On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients

Abstract

The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

“…This hypothesis, though contradicted by Dubinsky's data [49], merits further exploration and because biochemistry and ultrasound outcomes probably underestimate the real incidence of 6-TG induced NRH as the golden standard is based on histology we already started a liver biopsy study in our 6-TG-treated cohort. In our study 73% clinically benefited from 6-TG evaluated by a global physician score and the mean albumin level increased significantly [48]. However, we must be reserved in drawing firm conclusions as our retrospective study was not designed to study efficacy and no standard efficacy parameters as the Crohn's disease activity index (CDAI) or Truelove-Witts disease activity index (TWDAI) were used.…”

“…NRH is a serious complication also associated with AZA and 6-MP and a frequent cause of portal hypertension [51,52]. Therefore we im-139 mediately performed an abdominal ultrasonography in the 54% of patients already using 6-TG for 1 year and discovered only one patient with signs of portal hypertension indicated by an enlarged spleen [48]. Furthermore, mean steady state 6-TGN concentrations measured in Dubinsky's population (~1250 picomoles/8x10 8 RBC) were significantly higher than in our population (~570 picomoles/8x10 8 RBC) and 6-TG induced NRH may in fact be dependent of the reached 6-TGN concentrations.…”

“…Twenty patients discontinued 6-TG due to the occurrence of 26 adverse events of which gastrointestinal complaints (31%), hepatoxicity (15%) and general malaise (15%) were the most frequently occurring [48]. The mean 6-TGN concentrations measured in the 6-TG-intolerant cohort was 725 picomoles/8x10 8 RBC compared to 540 picomoles/8x10 8 RBC in the tolerant cohort, but this difference was not statistically significant [48]. While performing our study disturbing high frequencies of nodular regenerative hyperplasia (NRH) of the liver were reported in an IBD population treated with 6-TG by Dubinsky and collaegues: NRH occurred in 76% of patients undergoing biopsy after laboratory abnormalities [49,50].…”

“…Encouraged by these promising short-term data we then studied the tolerability and safety profile of a low-dose (0.3-0.4 mg/kg/day) maintenance therapy with 6-TG in 95 AZA or 6-MP intolerant IBD patients over a treatment period of at least 1 year and found out that 79% was able to tolerate long-term treatment [48]. Twenty patients discontinued 6-TG due to the occurrence of 26 adverse events of which gastrointestinal complaints (31%), hepatoxicity (15%) and general malaise (15%) were the most frequently occurring [48]. The mean 6-TGN concentrations measured in the 6-TG-intolerant cohort was 725 picomoles/8x10 8 RBC compared to 540 picomoles/8x10 8 RBC in the tolerant cohort, but this difference was not statistically significant [48].…”

“…In addition to this explanation, 6-methylmercaptopurine ribonucleotides (6-MMPR), which arise from 6-MP but not from 6-TG, are believed to contribute to the immunosuppressive and myelotoxic effects [47]. Encouraged by these promising short-term data we then studied the tolerability and safety profile of a low-dose (0.3-0.4 mg/kg/day) maintenance therapy with 6-TG in 95 AZA or 6-MP intolerant IBD patients over a treatment period of at least 1 year and found out that 79% was able to tolerate long-term treatment [48]. Twenty patients discontinued 6-TG due to the occurrence of 26 adverse events of which gastrointestinal complaints (31%), hepatoxicity (15%) and general malaise (15%) were the most frequently occurring [48].…”