Clinical Outcomes of Children with IBD with Unfavorable Thiopurine Metabolism

Abstract

Purpose: There are well-established data supporting the use of immunomodulatory therapy with the thiopurine agents azathioprine (AZA) or 6-mercaptopurine (6-MP) for the treatment of patients with inflammatory bowel disease (IBD). A poor clinical response to thiopurine can be seen in patients with preferential production of 6-MMP, an inactive thiopurine metabolite, and associated low 6-TGN levels. The use of allopurinol in 6-MP or AZA-treated adults with preferential 6-MMP production increases levels of 6-TGN while reducing 6-MMP. We describe the clinical outcomes of children with IBD who were treated with allopurinol because of preferential metabolism of AZA/6-MP to 6-MMP rather than 6-TGN. Methods: A retrospective chart review was performed. Subjects were poor responders to AZA/6-MP and had elevated 6-MMP metabolite levels. All were started by their clinicians on allopurinol and had their dose of AZA/6-MP reduced to 25–50% of their initial dose. A clinical goal was defined at the beginning of therapy for each subject, and response was defined as successfully achieving the goal by 3 months after initiating allopurinol. In addition, lab values (6-TGN, 6-MMP, WBC and ALT) were compared before and 3 months after starting allopurinol. Disease activity was categorized by physician's global assessment (PGA). Results: 12 children (ages 7–18 yrs, 8 males, 11 Crohns, 1 UC) met inclusion criteria. Indications for treatment included active disease (5) and increased transaminases (7). Lab values pre- and post-allopurinol are summarized in the Table. The addition of allopurinol led to achieving clinical goals in 10/12 subjects. One subject with high ALT did not respond, and 1 discontinued treatment due to leukopenia. A third initially had an improved PGA, but required resection 4 months after starting allopurinol. 4/4 steroid dependent patients discontinued steroids after starting allopurinol.Table: Laboratory Values Pre- and Post-Allopurinol.Conclusion: Allopurinol + reduced dose AZA/6-MP effectively optimizes 6-TGN levels and improves clinical outcomes in children whose metabolism promotes the production of 6-MMP. Hepatotoxicity can be reversed, and steroid dependence eliminated.