Baseline Thiopurine Methyltransferase (TPMT) Activity Combined with 6-Thioguanine (6-TGN) Metabolite Levels Predicts Clinical Response to Thiopurines in Patients with Inflammatory Bowel Disease

Abstract

Purpose: To determine if TPMT enzyme activity and post-therapy 6-TGN levels would predict response to therapy with thiopurines in patients with inflammatory bowel disease (IBD). Methods: Baseline TPMT enzyme activity prior to initiation of therapy with either 6-MP or AZA was determined in 40 patients with IBD (24 CD, 16 UC). Clinical response to at least 3 months of thiopurine treatment was defined by the treating physician's global assessment in conjunction with an objective decrease in activity indices (Harvey Bradshaw Index in CD and Simple Clinical Index in UC) and a reduction in the dosage of corticosteroids. Records were reviewed for clinical response and maximal 6-TGN levels (available in 35 individuals). Results: Eighteen of 40 patients (45%) responded to 6-MP or AZA therapy. The patient cohort was dichotomized based on 6-TGN levels and TPMT enzyme activity: maximal 6-TGN levels above or below 230 pmol/8 × 108 erythrocytes (6-TGN Hi) or (6-TGN Lo), and TPMT enzyme activity above or below the mean of 30.3 U (TPMT Hi) or (TPMT Lo). In the 6-TGN Hi group, 10/16 (62.5%) responded versus 7/19 (37%) in the 6-TGN Lo group (p= 0.18). In the TPMT Lo group 12/19 (63%) responded versus 6/21 (29%) in the TPMT Hi group (p= 0.06). When combining TPMT enzyme activity and 6-TGN level, 7/7 (100%) responded with the combination of TPMT Lo/6-TGN Hi, 5/11 (45%) with TPMT Lo/6-TGN Lo, 3/9 (33%) with TPMT Hi/6-TGN Hi, and 2/8 (25%) with TPMT Hi/6-TGN Lo (p= 0.01). Conclusions: A 6-TGN level above 230 pmol/8 × 108 erythrocytes was associated with a numerically higher response rate. There was a trend toward TPMT enzyme activity below 30.3 U being associated with clinical response. However, the combination of a baseline TPMT enzyme activity below 30.3 U and 6-TGN levels >230 pmol/8 × 108 erythrocytes was highly associated with clinical response. The combined determination of TPMT enzyme activity at baseline and 6-TGN levels better predicts clinical response to thiopurines in patients with IBD than either alone.