Article

Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn's disease: Open-label prospective study

Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
Journal of Gastroenterology and Hepatology (Impact Factor: 3.63). 03/2007; 22(2):268-74. DOI: 10.1111/j.1440-1746.2006.04393.x
Source: PubMed

ABSTRACT A substantial number of patients with Crohn's disease (CD) become dependent on steroids after induction therapy. Treatment with azathioprine (AZA) may be beneficial in such patients. The present open-label study evaluated the long-term safety and efficacy of AZA in steroid-dependent CD patients.
Adult patients with steroid-dependent CD were enrolled for AZA therapy over a 7-year period. The average dose of AZA was 2.0-3.0 mg/kg per day, adjusted according to clinical response and occurrence of adverse effects. Steroid therapy was tapered off according to a predefined schedule. Long-term outcome and adverse reactions were evaluated.
Sixty-nine patients were prospectively included. Steroid-free remission was achieved in 68-81% of patients, partial response in 14.5-27.3% and failure to respond to AZA in 4-15.9% over the initial 48 months. However, the rate of wean from steroid therapy decreased to 53-60% while the rate of failure increased from 6.7% to 17.6% after this period. A breakthrough of symptoms during continuous AZA therapy was common, particularly after 48 months on AZA. The mean leukocyte count at the end of 12 months of therapy was significantly lower in patients who achieved complete response on AZA than in the non-responders (5197 +/- 1250 cells/mm(3) vs 8340 +/- 1310 cells/mm(3), respectively; P < 0.01). Azathioprine was relatively well-tolerated and the incidence of serious adverse effects was small.
Azathioprine was relatively safe and moderately effective for long-term maintenance of steroid-free clinical remission in corticosteroid-dependent CD patients. Patients were more successfully weaned from prednisone treatment, and clinical remission was more often maintained during the first 48 months of AZA therapy. A significant decrease in the white blood cell count at the end of 12 months on AZA was the single factor associated with weaning from steroid dependence.

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Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. 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GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined azathioprine and infliximab group achieved steroid-free remission compared to 48% (91/189) of infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47). Azathioprine or 6-mercaptopurine therapy was found to be no better at inducing steroid free clinical remission compared to methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). 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    ABSTRACT: Azathioprine is of major importance in the treatment of Crohn's disease; its efficacy has been showed in several works, but real-life data regarding its use is scarce. Our aim was to address the outcome of patients with Crohn's disease under azathioprine in the real-life setting. Crohn's disease patients followed at an Inflammatory Bowel Disease Outpatient Clinic under azathioprine were consecutively enrolled, being allocated in one of four groups. Two groups included patients on treatment with this drug, regarding its two major indications - prevention of post-operative recurrence and steroid-dependent disease; a third group included patients who needed infliximab in addition to azathioprine and a fourth group comprised patients who did not tolerate azathioprine. A total of 221 patients were enrolled, 180 on azathioprine due to steroid-dependency (64 needing additional treatment with infliximab) and 41 for prevention of post-operative recurrence. Steroid-free remission was obtained in 48%. Immunosuppression decreased the number of hospitalized patients (64% vs 36%; p<0.001), but not the surgery rates per person per year. Azathioprine as a post-operative drug was effective in decreasing hospitalizations. The addition of infliximab decreased the number of patients hospitalized (p=0.009) and hospitalization rates per person per year (p<0.001), but had no effect in the surgery rates per person per year. Sixty patients (23%) experienced adverse effects with AZA, 39 requiring discontinuation of the drug. In this real-life study, azathioprine had a long-term steroid sparing effect and reduced hospitalizations. Combination with infliximab reduced hospitalizations but did not decrease the surgery rate.
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