Methotrexate Polyglutamate Monitoring in Patients With Crohn's Disease

Abstract

Methotrexate is an efficacious immunosuppressant for induction and maintenance of remission in Crohn's disease. The goal of this pilot study was to determine whether total or individual methotrexate glutamate levels (MTXGlu ) in red blood cells correlate with disease activity and adverse events in Crohn's disease. A cross-sectional study was undertaken with 12 patients on a stable dose of 25 mg weekly methotrexate (oral or subcutaneous). Clinical disease activity was assessed by the Harvey-Bradshaw Index (HBI), and biologic disease activity was measured by inflammatory markers. Concentrations of individual MTXGlu levels were measured in red blood cells (RBCs) using high-performance liquid chromatography-mass spectrometry. No association was observed between RBC individual (MTXGlu ) or total methotrexate glutamate concentrations and clinical disease activity (HBI score) or inflammatory markers or adverse events. Although Crohn's disease patients in remission appeared to generally have higher RBC total longer-chain methotrexate polyglutamate (MTXGlu ) concentrations compared with those with active disease, a definitive association between RBC MTXGlu levels and clinical disease activity could not be established. Larger longitudinal studies in patients with diverse disease activity are needed to establish the value of MTXGlu levels as indicators of treatment efficacy and clinical outcome.

Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn’s disease: a cross-sectional study

“…Both patients with CD and ulcerative colitis were enrolled, except in the study by Fischer et al . [ 18 ] The mean MTX-PG total concentration (140 ± SD 77 nmol/L) and inter-patient variability (CVs 27.2 to 103.5%) in our study was comparable with the data from most other studies, except for the study by Fischer et al . (Fig.…”

“…In our population, MTX-PG n and MTX-PG total concentration were not associated with either disease activity at baseline ( p > 0.05) or disease activity at one year (data not shown). All previous studies measuring MTX-PG concentrations in patients with IBD did draw conclusions on the association of MTX-PG with disease activity, despite their cross-sectional study design [ 17 , 18 , 20 ]. Of note, the majority of studies included both CD and ulcerative colitis (UC) patients, and patients on concomitant TNF-α inhibitors, which impedes meaningful analysis of drug efficacy [ 17 , 19 – 21 ].…”

A meta‐analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis

“…More recent studies ( n = 5) used ultra‐performance LC–tandem mass spectrometry (MS/MS), of which 2 studies used a stable‐isotope‐labelled internal standard 12,13 . Three studies reported drug levels in nmol/8 × 10 12 RBCs 44–46 …”

Potential Role of Methotrexate Polyglutamates in Therapeutic Drug Monitoring for Pediatric Inflammatory Bowel Disease

“…Previous studies of MTX-Glu n in IBD are sparse and limited to adult observational studies smaller than ours, which may explain why prior studies also failed to demonstrate a statistically significant association between MTX-Glu n and IBD treatment response. [ 17 , 18 ]. In a cross-sectional study of 12 adults, Fischer et al observed higher long-chain MTX-Glu 3–5 in patients with Crohn’s disease in remission vs. active disease, but the trend did not reach statistical significance.…”

“…In a cross-sectional study of 12 adults, Fischer et al observed higher long-chain MTX-Glu 3–5 in patients with Crohn’s disease in remission vs. active disease, but the trend did not reach statistical significance. [ 17 ] Brooks et al found long-chain MTX-Glu 4–5 to correlate inversely with MTX efficacy in 18 adults with Crohn’s disease, with higher levels noted in patients experiencing gastrointestinal adverse effects [ 18 ]. However, findings of an inverse relationship between MTX-Glu n and MTX efficacy are not substantiated in most rheumatology literature [ 5 , 6 , 7 ], except for one study that found a positive correlation for MTX-Glu n with MTX dose, but a negative correlation with treatment outcomes in RA [ 19 ].…”