P371 Concentrations of 6-thioguanine nucleotide correlate with both infliximab and adalimumab levels in patients with inflammatory bowel disease on combination therapy
O. Kelly*, A. Trajkovski, A. Weizman, G. Nguyen, A. H. Steinhart, M. Silverberg, K. Croitoru
Mount Sinai Hospital, Centre for Inflammatory Bowel Disease. Suite 437, Toronto, Canada
Combining immunomodulators with anti-TNF (tumour necrosis alpha) therapy in inflammatory bowel disease (IBD) is associated with higher anti-TNF drug levels. Optimal thiopurine dosing in this context remains unclear. Data suggest correlation between 6-Thioguanine (6TG) and infliximab (IFX) levels. We examined if this extended to adalimumab (ADA) levels and endoscopic outcome.
A cross-sectional study of IBD patients on combination therapy (IFX/ADA + thiopurine) was performed. Patients with simultaneous anti-TNF level/antibody (ADA/IFX; Prometheus assay) and 6TG were included. Endoscopic remission was defined as Mayo < 1 (ulcerative colitis [UC]) and SESCD < 3 (Crohn’s disease [CD]). Primary outcomes were anti-TNF levels/antibody to anti-TNF analysed as continuous and dichotomised variables with calculated IFX/ADA values predicting mucosal healing. Further, 6TG was examined as continuous and in quartile distribution (1, 0–124; 2, 125–250; 3, 251–400; and 4, > 400 pmol/8x108 RBC).
In total, 64 patients on combination were included (34 ADA and 30 IFX). Gender, age, phenotype, and treatment duration were not different. All were on thiopurines for a minimum 6 months. Mean 6TG (326, p = 0.84) and MMP levels (1572, p = 0.07) were similar. Mean IFX and ADA levels were higher in combination compared with a monotherapy cohort (n = 122; 12.3 vs 10.2 µg/mL IFX, p = 0.04; 11.4 vs 9.8µg/mL ADA, p = 0.04).% with antibodies was lower in the combination group(11% v 16.5%, p = 0.04) Amongst those with measurable antibodies, there was a trend towards lower antibodies(2.6 v 7.9 U/mL IFX, 3.5 vs 6 U/mL ADA) compared with monotherapy (p = 0.26, 0.35, respectively). Higher anti-TNF levels were associated with endoscopic remission and inversely correlated with Mayo (r = -0.69, p = 0.008, area under the curve [AUC] 0.6 [0.46–0.83]) and SESCD (r = -0.4, p = 0.039, AUC 0.64 [0.48–0.83]). In addition, 6TG levels were associated with higher anti-TNF levels. Based on receiver operating characteristic (ROC), using IFX level > 7.6 mcg/mL (sens. 82% and spec. 62%), 6TG >125 was associated with attaining adequate IFX (> 7.6) levels (p = 0.001, r = 0.49, Fishers p = 0.018).Using ADA level >6.6 mcg/ mL, (sens.83%, spec.54%), 6TG >125 correlated with adequate (> 6.6) ADA levels (r = 0.58, p = 0.001, Fishers p = 0.009); 6TG values in quartiles (Q) 2 and 3 (125–400) were associated with therapeutic anti-TNF levels as defined (p = 0.001) and with endoscopic healing (p = 0.001). Antibody presence was associated with endoscopic activity (p = 0.05). 6TG levels in Q2 and 3 had fewer antibodies but not significantly.
Although the accepted range of 6TG for thiopurine monotherapy is 235–400, levels as low as 125 correlate with IFX levels. Here we extend that concept and show a 6TG level of 125 pmol/8 x 108 is associated with therapeutic levels of both IFX and ADA and importantly with endoscopic remission.