Background: Thiopurine immunosuppressants such as 6-mercaptopurine (6-MP) are widely used to maintain remission in children with both Crohn's disease and ulcerative colitis. Therapeutic efficacy is associated with higher red blood cell levels of the thiopurine metabolite 6-thioguanine (6-TGN). Studies in both children and adults have inexplicably failed to demonstrate a significant correlation between prescribed dose and level of 6-TGN. We aimed to quantify the relationship between 6-TGN levels and adherence.
Methods: We used electronic monitoring devices to assess adherence in children and adolescents with inflammatory bowel diseases who were prescribed 6-MP.
Results: During 3230 days of monitoring in 19 subjects, adherence to 6-MP was 74.2%. Due to the generally low adherence to the prescribed dose of 6-MP, the 6-TGN level was not correlated with the prescribed dose. The 6-TGN level was significantly correlated with the adherence-adjusted dose (R2 = 0.395). It was also significantly correlated to adherence alone (R2 = 0.478). Adherence to 5-aminosalicylic acid and 6-MP were significantly positively correlated (rs (9) = 0.82, P = 0.00), and a significant relationship was found between 5-aminosalicylic acid adherence and 6-TGN levels independent of 6-MP adherence. Furthermore, low adherence to 6-MP was associated with increased likelihood of escalation of medical therapy.
Conclusions: Red blood cell 6-TGN levels are strongly correlated with the dose, when the dose is actually taken. Lack of efficacy of thiopurines may often be the result of poor adherence. Novel ways of assessing and improving adherence are necessary. Future trials should assess adherence in study participants. Intake of 5-aminosalicylic acid positively influences 6-TGN levels.
Article first published online 7 October 2013
*Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Department of Pediatrics, Hasbro Children's Hospital/The Rhode Island Hospital, Providence, Rhode Island;
†Warren Alpert Medical School of Brown University, Providence, Rhode Island;
‡Division of Child and Adolescent Psychiatry, Department of Psychiatry, Hasbro Children's Hospital/The Rhode Island Hospital, Providence, Rhode Island;
§Bradley Hasbro Children's Research Center, Providence, Rhode Island; and
‖E. P. Bradley Hospital, East Providence, Rhode Island.
Reprints: Neal S. LeLeiko MD, PhD, Department of Pediatrics, MPH Room 134, 593 Eddy Street, Providence, RI 02903 (e-mail: firstname.lastname@example.org).
This study was supported by NIH R21 HD058828 (NL, DL).
Presented in part at a platform session of Digestive Diseases Week (American Gastroenterological Association), May 2011, Chicago, IL.
The authors have no conflicts of interest to disclose.
N. S. LeLeiko and D. Lobato contributed equally to this work.
Received July 31, 2013
Accepted August 26, 2013