The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic

Abstract

Summary Background: Thioguanine nucleotides (TGNs) are the active product of thiopurine metabolism. Levels have been correlated with effective clinical response. Nonetheless, the value of TGN monitoring in clinical practice is debated. We report the influence of introducing TGN monitoring into a large adult inflammatory bowel disease (IBD) clinic. Patients and methods: Patients with IBD undergoing TGN monitoring were identified from Purine Research Laboratory records. Whole blood TGNs and methylated mercaptopurine nucleotides were hydrolysed to the base and measured using HPLC. Clinical and laboratory data were obtained retrospectively. Results: One hundred and eighty‐nine patients with 608 available TGN results were identified. In non‐responders, TGNs directed treatment change in 39/53 patients. When treatment was changed as directed by TGN, 18/20 (90%) improved vs. 7/21 (33%) where the treatment decision was not TGN‐directed, p < 0.001. Where treatment change was directed at optimisation of thiopurine therapy, 14/20 achieved steroid‐free remission at 6 months vs. 3/10 where the TGN was ignored, (p = 0.037). Six per cent of patients were non‐adherent, 25% under‐dosed and 29% over‐dosed by TGN. Twelve per cent of patients predominantly methylated thiopurines, this group had low TGN levels and high risk of hepatotoxicity. In responders, adherence and dosing issues were identified and TGN‐guided dose‐reduction was possible without precipitating relapse. Mean cell volume (MCV), white blood cell count (WBC) and lymphocyte counts were not adequate surrogate markers. MCV/WBC ratio correlated with clinical response, but was less useful than TGN for guiding clinical decisions. Conclusions: Monitoring TGNs enables thiopurine therapy to be optimised and individualised, guiding effective treatment decisions and improving clinical outcomes.

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

“…A meta-analysis highlighted that patients who achieved clinical remission were more likely to have levels of 6-TGN >230-260 pmol/8×10 8 red blood cells compared with patients who had persistently active disease (62% vs. 36%, respectively) ( 65 ). A small randomized trial suggested that antimetabolite dose modifi cation based on metabolite determination was not superior to simple weight-based dosing ( 66 ); however, other more recent evidence suggests that the use of metabolites can benefi t clinicians who are treating IBD patients with antimetabolites ( 67,68 ). Th e current role of TGN measurement remains controversial and is further complicated by inconsistent coverage and availability.…”

Are We Using and Monitoring Thiopurines and Biologics Optimally?

“…High TGN levels are associated with an increased chance of myelotoxicity, although accurate definition of a level above which dose reduction should be considered is less clear. An upper therapeutic limit of 400 pmol/8 × 10 8 RBC has been used in clinical practice and dose reduction with levels >550 pmol/8 × 10 8 RBC has been described without loss of efficacy [37]. The significance of MMP levels was first recognised as a predictor of side effects; levels >5,700 pmol/8 × 10 8 RBC were associated with hepatotoxicity [35].…”

“…Second, a group of underdosed patients who have TGN levels <235 pmol/8 × 10 8 RBC without high MMP levels exists. These patients, who can respond to increased doses of thiopurines [37], represent a significant proportion of all patients treated with thiopurines, accounting for approximately 40% in one large cohort [40]. Third is a group of patients with adequate or supratherapeutic levels of TGN.…”

Thiopurines and myeloid disorders: is more caution needed when treating inflammatory bowel disease patients?

“…Association between myeloid disorders and thiopurines. 1.44-20.36 [13] Asten et al Morton et al risk', with a threshold of 550 pmol/8Â10 8 erythrocytes [23]. In the CESAME cohort, mean duration of thiopurines treatment was 8 years [13], and among pediatric patients on 6MP/methotrexate maintenance therapy for an acute lymphoblastic leukemia, longer duration of treatment was related to an increased risk of MD (p = 0.02) [24].…”