De novo combination allopurinol-thiopurine vs standard thiopurine in inflammatory bowel disease (IBD) patients escalating to immunomodulators: a randomized controlled trial

The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are immune system related conditions where an overactive immune response from the body’s white blood cells causes inflammation and damage to the intestines and in turn the typical symptoms of diarrhoea, abdominal pain and weight loss. Immune-modifying drugs (immunomodulators) like azathioprine (AZA) and 6-mercaptopurine (6MP) dampen down the overactive white blood cells that are the cause of the inflammation. Over 50% of patients who attend an IBD clinic at Eastern Health are on one of these medications. In IBD like other immune related conditions, AZA and 6MP have been shown to both get patients well (induce remission), and keep patients well (maintain remission). Importantly, they also reduce the need for cortisone-based medicines such as prednisolone that are associated with many side effects and no long-term benefits. We know that AZA and 6MP to produce two chemical end-products (metabolites) that are responsible for the benefits and also side effects of these drugs. These metabolites are known as 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). 6-TGN is the good metabolite that makes these drugs work, while 6-MMP instead can cause side-effects, especially affecting the liver. Therefore it is desirable to have high levels of 6-TGN and low levels of 6-MMP to get the best out of these drugs. Recent research has shown that by adding another drug called allopurinol to AZA/6MP in almost all cases the 6TGN levels improve and the 6MMP levels greatly reduce. Also, we generally use a much lower dose of the AZA/6MP combined with the allopurinol and thus most patients end up getting a greater benefit but with fewer tablets, with no increase in side effects. It should be noted that the use of allopurinol in combination with azathioprine or 6-mercaptopurine remains experimental, and is not currently approved by the TGA. In this study we are comparing patients who are commencing on treatment with azathioprine with those who will be started on a combination of azathioprine and allopurinol to see if this combination of drugs is more effective and quicker to work, yet similarly safe, to those taking the standard AZA alone. If we are able to show that the combination is better in this study, then this will have major consequences to how azathioprine is used in the treatment of IBD in the future.