An open‐label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6‐mercaptopurine therapy

Background and Aims A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6‐mercaptopurine (6‐MP) and azathioprine (AZA). Inability to achieve therapeutic 6‐thioguanine nucleotide (6‐TGN) levels due to the preferential overproduction of 6‐methylmercaptopurine ribonucleotides (6‐MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6‐MP/AZA therapy. Treatment with 6‐thioguanine (6‐TG), a related thiopurine, which forms 6‐TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6‐TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6‐MP/AZA therapy. Methods Ten CD patients with preferential 6‐MMPR production upon 6‐MP/AZA dose escalation were enrolled in an open‐label pilot study. Seven of 10 patients had experienced dose‐related 6‐MP toxicities. Results Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6‐TGN levels were nine‐fold higher with 6‐TG treatment than with 6‐MP, whereas 6‐MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. Conclusions 6‐TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6‐MP therapy. Larger controlled trials are warranted to further evaluate both the short‐and long‐term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.