To improve long-term outcomes and response in patients with inflammatory bowel disease, many experts advocate the use of combination therapy (thiopurine with anti-tumor necrosis factor).  Thiopurine cotherapy resulted in higher response rates in pivotal studies (eg. SONIC, UC Success), likely due to lower rates of antidrug antibody (ADA) and higher serum levels of biologic agents (e.g. infliximab).  To achieve these advantages, it is not clear whether a lower dose of a thiopurine may be similarly effective as a higher dose.  If a lower dose could result in a similar effect, it would likely result in fewer adverse effects.

A recent study (Yarur AJ, et al. Clin Gastroenterol Hepatol 2015; 13: 1118-24) provide some data to address the issue of optimal dosing of thiopurines.  The authors performed a cross-sectional study of 72 patients receiving infliximab (IFX) and a thiopurine.

Key findings:

• The thiopurine metabolite 6-thioguanine (6-TG) that “best predicted a higher level of infliximab was 125 pmol/8 x 10 to the 8th RBCs.”
• Only 8 patients (11%) had detectable antibodies to infliximab (ATI)
• Patients with 6-TG <125 were more likely to have ATI (OR 1.3)
• Higher 6-TG levels did not confer additional benefit

This study had many limitations including the small number of patients and the cross sectional design.  In addition, the patients may not be representative of typical patients; more than 50% were in endoscopic remission. A randomized controlled trial with larger number of patients is needed for a more definitive answer.

Take-home message: (from authors); “6-TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizing treatment when using thiopurines in combination with IFX…lower target 6-TGN levels (125-176 pmol/8 x 10 to the 8th RBCs) may be adequate to maximize IFX levels and reduce immunogenicity while potentially minimizing toxicity.”

Briefly noted:

Ananthakrishnan AN et al. Clin Gastroenterol Hepatol 2015; 13: 1197-1200.  In this prospective study with 1659 patients with Crohn’s disease (CD) and 946 patients with ulcerative colitis, the authors found wide variation among the 7 participating academic centers, particularly with regard to CD treatment.  Comparing the site with the lowest usage to the highest usage, for CD:

• Oral mesalamine 13% vs. 46%
• Immunomodulator use 16% vs. 56%
• Anti-TNF use 31% vs 60%
• Combination therapy 8% vs 32%
• Immunomodulator-naive anti-TNF use 10% vs. 17%
• Surgery 32% vs 55%

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