Autor:innen:
J. Essmann (Hannover, DE)
C. Keil (Hannover, DE)
M. Manns (Hannover, DE)
O. Bachmann (Hannover, DE)
Background: Azathioprine (AZA) belongs to the first-line immunosuppressants for the treatment of Crohn’s disease. While recent studies have reported a positive association of its active metabolite 6-thioguanine (6-TGN) with clinical outcomes, 6-TGN levels have not been correlated with surrogate markers of mucosal healing, which is an increasingly recognized therapeutic goal.
Aim: We therefore asked whether 6-TGN levels within a defined therapeutic range are associated with lower fecal calprotectin (FC) in Crohn’s disease.
Methods: 6-TGN and corresponding FC levels of 96 Crohn’s disease patients (Median age 31 years, 64% female) without further immunosuppressive therapy visiting the Hannover IBD outpatient clinic between 2009 and 2016 were retrospectively analysed. Calprotectin and laboratory parameters of 33 patients with TGN levels within the therapeutic range of 250 to 450 pmol/8x10^8 red blood cells (RBCs; Estevinho MM JCC 2017) were then compared to 54 patients below and 9 patients above this range using Kruskal-Wallis test and Bonferroni correction for p values. In a small sub-cohort (n=26) with repeated serial 6-TGN measurements, longitudinal FC measurements were evaluated (Registered as DRKS00013246).
Results: In the cross-sectional approach, 6-TGN levels between 31 and 780 pmol/8x10^8 red blood cells (RBCs; median 6-TGN 227 pmol/8x10^8 RBCs, interquartile range 154,5 to 312,5) and a mean AZA dose of 2.23 mg/kg body weight were observed. In patients with 6-TGN levels within the defined range of 250–450 pmol/8x10^8 RBCs, fecal calprotectin levels were significantly lower than in patients below this level (median FC 142,5 vs. 308,4 mg/kg, Kruskal-Wallis test, adjusted p=0,037, r=0,27) and also than in patients above this level (median FC 142,5 vs. 559,1 mg/kg, Kruskal-Wallis Test, adjusted p=0,003, r=0,48). Haemoglobin (HB) concentrations in patients within therapeutic range were significantly higher than in patients with lower metabolites (median HB 13,1 vs. 12,5, adjusted p=0.041). CRP, transferrin saturation and protein levels were not different among the groups. In the small cohort that was followed over a maximum time of one year, 8/9 patients who received AZA dose escalation or initiation of allopurinol treatment achieved an increase in 6-TGN levels (median 45 pmol/8x10^8 RBCs, range -159 to 200), which was paralleled by a decrease in FC (at least -50mg/kg) in 4/9, stagnation in 3/9 and increase in 2/9 (FC difference ranging from -603 to +123 mg/kg), but patient number was insufficient for statistical testing.
Summary: In our retrospective analysis on Crohn’s disease patients receiving thiopurine monotherapy, 6-TGN levels within a defined range (250–450 pmol/8x10^8 red blood cells) were associated with significantly lower fecal calprotectin levels as a surrogate marker for mucosal healing. A treat-to target concept directed by 6-TGN levels to reach mucosal healing in Crohn’s disease appears promising, but requires prospective studies.