How Should Azathioprine Be Dosed in Crohn's Disease? A Novel Strategy of Maximum Dose-titration Based on the Lower Limit of Leukocyte Count and Tolerability

Chang Sup Lim; Won Moon; Seun Ja Park; Moo In Park; Jeong Moon Choi; Jae Hoon Yoo; Jong Bin Kim; Jun Sik Lee

doi:10.4166/kjg.2013.62.2.111

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Lim, Moon, Park, Park, Choi, Yoo, Kim, and Lee: How Should Azathioprine Be Dosed in Crohn's Disease? A Novel Strategy of Maximum Dose-titration Based on the Lower Limit of Leukocyte Count and Tolerability

Original Article

Korean J Gastroenterol 2013;62(2):111-116.

Published online: 4 October 2013

DOI: https://doi.org/10.4166/kjg.2013.62.2.111

How Should Azathioprine Be Dosed in Crohn's Disease? A Novel Strategy of Maximum Dose-titration Based on the Lower Limit of Leukocyte Count and Tolerability

Chang Sup Lim¹, Won Moon^1,², Seun Ja Park¹, Moo In Park¹, Jeong Moon Choi¹, Jae Hoon Yoo¹, Jong Bin Kim¹, Jun Sik Lee¹

¹Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea

²Institute for Medical Science, Kosin University College of Medicine, Busan, Korea

Correspondence to: Won Moon, Department of Internal Medicine and Institute for Medical Science, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 602-702, Korea. Tel: +82-51-990-5205, Fax: +82-51-990-3005, E-mail: moonone70@hanmail.net

Received 17 January 2013 Revised 28 June 2013 Accepted 28 June 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Although general guidelines have suggested weight-based dosing of azathioprine (AZA, 2.5 mg/kg/day) for Crohn's disease (CD), a substantial number of patients develop bone marrow suppression. The aim of this study was to evaluate the maximum dose of AZA not based on weight but titrated according to the lower limit of leukocyte count for maintaining remission in patients with CD.

Methods

Among a total of seventy-eight patients with CD, who had been followed-up at Kosin University Gospel Hospital (Busan, Korea) from 2010 to 2011, those treated with the maximum dose of AZA meeting both drug-tolerability and leukocytes count of more than 4,000/mm³ for steroid-free maintaining remission were enrolled. The titrated maximum AZA dose and its relationship with weight were evaluated.

Results

A total of 42 patients (male, 32 patients; mean age, 31 years) were enrolled. The maximum dose of AZA was 49.1 mg/day. The dose per weight was 0.87 mg/kg/day and negatively correlated with body weight (γ=−0.51, p=0.01) and BMI (γ=−0.33, p=0.034). AZA dose per weight in the below 40 years old group was significantly higher than that in the above 40 years old group (p=0.039).

Conclusions

Dose decision of AZA based only on weight could put the patients to inappropriately low or high dose resulting in need of additional therapy or serious side effect, respectively. Therefore, the maximum dose-titration based on the lower limit of leukocyte count and tolerability is a novel and a valuable strategy in deciding the dose of thiopurines.

Keywords: Azathioprine, Crohn disease, Bone marrow, Leukocyte count

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Fig. 1.

Distribution of maximal dose of azathioprine. The number of patients according to the azathioprine dose/body weight/day were 10 (23.8%) in 0.1–0.5 mg/kg/day group, 23 (54.8%) in 0.6–1.0 mg/kg/day group, 6 (14.3%) in 1.1–1.5 mg/kg/day group, and 3 (7.2%) in 1.6–3.0 mg/kg/day group.

Table 1.

Clinical Characteristics of the Patients

Characteristic	Value (n=42)
Sex, male	32 (76.2)
Age (yr)	31.1±12.7
Disease duration (mo)	63.1±61.2
Diagnostic time lag (mo)	15.3±21.5
Body mass index (kg/m²)	20.8±2.79
Crohn's disease activity index	72.1±45.5
Remission	38 (90.5)
Mild	4 (9.5)
Moderate	0 (0)
Severe	0 (0)
Involvement location
Ileal	1 (2.4)
Colonic	7 (16.7)
Ileocolonic	34 (80.9)
Isolated upper	0 (0)
Behavior
Nonstricturing/nonpenetrating	22 (52.4)
Stricture	18 (42.9)
Fistularization	2 (4.8)
Perianal lesion	15 (35.7)
Hemoglobin (g/dL)	13.2 (1.7)
White blood cells (/mm³)	5,269.1±1,537.0
Platelet (×10³/mm³)	264.1±75.0
C-reactive protein (mg/L)	0.34±0.37
Serum albumin (g/dL)	4.33±0.44
Total bilirubin (mg/dL)	0.86±0.34
ALT (U/L)	19.8±19.2
Lipase (U/L)	39.8±12.6

Values are presented as mean±SD or n (%).

Table 2.

Correlation between Physical Measurements and Azathioprine Dose

	Pearson's correlation (γ)	p-value
Azathioprine dose/body weight versus weight	−0.51	0.010
Azathioprine dose/weight versus body mass index	−0.33	0.034

Table 3.

Comparison of Azathioprine Dose according to Clinical Factors

Clinical factors	Azathioprie dose/body weight (mg/kg/day)	p-value
Diagnostic time lag (yr)		0.067
＜2 (n=35)	0.80 (0.51)
≥2 (n=7)	1.21 (0.67)
Stricture		0.060
Yes (n=24)	0.73 (0.28)
No (n=18)	1.05 (0.75)
Perianal lesion		0.658
Yes (n=15)	0.82 (0.37)
No (n=27)	0.90 (0.63)
Age (yr)		0.039
＜40 (n=30)	0.98 (0.60)
≥40 (n=12)	0.59 (0.24)

Values are presented as mean (SD).

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