DOUBLE-BLIND WITHDRAWAL TRIAL OF AZATHIOPRINE AS MAINTENANCE TREATMENT FOR CROHN'S DISEASE

doi:10.1016/S0140-6736(78)92524-2

The Lancet

Volume 312, Issue 8097, 4 November 1978, Pages 955-957

https://doi.org/10.1016/S0140-6736(78)92524-2 Get rights and content

Abstract

51 patients with Crohn's disease who were in good health while taking azathioprine, 2 mg/kg body-weight/day, for at least six months were allocated either to a group in which azathioprine was continued or to one in which a control tablet was substituted. The trial lasted one year unless relapse recurred earlier. The cumulative probability of relapse was nil at six months and 5% (±5 S.D.) at a year among those on azathioprine, compared with 25% (±9 S.D.) at six months and 41% (±11 S.D.) at a year among those in the control group (P<0·01). 1 patient in whom azathioprine was continued died of pancytopenia in the fourth month of the trial. Azathioprine is potentially toxic but appears to reduce the relapse-rate in Crohn's disease.

References (14)

J.M.T. Willoughby et al.
Lancet
(1971)
J.D. Rhodes et al.
Lancet
(1971)
M. Klein et al.
Gastroenterology
(1974)
B.N. Brooke et al.
Lancet
(1969)
B.I. Korelitz et al.
Gastroenterology
(1978)
R.W. Summers et al.
Gastroenterology
(1978)

There are more references available in the full text version of this article.

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Citation Excerpt :
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DOUBLE-BLIND WITHDRAWAL TRIAL OF AZATHIOPRINE AS MAINTENANCE TREATMENT FOR CROHN'S DISEASE

Abstract

Lancet

Lancet

Gastroenterology

Lancet

Gastroenterology

Gastroenterology