[45] In 2005, the efficacy of combination therapy was first demonstrated in a group of 15 patients with clinically active IBD, who were documented thiopurine

shunters (mean 6TGN = 186, mean 6MMP = 10 380). With the addition of 100 mg allopurinol and a dose reduction of AZA to 25–50% of the original thiopurine dose, this adverse metabolic profile was reversed with mean 6TGN increasing to 385 and mean 6MMP decreasing to 1732 (P < 0.001). Clinically, most patients improved. While six patients developed myelosuppression (white cell count < 3.5), all counts Gefitinib chemical structure recovered and remained within normal range with temporary drug cessation and subsequent reduced thiopurine dose.[46] There are at least another eight publications where clinical indices and thiopurine metabolites have been documented pre- and post-addition of allopurinol.[27, 47-53] The largest series included 110 patients who were prescribed allopurinol, with resultant 76% clinical remission.[53] In the pediatric IBD literature, there have been two publications, also demonstrating similar efficacy.[54, 55] Unfortunately, all of these publications are retrospective analyses of prospectively collected data, which include a wide range of allopurinol dosages (50–300 mg/day)

Tacrolimus cell line and a variety of thiopurine dose reduction strategies. A similar effect has also been noted in autoimmune hepatitis. In a Dutch study, eight patients with autoimmune hepatitis with ongoing abnormal liver enzymes (median ALT = 62) were also identified as thiopurine shunters. The addition of allopurinol resulted in an increase in 6TGN levels from a median of 100 to

200 and decreased 6MMP levels from a median of 6090 to 175, and sustained remission in 88%.[56] The downside of such combination therapy is that the patient is exposed to potential adverse effects of two drugs. Allopurinol is generally very well tolerated in the long term. However, rare side effects such as rash (including Stevens–Johnson syndrome), Clostridium perfringens alpha toxin severe hypersensitivity reactions, nephrotoxicity and cytopenias can occur. While the marked reversal in thiopurine metabolite profiles has been noted across all patients, the exact mechanism by which allopurinol acts is still unknown. There is no evidence that allopurinol directly inhibits TPMT activity.[57] Studies to elucidate allopurinol’s action are needed. Multiple genetic polymorphisms in the TPMT gene result in decreased TPMT activity and cause early myelosuppression from thiopurine therapy.[58, 59] The prevalence of TPMT deficiency is approximately one in 300 patients who, if treated with full-dose thiopurines, will suffer life-threatening myelosuppression.[60] The vast majority of patients who develop leucopenia have normal TPMT levels.[61] A systematic review found there to be insufficient evidence to recommend TPMT testing prior to commencement of thiopurines.