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P534. Co-prescription of allopurinol can overcome adverse events of thiopurine therapy and lead to remission in inflammatory bowel disease patients

L. Beswick1, J.P. Dwyer2, A.B. Friedman1, S.L. Jakobovits1, E. Paul3, B. Headon1, A. McFarlane2, P.R. Gibson1, D.R. Van Langenberg2, M.P. Sparrow1, 1Alfred Health, Department of Gastroenterology, Melbourne, Australia, 2Eastern Health, Department of Gastroenterology, Melbourne, Australia, 3Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Australia

Background

Thiopurines are an established therapy in inflammatory bowel disease (IBD). Treatment failure due to intolerance can occur in up to 30% of patients. Allopurinol usage to optimise thiopurine therapy is well documented in non-responders who preferentially metabolise thiopurines to produce 6-methyl-mercaptopurine (6MMP) instead of the active 6-thioguanine nucleotides (6TGN). The aim was to examine the ability of a reduced-dose thiopurine-allopurinol combination therapy to enable avoidance of adverse effects while achieving a clinical response in patients intolerant of monotherapy.

Methods

Patients intolerant to azathioprine (AZA) and/or 6-mercaptopurine (6MP) due to side effects that included nausea, fatigue, arthralgias, hepatotoxicity and headache were treated with 100 mg allopurinol and thiopurine at 25%-33% of intended monotherapy dose. Patient outcomes and adverse effects were recorded.

Results

30 patients were identified from July 2011 to July 2013 at two Australian IBD centres. The mean age of the patients was 40 (range 22–68) years with 14 being male. 25 patients had Crohn's disease, 4 ulcerative colitis and 1 indeterminate colitis. 13 patients trialled AZA then 6MP monotherapy, whilst 17 patients had trialled solely AZA (n = 11) or 6MP (n = 6) prior to combination therapy. 10 patients developed hepatotoxicity, 18 suffered non-hepatotoxic reactions and 2 had a combination of hepatotoxic and non-hepatotoxic reactions on monotherapy. Median AZA dose at the onset of adverse effects was 150 mg (1.97 mg/kg)/day and median 6MP dose was 75 mg (1.06 mg/kg)/day. On monotherapy, 17 patients were documented thiopurine ‘shunters’, 9 patients had metabolites in the normal/low range and in the remaining 4 patients thiopurine metabolites were not measured prior to starting combination therapy.

Twenty-seven patients (90%) tolerated combination therapy. 63% were in clinical remission on the combination after a median follow-up of 8.4 (0.4–22.8) months. Significant differences were seen in pre and post intervention median 6TGN:6MMP ratio, 6TGN & 6MMP levels (p < 0.001), alanine aminotransferase levels (p < 0.005), white cell (p < 0.002) and neutrophil counts (p < 0.001). There were no significant differences in lymphocyte count or CRP. 3 patients who did not tolerate combination therapy required cessation of treatment due to development of similar symptoms while on monotherapy. There were no adverse effects due to allopurinol for patients on combination therapy.

Conclusion

Combination therapy with allopurinol and low-dose thiopurine can be used to overcome adverse drug effects in the majority of patients, whether ‘shunters’ or not. Remission can be achieved in two-thirds. This is an important therapeutic manoeuvre in the limited IBD medication armamentarium.