Safety and Effectiveness of Long-term Allopurinol–Thiopurine Maintenance Treatment in Inflammatory Bowel Disease

Background:Thiopurines are the mainstay of conventional maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to 50% of patients discontinue immunosuppressive therapy within 2 years due to intolerance or lack of efficacy. Allopurinol with low-dose thiopurine can optimize thiopurine metabolism for IBD patients with preferential shunting toward 6-methyl mercaptopurine (6-MMP) formation. The aim of this study was to assess long-term maintenance effectiveness and tolerability of allopurinol-thiopurine therapy in a larger multicenter cohort of IBD patients. Methods:Enrolled patients who failed monotherapy with thiopurines due to a skewed metabolism were subsequently treated with a combination therapy of allopurinol and low-dose thiopurine. Adverse events were monitored and therapeutic adherence was assessed. Seventy-seven IBD patients were enrolled with a mean follow-up of 19 months. Results:The median 6-thioguanine nucleotide concentration increased from 145 during monotherapy to 271 pmol/8 × 108 red blood cell (RBC) after at least 8 weeks of combination therapy while reducing the thiopurine dosage (P < 0.001). In contrast, median 6-MMP concentrations decreased from 10,110 to 265 pmol/8 × 108 RBC (P < 0.001). Leukopenia occurred in 12 patients (16%), requiring dose adaptation. Liver test abnormalities normalized in 81% of patients after the addition of allopurinol. Sixteen (21%) patients had to discontinue combination therapy. The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 87%, 85%, 76%, and 65%, respectively. Conclusions:Long-term combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment in IBD patients with a skewed thiopurine metabolism.

[1]  S. Vikingsson,et al.  Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease. , 2014, Journal of Crohn's & colitis.

[2]  D. Rubin,et al.  Two Brothers with Skewed Thiopurine Metabolism in Ulcerative Colitis Treated Successfully with Allopurinol and Mercaptopurine Dose Reduction , 2011, Digestive Diseases and Sciences.

[3]  G. Peters,et al.  Allopurinol Enhances the Activity of Hypoxanthine-Guanine Phosphoribosyltransferase in Inflammatory Bowel Disease Patients During Low-Dose Thiopurine Therapy: Preliminary Data of an Ongoing Series , 2011, Nucleosides, nucleotides & nucleic acids.

[4]  J. Sanderson,et al.  A Biochemical Mechanism for the Role of Allopurinol in TPMT Inhibition , 2011 .

[5]  S. Vikingsson,et al.  The Role of Inosine-5′-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease , 2011, Therapeutic drug monitoring.

[6]  J. V. van Ginkel,et al.  Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8‐year intercept cohorts , 2010, Inflammatory bowel diseases.

[7]  M. Schwab,et al.  Influence of 5‐aminosalicylic acid on 6‐thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy , 2010, British journal of pharmacology.

[8]  N. D. de Boer,et al.  Limited stability of thiopurine metabolites in blood samples: relevant in research and clinical practise. , 2010, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[9]  J. Sanderson,et al.  Low‐dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease , 2010, Alimentary pharmacology & therapeutics.

[10]  G. Peters,et al.  On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance. , 2009, Current drug metabolism.

[11]  M. Schwartz,et al.  Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. , 2009, Journal of Crohn's & colitis.

[12]  A. Eriksson,et al.  Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease , 2009, Alimentary pharmacology & therapeutics.

[13]  K. Van Steen,et al.  Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort , 2008, Gut.

[14]  J. Sanderson,et al.  Long‐term outcome of using allopurinol co‐therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease , 2008, Alimentary pharmacology & therapeutics.

[15]  J. Gisbert,et al.  Thiopurine-Induced Myelotoxicity in Patients With Inflammatory Bowel Disease: A Review , 2008, The American Journal of Gastroenterology.

[16]  C. Lees,et al.  Tolerability and safety of mercaptopurine in azathioprine‐intolerant patients with inflammatory bowel disease , 2007, Alimentary pharmacology & therapeutics.

[17]  C. Mulder,et al.  Dose-Dependent Influence of 5-Aminosalicylates on Thiopurine Metabolism , 2007, The American Journal of Gastroenterology.

[18]  S. Hanauer,et al.  Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[19]  J. Lewis,et al.  Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. , 2006, Gastroenterology.

[20]  P. Söderkvist,et al.  Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease , 2006, Gut.

[21]  J. Duley,et al.  Observations on the use of allopurinol in combination with azathioprine or mercaptopurine , 2005, Alimentary pharmacology & therapeutics.

[22]  S. Hanauer,et al.  Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine , 2005, Alimentary pharmacology & therapeutics.

[23]  Michel Eichelbaum,et al.  Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. , 2004, Pharmacogenetics.

[24]  D. McGovern,et al.  Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. , 2002, Gastroenterology.

[25]  T. Bayless,et al.  Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease , 2001, Gut.

[26]  S. Targan,et al.  Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. , 2000, Gastroenterology.

[27]  R. D. De Abreu,et al.  Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. , 1998, Arthritis and rheumatism.

[28]  R. Boulieu,et al.  Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC. , 1998, Clinical chemistry.

[29]  L. Lennard,et al.  High-performance liquid chromatographic assay of the methyl and nucleotide metabolites of 6-mercaptopurine: quantitation of red blood cell 6-thioguanine nucleotide, 6-thioinosinic acid and 6-methylmercaptopurine metabolites in a single sample. , 1992, Journal of chromatography.