of consensus statements for the diagnosis and management of intestinal Behcet’s disease using a modified Delphi approach. J Gastroenterol. 2007;42:737–745.PubMedCrossRef
4.
go back to reference Loftus EV Jr, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:1–20.PubMedCrossRef Loftus EV Jr, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:1–20.PubMedCrossRef
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
7.
8.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
10.
go back to reference Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Internal Med. 1995;123:132–142.CrossRef Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Internal Med. 1995;123:132–142.CrossRef
11.
go back to reference Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478. Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478.
12.
go back to reference Jung YS, Cheon JH, Hong SP, et al. Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet’s disease. Inflamm Bowel Dis. 2012;18:750–757.PubMedCrossRef Jung YS, Cheon JH, Hong SP, et al. Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet’s disease. Inflamm Bowel Dis. 2012;18:750–757.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
14.
go back to reference Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641–649.PubMedCrossRef Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641–649.PubMedCrossRef
15.
go back to reference Tanis AA. Azathioprine in inflammatory bowel disease, a safe alternative? Mediat Inflamm. 1998;7:141–144.CrossRef Tanis AA. Azathioprine in inflammatory bowel disease, a safe alternative? Mediat Inflamm. 1998;7:141–144.CrossRef
16.
go back to reference Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–1800.PubMedCrossRef Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–1800.PubMedCrossRef
17.
go back to reference Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–987.PubMedCrossRef Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–987.PubMedCrossRef
18.
go back to reference Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998;115:813–821.PubMedCrossRef Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998;115:813–821.PubMedCrossRef
19.
go back to reference Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000;119:895–902.PubMedCrossRef Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000;119:895–902.PubMedCrossRef
20.
go back to reference Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:1081–1085.PubMedCrossRefPubMedCentral Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:1081–1085.PubMedCrossRefPubMedCentral
22.
go back to reference 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 (Taehan Sohwagi Hakhoe chi). 2008;51:291–297. 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 (Taehan Sohwagi Hakhoe chi). 2008;51:291–297.
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
25.
go back to reference 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:e242–e248.PubMedCrossRef 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:e242–e248.PubMedCrossRef
26.
go back to reference Cheon JH, Kim ES, Shin SJ, et al. Development and validation of novel diagnostic criteria for intestinal Behcet’s disease in Korean patients with ileocolonic ulcers. Am J Gastroenterol. 2009;104:2492–2499.PubMedCrossRef Cheon JH, Kim ES, Shin SJ, et al. Development and validation of novel diagnostic criteria for intestinal Behcet’s disease in Korean patients with ileocolonic ulcers. Am J Gastroenterol. 2009;104:2492–2499.PubMedCrossRef
27.
go back to reference Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6 (discussion 16–19). Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6 (discussion 16–19).
28.
go back to reference Lee HW, Kim WH, Cheon JH. The medical treatments of intestinal Behçet’s disease: an update. Intest Res. 2013;11:155–160.CrossRef Lee HW, Kim WH, Cheon JH. The medical treatments of intestinal Behçet’s disease: an update. Intest Res. 2013;11:155–160.CrossRef
29.
go back to reference Stange EF, Travis SP, Vermeire S, et al. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn’s Colitis. 2008;2:1–23.CrossRef Stange EF, Travis SP, Vermeire S, et al. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn’s Colitis. 2008;2:1–23.CrossRef
30.
go back to reference Park JJ, Cheon JH, Hong SP, et al. Outcome predictors for thiopurine maintenance therapy in patients with Crohn’s disease. Dig Dis Sci. 2012;57:133–141.PubMedCrossRef Park JJ, Cheon JH, Hong SP, et al. Outcome predictors for thiopurine maintenance therapy in patients with Crohn’s disease. Dig Dis Sci. 2012;57:133–141.PubMedCrossRef
31.
go back to reference Burke DA, Dixon MF, Axon AT. Ulcerative colitis: prolonged remission following azathioprine-induced pancytopenia. J Clin Gastroenterol. 1989;11:327–330.PubMedCrossRef Burke DA, Dixon MF, Axon AT. Ulcerative colitis: prolonged remission following azathioprine-induced pancytopenia. J Clin Gastroenterol. 1989;11:327–330.PubMedCrossRef
32.
go back to reference Choi YS, Suh JP, Song KH, et al. A case of Crohn’s disease with improvement after azathioprine-induced pancytopenia. Case Rep Gastroenterol. 2011;5:344–349.PubMedCrossRefPubMedCentral Choi YS, Suh JP, Song KH, et al. A case of Crohn’s disease with improvement after azathioprine-induced pancytopenia. Case Rep Gastroenterol. 2011;5:344–349.PubMedCrossRefPubMedCentral
33.
go back to reference Colonna T, Korelitz BI. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol. 1994;89:362–366.PubMed Colonna T, Korelitz BI. The role of leukopenia in the 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol. 1994;89:362–366.PubMed
34.
go back to reference Korelitz BI, Zlatanic J, Smith MJ, et al. Significance of WBC differential when leukopenia is induced by 6-MP for IBD. Gastroenterology. 1997;113:1810–1811.PubMedCrossRef Korelitz BI, Zlatanic J, Smith MJ, et al. Significance of WBC differential when leukopenia is induced by 6-MP for IBD. Gastroenterology. 1997;113:1810–1811.PubMedCrossRef
36.
go back to reference Campbell S, Ghosh S. Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease? Eur J Gastroenterol Hepatol. 2001;13:1073–1076.PubMedCrossRef Campbell S, Ghosh S. Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease? Eur J Gastroenterol Hepatol. 2001;13:1073–1076.PubMedCrossRef
37.
go back to reference Persley KM, Present DH. Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2001;13:1053–1055.PubMedCrossRef Persley KM, Present DH. Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2001;13:1053–1055.PubMedCrossRef
38.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
39.
go back to reference 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.PubMedCrossRefPubMedCentral 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.PubMedCrossRefPubMedCentral
40.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
41.
go back to reference 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. 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.
42.
go back to reference Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–533.PubMedCrossRef Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–533.PubMedCrossRef
43.
go back to reference Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science (New York, NY). 2005;307:1920–1925.CrossRef Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science (New York, NY). 2005;307:1920–1925.CrossRef
44.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
45.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
46.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
47.
go back to reference Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev. 2000:CD000067. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev. 2000:CD000067.
48.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
49.
go back to reference Ha C, Dassopoulos T. Thiopurine therapy in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4:575–588.PubMedCrossRef Ha C, Dassopoulos T. Thiopurine therapy in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4:575–588.PubMedCrossRef
Metadata
Title
Leukopenia Predicts Remission in Patients with Inflammatory Bowel Disease and Behcet’s Disease on Thiopurine Maintenance
Authors
Mi Sung Park
Dong Hyun Kim
Duk Hwan Kim
Soo Jung Park
Sung Pil Hong
Tae Il Kim
Won Ho Kim
Jae Hee Cheon
Publication date
01-01-2015
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 1/2015
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-014-3355-4

Other articles of this Issue 1/2015

Digestive Diseases and Sciences 1/2015 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.