A total of 541 patients were eligible for analysis, with a median age of 40 years (IQR 30–53), 50.1% female, and 70.2% Crohn's disease, with 28.3% having ulcerative colitis, with median IBD disease duration of 10.2 years (IQR 5.8–16.8) (see Table 2). The majority of patients (61.2%) had active disease at baseline. 314 patients (58.0%) were on an IBD medication in addition to their thiopurine at baseline.
Baseline population median 6-TGN and 6MMPR concentrations were within the therapeutic reference range for all indications except for suspected non-adherence (see Table 3). However, only 215 patients (39.7%) had thiopurine metabolite levels consistent with appropriate dosing, with 27.2% felt to be underdosed, and a further 16.3% identified as shunters. Overall, 335 patients (61.9%) had a change in medication management based on their thiopurine TDM.
Repeat thiopurine TDM was available for 259 patients. 6-TGN was significantly higher at repeat TDM than at baseline (306 (235–417) vs. 255 (168–368), respectively, p < 0.001). 6-MMPR was not significantly different (1107 (482–3165) vs. 1151 (456–3554) p = 0.64) (median, inter-quartile range). The proportion of patients with therapeutic 6-TGN level (Target 6-TGN range 235–450 pmol/8 × 108 RBC) at 12 months was significantly higher than those at baseline (55.9% v 39.0%, p < 0.001).
The thiopurine TDM result for those with active disease as the indication for TDM was: 39.7% (98) appropriately dosed, 29.9% (74) under-dosed or non-compliant, 13.8% (34) overdosed, 16.6% (41) were consistent with MMP-6 shunting (see Table 3). Median 6-TGN level was only slightly lower in those with active disease, as defined by physician global assessment, compared to inactive disease (248 (IQR156-348) vs 265 (199–402), respectively, p = 0.012).
Thiopurine TDM and Medication Outcomes
Overall, the majority of patients (88.8%) were able to continue thiopurine based therapy following the baseline metabolite measurement without the need for escalation to biologics agents, trial of a different medical therapy or surgery. Medications at baseline and at 12 months post TDM are shown in Fig. 1. The proportion of patients on allopurinol and thiopurine therapy for management of 6-MMP shunting increased from study entrance to 12 months post TDM (3.1% vs. 13.0% p = 0.001). At 12 months 4.1% (22) of patients required a non-thiopurine containing regime, and 4 patients required surgical treatment.
Thiopurine TDM was performed proactively in 233 patients (43.1%), resulting in a change in medication management in over half of patients (52.3%). In those with TDM performed for proactive indication, thiopurines were continued at twelve months in 93.9%. Escalation to biologic medication occurred in 7.3% (17 patients). Addition of allopurinol due to shunting metabolism occurred in 9.0% (21 patients). For those with proactive TDM indication there were 30.0% with active disease at baseline which reduced to 15.0% at twelve months post TDM (p < 0.001).
Metabolite Measurement for Adverse Drug Reactions
Metabolite measurement was performed for suspected ADR in 47 patients (8.6%). Of these, 24 patients (51%) were judged to have unexplained symptoms/reactions not due to AZA/6MP. Fourteen patients (30%) were judged to have idiosyncratic ADR and 9 patients (19%) to have dose-dependent ADR. Lymphopenia was common, present in 23.1% of the cohort, with hepatoxicity and leukopenia uncommon (see Table 4). 6-TGN was significantly higher in those with leukopenia and trended to significance in those with lymphopenia (p = 0.0003, p = 0.06, respectively). The proportion with elevated 6-MMPR was not significantly different in those with hepatotoxicity (p = 0.10). The majority of patients with lymphopenia, leukopenia or hepatoxicity continued on thiopurine therapy at 12 months post study entrance (see Table 4).
Longitudinal Clinical Outcomes
At baseline, a majority (61.2%) of patients had active disease and 37.1% of patients were in clinical remission. In comparison, 12 months following TDM, 22.9% had active disease, while 73.7% of patients (n = 399) had achieved clinical response, and significantly more patients 68.0% (n = 368) were in clinical remission (p < 0.001). Of the 399 patients who achieved clinical response at 12 months, 291 (72.9%) were able to do so while remaining on azathioprine without the need to escalate to other therapies. Clinical response and clinical remission in patients with ulcerative colitis were 76.2% and 70.7%, and similarly, respectively, in Crohn's disease were 76.8% and 71.1%.