Infliximab (IFX) and thiopurine combination therapy is more effective than monotherapy with either agent in patients with inflammatory bowel disease (IBD). The underlying mechanism may originate from concomitant thiopurine treatment leading to higher IFX levels along with decreased immunogenicity. Influence of the main pharmacologically active thiopurine metabolite, 6-thioguanine nucleotide (6-TGN), on IFX concentrations as well as anti-IFX antibody (Ab) detection has been observed.1 However, IFX has also been reported to influence 6-TGN levels.2 This study investigated potential interplays between principal thiopurine metabolites and IFX and anti-IFX Abs, along with clinical implications.Methods:
Two independent cohorts comprising IBD patients in IFX maintenance therapy, with stable thiopurine dosing ≥2 months prior to sampling and without low TPMT activity were included. Cohort A assessed influence of thiopurine metabolites on IFX and anti-IFX Abs. Cohort B assessed if IFX influences thiopurine metabolites.Cohort A:
All 89 patients assessed for anti-IFX Abs at our center since 2009 (n = 40 in IFX-thiopurine-combination therapy; n = 49 in IFX monotherapy). Thiopurine metabolites in form of 6-TGN and methylated thiopurine metabolites (6-MeMP), which inhibit purine de novo synthesis, were determined in red blood cells (RBC) in stored samples at time points corresponding to those where IFX and anti-IFX Abs had been measured.Cohort B:
Eight patients in IFX-thiopurine-combination therapy and with IFX treatment failure who all attained clinical response to 12 weeks of IFX treatment intensification (5 mg/kg every 4 wk) at a stable thiopurine dosing. Six-TGN and 6-MeMP were determined in RBC in stored samples corresponding weeks 0, 4, 8, and 12.Results:
Cohort A: Anti-IFX Ab detection was lower in patients receiving IFX-thiopurine-combination therapy (8/40 [20%]) as compared to those in IFX monotherapy (22/49 [45%]): OR 0.31 (0.12–0.80), P = 0.01. Patients in IFX-thiopurine-combination therapy with detectable anti-IFX Abs had lower 6-TGN than anti-IFX Ab negative patients (6-TGN median 50 pmol/8 × 108 RBC versus 105, P < 0.01). Hence, all anti-IFX Ab positive patients had 6-TGN <117 pmol/8 × 108 RBC (sensitivity 100% [63–100], specificity 47% [29–65], AUCROC = 0.82, P < 0.01). Trough IFX was similar between anti-IFX Ab negative patients in IFX monotherapy and IFX-thiopurine-combination therapy (IFX median 5.1 μg/mL versus 4.9, P = 0.76). Six-TGN and IFX did not correlate (rP = 0.04, P = 0.83; rS = 0.02, P = 0.89). Levels of IFX and 6-TGN were similar between patients with or without clinical-, biochemical-, or endoscopical remission. All 6-MeMP associations were negative. Cohort B: Trough IFX increased significantly during the 12 week period of IFX intensification (ΔIFX median 6.5 μg/mL, P = 0.02), but thiopurine metabolite levels were stable (6-TGN medians at weeks 0/4/8/12: 90 pmol/8 × 108 RBC, 93, 101, and 90; 6-MeMP medians 403, 559, 294, and 860; all P > 0.05).Conclusions:
Superior effect of IFX-thiopurine-combination therapy over IFX monotherapy partly relates to decreased anti-IFX Abs which is under influence by 6-TGN. Additional benefit likely stem from synergy between different anti-inflammatory modes of action rather than direct interactions between thiopurine metabolites and IFX or vice versa.