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P504. Effectiveness and adverse events of azathioprine in inflammatory bowel disease: 9-year follow-up study

I. Guerra1, A. Algaba1, Á. Serrano2, C. Aulló3, D. Alcalde1, M. de Lucas1, D. Bonillo1, A. Zapatero4, F. Bermejo1, 1Hospital Universitario de Fuenlabrada, Gastroenterology, Madrid, Spain, 2Hospital Universitario de Fuenlabrada, Surgery, Madrid, Spain, 3Hospital Universitario de Fuenlabrada, Radiology, Madrid, Spain, 4Hospital Universitario de Fuenlabrada, Internal Medicine, Madrid, Spain

Background

Thiopurines are an inflammatory bowel disease (IBD) useful therapy although adverse events (AE) limit their use. Our aims were to evaluate the long-term effectiveness of azathioprine (AZA) in IBD and to determinate the AE, their incidence and the potential relationship of them with thiopurine methyltransferase (TPMT) activity.

Methods

We included all IBD patients treated with AZA in our hospital from June 2004 to May 2013. Epidemiological, clinical and analytical data were prospectively recorded. TPMT activity was measured by a radiochemical method.

Results

273 consecutive IBD patients (212 Crohn's disease (CD), 57 ulcerative colitis (UC), 4 unclassified colitis) starting treatment with AZA were included. Mean age was 42±13 years, 50% male, 40% smokers. Indications: 78% steroid-dependence, 10.8% fistulizing CD, 4.8% post-resection prophylaxis of recurrence, 3% steroid-refractoriness and 3.4% others. Median time from IBD diagnosis to initiation of AZA therapy was 24 months (IQR 10–84) with a median follow-up time of 36 (8–84) months. The mean AZA dose was 2.2±0.4 mg/kg/day. AE were reported in 43.6% (95% CI 37–50%) of patients: 91 (42.9%) of CD, 28 (49.1%) of UC (p = 0.27). Early discontinuation of AZA was necessary in 58 patients (21.2%) because of AE. 137 of the 215 remaining patients had response to treatment (63.7%; 57–70%) without further therapy changes (biologics/methotrexate/surgery). The most frequent AE was hepatotoxicity (11.7%) followed by gastrointestinal intolerance (11.4%), mielotoxicity (7%), fever (6.2%), acute pancreatitis (4.8%) and arthralgia/myalgia (1.5%). Hospitalization due to AE was necessary in 24 cases (20.2% of patients with AE). The actions taken when AE appeared were: 1) Maintenance of AZA at the same dose with frequent controls (8.9%); 2) dose reduction (36.6%); 3) temporary AZA withdrawal with subsequent reintroduction (6.5%) and 4) definitive AZA withdrawal (48%). Mercaptopurine was used in 37 patients after AZA withdrawal, with clinical response in 41%. In 109 patients (40%) AZA was discontinued during follow-up (AE 60%, no response 13%, patient decision 13%, others 14%). During AZA treatment, hospitalization was required in 95 patients (36%) due to IBD flare-up, and 51 (19%) patients required surgery for IBD control. Mean TPMT value in patients treated with AZA was 19.9±5.3 U/mL (range 7.3–48). TPMT levels were not different in patients with and without AE (20.2 vs. 19.6 U/ml; p = 0.39).

Conclusion

AZA is an IBD effective treatment when is well-tolerated. AE associated to therapy are common but AZA definitive withdrawal is require in less than half of patients with AE, and many of them are managed successfully by switching to mercaptopurine. TPMT levels are not related to the appearance of AE.