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Background and Aims Scepticism about the efficacy of thiopurines for ulcerative colitis (UC) is rising.This study aimed to evaluate mercaptopurine treatment for UC. Methods In this prospective, randomised, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates (5-ASA), were randomised for therapeutic drug monitoring (TDM)-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first eight weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week six onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement (total Mayo score ≤2 points and no item >1) at week 52 in an intention-to-treat analysis. Results Between December 2016 and April 2021, 70 patients were screened and 59 were randomised at six centres. In the mercaptopurine group, 16/29 (55.2%) patients completed the 52-week study, compared to 13/30 (43.3%) on placebo. The primary endpoint was achieved by 14/29 (48.3%) patients on mercaptopurine and 3/30 (10%) receiving placebo (Δ=38.3%, 95% CI 17.1-59.4, p=0.002). Adverse events occurred more frequently with mercaptopurine (808.8 per 100 patient years) compared to placebo (501.4 per 100 patient years). Five serious adverse events occurred; four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 (75.9%) patients, leading to lower mercaptopurine doses at week 52 compared to baseline. Conclusions Optimised mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at one year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.

SUMMARY Background and aims Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease (IBD) patients. Prospective, effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD. Methods IBD patients, who previously failed azathioprine or mercaptopurine, and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (HBI ≤ 4 or SCCAI ≤ 2). Primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment (PGA) and quality of life (QoL). Results Sustained corticosteroid-free clinical remission at month 3, 6 or 12 months was observed in 75 (69%), 66 (61%) and 49 (45%) of 108 patients, respectively. Thioguanine was continued in 86 patients (80%) for at least 12 months. Loss of response (55%) included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6% and portal hypertension in 1% of patients. Conclusion Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Background Prediction and monitoring of drug response of methotrexate (MTX) in patients with Crohn’s disease (CD) is an unmet need. MTX-polyglutamates (MTX-PGs) in red blood cells (RBC) are potential markers for response in other immune-mediated inflammatory diseases. Our objectives were investigating the relation between MTX-PGs and efficacy and defining predictors of response in CD patients treated with MTX. Methods In a multicenter prospective cohort study, CD patients starting subcutaneous (s.c.) MTX without biologics were included and followed for 12 months or until MTX s.c. was discontinued or a concomitant step-up therapy was started. At baseline clinical and biochemical predictors were recorded. At 2, 3, 6 and 12 months after start of therapy or when dropping out, blood samples were collected and individual MTX-PGs (MTX-PG1 - MTX-PG5) were analyzed in RBC using a validated UHPLC-MS/MS method. The outcome was either MTX s.c. discontinuation or initiation concomitant step-up therapy, due to disease activity or toxicity. Predictors were analysed in an univariate Cox regression model and MTX-PGs in an extended Cox model, corrected for prednisone (at start) and budesonide. Results Eighty CD patients were included (age mean±SD 55±13y, 35% male). The median Harvey Bradshaw Index (HBI) was 4 (IQR 2-7). After 12 months 21 patients were still on MTX s.c. monotherapy, 21 patients stopped because of disease activity, 29 because of toxicity, 4 because of a combination of both and 5 patients were censored (4 ended study participation, 1 MTX was stopped on patient’s own initiative) [Figure 1]. A higher HBI at baseline was associated with an increased rate of MTX s.c. monotherapy discontinuation (HR 1.08, 95% CI 1.02-1.16). Predictors of discontinuation because of disease activity (cause specific hazards) were male sex (3.83, 1.62-9.05), baseline eGFR (1.06, 1.02-1.09), baseline HBI (1.12, 1.02-1.23) and baseline plasma folate (0.94, 0.88-0.99). Sex and plasma folate were not correlated with HBI. No cause specific hazards for stopping MTX because of toxicity were identified. MTX-PG3 was the most abundant MTX-PG subspecie with a median concentration of 51 nmol/L RBC (IQR 37-62) at month 3 and was associated with better MTX survival (HR 0.98, 95% CI 0.971-0.999). For every ten points increase in the MTX-PG3 concentration, the rate of MTX s.c. monotherapy discontinuation decreases with 14%. Conclusion Higher eGFR, higher HBI, lower plasma folate at baseline and male sex are predictors for MTX failure in the first year in CD patients. The last two parameters are likely predictors of MTX response specifically rather than prognostic disease factors. The measurement of MTX-PG3 in packed RBC holds potential as a tool for therapeutic drug monitoring in CD.