Azathioprine vs Conventional Management of Crohn's Disease
Azathioprine vs Conventional Management of Crohn's Disease
Background & Aims Immunomodulator therapy is effective for patients with Crohn's disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease.
Methods We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg · kg · day, n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti–tumor necrosis factor (TNF)—free remission during the first 3 years after inclusion.
Results During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%–85%) compared with 56% in the conventional management group (interquartile range, 29%–73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups.
Conclusions Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.
Crohn's disease (CD) is a chronic, progressive, disabling, and destructive inflammatory disorder. The conventional "step-care" incremental approach using corticosteroids and immunomodulators (thiopurines or methotrexate) sequentially has no clear effect on disease progression and the rate of surgery. The lack of efficacy of immunomodulators could be related to a delayed prescription at a time when irreversible damage has already occurred. An alternative concept of "accelerated step care" using early intervention with immunomodulators was proposed by pediatricians more than 10 years ago; in a small randomized placebo-controlled trial conducted in 53 children with disease duration ≤8 weeks, combination therapy with corticosteroids (induction) and mercaptopurine for maintenance significantly lessened the need for prednisone and improved maintenance of remission. This strategy needs to be evaluated in adult cases of CD, which are often less severe than pediatric cases of CD. There is a subgroup of adult patients who experience a mild to moderate disease course, never requiring the use of immunomodulators or biologic therapies, and increasing concern about the toxicity of thiopurines would likely preclude their early use in unselected patient populations. However, clinical features associated with high risk of progression to disabling disease have been identified that can be used to select patients at diagnosis who might benefit the most from early intervention with immunomodulators.
The aim of this randomized, open-label, controlled trial was thus to evaluate the benefits on the 3-year course of CD of an early prescription of azathioprine compared with conventional step-care therapy in patients with a high risk of disabling disease.
Abstract and Introduction
Abstract
Background & Aims Immunomodulator therapy is effective for patients with Crohn's disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease.
Methods We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg · kg · day, n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti–tumor necrosis factor (TNF)—free remission during the first 3 years after inclusion.
Results During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%–85%) compared with 56% in the conventional management group (interquartile range, 29%–73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups.
Conclusions Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.
Introduction
Crohn's disease (CD) is a chronic, progressive, disabling, and destructive inflammatory disorder. The conventional "step-care" incremental approach using corticosteroids and immunomodulators (thiopurines or methotrexate) sequentially has no clear effect on disease progression and the rate of surgery. The lack of efficacy of immunomodulators could be related to a delayed prescription at a time when irreversible damage has already occurred. An alternative concept of "accelerated step care" using early intervention with immunomodulators was proposed by pediatricians more than 10 years ago; in a small randomized placebo-controlled trial conducted in 53 children with disease duration ≤8 weeks, combination therapy with corticosteroids (induction) and mercaptopurine for maintenance significantly lessened the need for prednisone and improved maintenance of remission. This strategy needs to be evaluated in adult cases of CD, which are often less severe than pediatric cases of CD. There is a subgroup of adult patients who experience a mild to moderate disease course, never requiring the use of immunomodulators or biologic therapies, and increasing concern about the toxicity of thiopurines would likely preclude their early use in unselected patient populations. However, clinical features associated with high risk of progression to disabling disease have been identified that can be used to select patients at diagnosis who might benefit the most from early intervention with immunomodulators.
The aim of this randomized, open-label, controlled trial was thus to evaluate the benefits on the 3-year course of CD of an early prescription of azathioprine compared with conventional step-care therapy in patients with a high risk of disabling disease.
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