Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease.

BACKGROUND: The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR. AIMS: This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring. METHODS: A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications. RESULTS: The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy. CONCLUSION: Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical remission.

Development of a Simple, Serum Biomarker-based Model Predictive of the Need for Early Biologic Therapy in Crohn's Disease.

BACKGROUND: Early or first-line treatment with biologics, as opposed to conventional immunomodulators, is not always necessary to achieve remission in Crohn's disease [CD] and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy, in order to risk-stratify CD patients and guide initial treatment selection. METHODS: A model-building study using supervised statistical learning methods was conducted using a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between January 1, 2004 and December 31, 2016, were included. A predictive score was derived using Cox regression modelling of immunomodulator failure, and was internally validated using bootstrap resampling. RESULTS: Of 410 patients [median age 37 years, 47% male, median disease duration 4.7 years], 229 [56%] experienced immunomodulator failure [39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation] with a median time to failure of 16 months. Independent predictors of treatment failure included raised C-reactive protein [CRP], low albumin, complex disease behaviour, younger age, and baseline steroids. Highest CRP and lowest albumin measured within the 3 months preceding immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin [CICA] index demonstrated robust optimism-corrected discriminative performance at 12, 24, and 36 months (area under the curve [AUC] 0.84, 0.83, 0.81, respectively). CONCLUSIONS: The derived CICA index based on simple, widely available markers is feasible, internally valid, and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.

Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease.

BACKGROUND: There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). AIM: To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. METHODS: A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. RESULTS: There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). CONCLUSION: Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.