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P374 Safety and drug survival of methotrexate versus tioguanine after failure of conventional thiopurines in patients with Crohn’s disease.

Savelkoul, E.(1);Maas, M.(1);Bourgonje, A.(2);Crouwel, F.(3);Russel, M.(4);Römkens, T.(5);De Boer, N.(3);Dijkstra, G.(2);Hoentjen, F.(1);

(1)Radboud University Medical Centre- Nijmegen- The Netherlands., Department of Gastroenterology and Hepatology, Nijmegen, The Netherlands;(2)University Medical Centre Groningen- Groningen- The Netherlands., Department of Gastroenterology and Hepatology, Groningen, The Netherlands;(3)Amsterdam University Medical Centre- VU University- AGEM Research Institute- Amsterdam- the Netherlands., Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands;(4)Medisch Spectrum Twente- Enschede- The Netherlands., Department of Gastroenterology and Hepatology, Enschede, The Netherlands;(5)Jeroen Bosch Ziekenhuis- 's-Hertogenbosch- The Netherlands., Department of Gastroenterology and Hepatology, 's-Hertogenbosch, The Netherlands

Background

Both methotrexate (MTX) and tioguanine (TG) can be considered as viable treatment options before initiating biological therapy following failure of conventional thiopurines for Crohn’s disease. It is unclear how safety and effectiveness compare for both therapies. This study aimed to compare tolerability and drug survival of MTX and TG therapy after failure of conventional thiopurines in patients with Crohn´s disease.

Methods

We conducted a retrospective, multi-centre study in five Dutch hospitals, including patients initiating MTX or TG for Crohn’s disease after failure (all causes) of conventional thiopurines. Patients with prior MTX or TG use, MTX or TG not primarily prescribed for Crohn’s disease, or patients receiving concomitant biological treatment at baseline were excluded. Follow-up duration from starting treatment was 104 weeks or until treatment discontinuation. Primary outcome was therapy discontinuation rate due to adverse events (AE). Secondary outcome was ongoing treatment without initiation of biological treatment.

Results

In total, 221 patients with failure of conventional thiopurines and subsequent therapy with either MTX (n=106) or TG (n=115) were included. Median follow-up was 89 weeks (IQR 28-104). Previous biological failure was present in 28 (26%) MTX and 17 (15%) TG treated patients (p=0.044). Sixty-four (29%) patients (MTX 41.5%, TG 17.4%, p<0.001) discontinued their treatment due to AE during follow-up (Figure 1). Median time until discontinuation due to AE was 16.5 weeks (IQR 8.0–39.0) for MTX and 17.5 weeks (IQR 1.3–69.8) for TG (p=0.925). MTX use was associated with a significantly higher risk of treatment failure due to AE (OR 3.37 [95% CI 1.82–6.25] p<0.001). Previous biological failure was not predictive for MTX or TG  failure due to AE (OR 1.086, p=0.828). The most frequent discontinuation reasons were nausea for MTX (n=11) and abdominal pain for TG (n=4). In both groups, 8 (MTX 8%, TG 7%) serious adverse events (SAE) occurred. Infections comprised the majority of all SAE, 4 (50%) for MTX and 7 (88%) for TG. Discontinuation because of elevated liver enzymes occurred in 5 (11%) MTX and 4 (20%) TG treated patients. There were no cases of histological nodular regenerative hyperplasia, liver fibrosis, or cirrhosis. Initiation of concomitant biological therapy was not significantly different (MTX: n=26, TG: n=30, p=0.877). Total monotherapy drug survival after 104 weeks was 46% for TG and 25% for MTX (p<0.001).

Conclusion

Forty-two percent of MTX, compared to 17% of TG treated patients, discontinued therapy due to AE in patients with Crohn’s disease with prior failure of conventional thiopurines. These data may aid in the selection of subsequent therapy after failure of conventional thiopurine therapy.

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