Does switching to low dose thiopurine and allopurinol prevent IBD patients with evidence of hypermethylation on standard dose thiopurines from developing hepatotoxicity and drug side effects?

Background: It is accepted that low dose thiopurine and allopurinol (LDTA) therapy is effective in those who develop side effects or abnormal liver functions tests (LFTs) to standard dose therapy. Some units switch to LDTA if there is evidence of hypermethylation (6MMPN:6TGN ratio >11:1) even without side effects or abnormal LFTS due to concern that these may develop with time. To our knowledge there is no evidence that this practice is beneficial. In our unit 1 clinician switches all patients with evidence of hypermethylation and another does not. Aim: Compare outcomes at 1 year in IBD patients with evidence of hypermethylation who remained on standard dose thiopurine against those who were switched to LDTA. Methods: A prospective database of IBD patients is maintained at our hospital. We identified patients with hypermethylation between weeks 4 and 6 who had started standard dose thiopurine Results: 72 patients were identified, 24 (33%) had abnormal LFTs. 7 (29%) continued standard dose azathioprine (LFTs normalised in subsequent weeks), 3 had drug reactions, 2 switched to mercaptopurine (MP), 1 switched to methotrexate (MXT), 1 reduced dose of thiopurine, 1 stopped due to myelosuppression, and 2 stopped due to evidence of hypermethylation and a desire to conceive. 14 of 72 developed side effects; nausea, vomiting, fatigue, abdominal pain, joint pain, sore throat headaches. In 4 symptoms resolved on starting LDTA, 1 developed pancreatitis and switched to MXT, 1 switched to MP, 3 had ongoing symptoms on LDTA, 4 did not try LDTA (2 refused, 1 stayed on infliximab monotherapy, and 1 on 5-ASA). At one year 20 of 29 (68.9%) who continued LDTA were in remission. 3 (10.3%) commenced biologics whilst on LDTA due to disease activity, 2 (6.9%) switched to IFX monotherapy, 1 (3.5%) started MXT, 1 (3.5%) had abnormal LFTs after 9 months, 2 (6.9%) stopped due to myelosuppression. 5 (17.2%) had abnormal LFTS after 1 year on LDTA: 3 (10.3%) stayed on LDTA, 1 (3.5%) stopped LDTA and 1 (3.5%) switched to IFX monotherapy. At 1 year of those who remained on standard dose thiopurine 21 of 30 (70%) were in remission. 3 (10.3%) commenced biological co-therapy, 2 (6.7%) started biological monotherapy, 1 (3%) stopped due to skin cancer risk, 1 (3%) lost to follow up, 1 (3%) switched to LDTA, 1 (3%) stopped due to anaemia. 3 of 30 (10.3%) on standard thiopurine dose developed raised LFTS; 2 (6.7%) mildly elevated ALT so no changes to thiopurine, 1 (3%) significantly raised ALT 65 therefore switched to LDTA. Conclusions: At one year switching patients with evidence of hypermethylation to LDTA did not reduce the risk of hepatotoxicity, drugs side effects or reduce the number of patients requiring biologic therapy.