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Therapeutics

Azathioprine combined with prednisolone was more effective than prednisolone alone for active Crohn disease

ACP J Club. 1994 Jan-Feb;120:13. doi:10.7326/ACPJC-1994-120-1-013


Source Citation

Ewe K, Press AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn's disease. Gastroenterology. 1993 Aug;105:367-72.


Abstract

Objective

To evaluate the effectiveness of azathioprine combined with standard prednisolone in patients with active Crohn disease.

Design

Randomized controlled trial with 4 months of follow-up.

Setting

Clinic in Germany.

Patients

42 consecutive patients (mean age 28 y) with active Crohn disease and a Crohn Disease Activity Index (CDAI) > 150. The diagnosis of Crohn disease was based on clinical, endoscopic, radiologic, and histologic criteria. Exclusion criteria were symptoms of < 3 months duration, impending surgery, age < 18 years, contraindications to corticosteroid or azathioprine treatment, diminished life expectancy, pregnancy, treatment with azathioprine within the last 4 months, severe Crohn disease with CDAI > 450, intraabdominal abscess, or enteroenteral fistulas. All patients completed the trial.

Intervention

All patients received 60 mg of prednisolone daily in a tapering regimen to a maintenance dose of 10 mg. In addition, patients received azathioprine, 2.5 mg/kg body weight (n = 21), or placebo (n = 21).

Main outcome measures

Remission; change in CDAI, severity-activity index (SAI), and the Dutch index; and laboratory tests, including complete blood cell count and differential, erythrocyte sedimentation rate, C-reactive protein and serum albumin concentrations, electrophoresis, and lipase and amylase levels.

Main results

At 4 months, 16 patients (76%) receiving azathioprine were in remission compared with 8 patients (38%) receiving placebo { P = 0.03}* (Table). The CDAI decreased significantly in both groups. At 8 weeks, the CDAIs in patients receiving azathioprine were lower than in the placebo group (P = 0.02) as were the SAIs (P = 0.006) and the Dutch indices (P = 0.02). At 4 months, the differences remained significant for only the SAI and the Dutch index. The mean dose of prednisolone was 20.9 mg daily in patients receiving azathioprine and 26.7 mg in patients receiving placebo (P = 0.02). Most laboratory values reflecting disease activity improved in both groups, with C-reactive protein and leukocyte counts improving significantly more at 8 weeks in azathioprine-treated patients. No serious side effects occurred during the study.

Conclusion

Azathioprine combined with prednisolone was more effective than prednisolone alone in treating patients with active Crohn disease.

Source of funding: In part, Merck and Deutsche Wellcome GmbH.

For article reprint: Dr. K. Ewe, I. Med. Klinik und Poliklinik, Johannes-Gutenberg-Universität, Langenbeckstr., 1 D-6500 Mainz 1, Germany. FAX 49-6131--331185.

*Numbers calculated from data in article.


Table. Azathioprin plus prednisolone vs prednisolone for active Crohn disease†

Outcome at 4 mo Azathioprine and prednisolone Prednisolone RBI (95% CI) NNT (CI)
Remission 76% 38% 100% (16 to 280) 3 (2 to 12)

†Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.


Commentary

Current treatment of Crohn disease involves the use of aminosalicylates, glucocorticoids, antibiotics, and immunosuppressive or immunomodulatory agents. The most extensively studied immunosuppressive agents are 6-mercaptopurine and azathioprine (a prodrug that is metabolized to 6-mercaptopurine).

The role of immunosuppressants in the treatment of active Crohn disease has been controversial. The National Cooperative Crohn's Disease Study failed to show the efficacy of azathioprine monotherapy (1). Present and colleagues (2), however, added 6-mercaptopurine (1.5 mg/kg) to patients who had failed to respond to other therapies and showed efficacy, although a mean time of 3.1 months was needed to show a response. Although of concern, the reported toxicities of immunosuppressants in Crohn disease have a low incidence (< 10%) and typically are dose related and reversible (3). In the randomized controlled study by Ewe and colleagues, the addition of azathioprine to prednisolone to treat active Crohn disease decreased the time to remission and was steroid sparing. Of importance, this trial used relatively high doses of azathioprine (2.5 mg/kg), aminosalicylates were not uniformly given, toxicity was minimal, and the time required to show a response was 8 weeks (shorter than previously reported, possibly because of the high dose used).

The principal controversy regarding the use of immunosuppressive medications in Crohn disease does not concern efficacy or toxicity but rather the indications for their use. Previous studies have shown that these agents are effective in treating fistulas, maintaining disease remission, and reducing the steroid dose. This study supports the addition of immunosuppressant agents in selected patients with active Crohn disease refractory to conventional therapy.

John R. Saltzman, MD
University of Massachusetts Medical CenterWorcester, Massachusetts, USA


References

1. Summers RW, Switz DM, Session JT Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology. 1979;77:847-69.

2. Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study.N Engl J Med. 1980;302:981-7.

3. Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641-9.