5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine.
BACKGROUND
Small uncontrolled trials have suggested that 5-aminosalicylate (5-ASA) medications increase 6-thioguanine nucleotide (6-TGn) levels in adults with Crohn's disease (CD) on azathioprine (AZA) or 6-mercaptopurine (6-MP), presumably through the inhibition of thiopurine methyltransferase (TPMT). We tested the theory that coadministration of 5-ASA agents with AZA/6-MP results in higher 6-TGn levels in a large cohort of children and adults with CD or ulcerative colitis (UC).


METHODS
A retrospective cohort study identified all children and adults treated for IBD with AZA/6-MP at 2 tertiary medical centers. Patients were included if their TPMT genotype was known and 6-TGn and 6-methymercaptopurine (6-MMP) levels had been obtained after 3 months of clinical remission at a stable dose of AZA/6-MP. 6-TGn and 6-MMP levels were compared between patients taking and those not taking 5-ASA medications through the use of linear regression models to identify and adjust for potentially confounding variables.


RESULTS
Of the 126 patients included, 88 were taking 5-ASA medications. Patients on 5-ASA agents had higher mean 6-TGn levels after adjustment for confounding variables (Delta6-TGn, 47.6 +/- 21.8 pmol/8 x 10 red blood cells; P = 0.03). CD and TPMT heterozygosity was independently associated with higher 6-TGn levels (P = 0.01 and P = 0.03, respectively). 5-ASA exposure was not associated with a change in 6-MMP levels.


CONCLUSIONS
We found that 5-ASA therapy is associated with higher 6-TGn levels in children and adults with IBD on 6-MP/AZA. TPMT inhibition may not explain this effect because 5-ASA exposure did not affect 6-MMP levels. The observed association of CD with higher 6-TGn levels is novel and needs to be verified in prospective studies.
Hande
Scott
S
Brigham and Women's Hospital, Boston, Massachusetts, USA. shande@partners.org
Wilson-Rich
Noah
N
Bousvaros
Athos
A
Zholudev
Anna
A
Maurer
Rie
R
Banks
Peter
P
Makrauer
Frederick
F
Reddy
Sarathchandra
S
Burakoff
Robert
R
Friedman
Sonia
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001379:Azathioprine / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D019804:Mesalamine / Q000627:therapeutic use*; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013866:Thioguanine / Q000097:blood*; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D007166:Immunosuppressive Agents; D019804:Mesalamine; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine