Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience

Abstract

Objectives: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting.

Materials and methods: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported.

Results: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2–75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn’s disease (p = .04).

Conclusions: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Keywords:

• 6-Mercaptopurine
• adverse events
• azathioprine
• safety
• thiopurines

Acknowledgements

We thank Francesca Dolce for her support in reporting all adverse events to Italian Medicines Agency (AIFA).

Disclosure statement

Fabio Salvatore Macaluso: lecture grant from MSD.

Sara Renna: served as an advisory board member for AbbVie and MSD, received lecture grants from AbbVie, MSD, Takeda Pharmaceuticals, Zambon.

Mario Cottone: received financial support for the organization of a second level Master degree in inflammatory bowel disease from AbbVie, MSD, Takeda Pharmaceuticals and Sofar.

Ambrogio Orlando: served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, received lecture grants from AbbVie, MSD, Takeda Pharmaceuticals, Sofar, Chiesi.

Marcello Maida, Mariangela Dimarco, Chiara Sapienza, Marco Affronti, Emanuele Orlando, Giulia Rizzuto, Marco Ventimiglia, Rosalba Orlando: nothing to disclose.

Sources of support: Data collection was performed as part of a post-marketing surveillance project on the adverse events of immunosuppressants and biologics in inflammatory bowel disease granted by the Italian Medicines Agency (AIFA).