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P469. Higher red blood cell methotrexate polyglutamates correlate with increased disease activity, and are useful in assessing adherence

S. Fong1, M.G. Ward1, I. Nasr1, R.M. Goel1, K.V. Patel1, S. Ray1, M. Arenas Hernandez2, S.A. Anderson1, T. Marinaki2, J.D. Sanderson1, P.M. Irving1, 1Guy's and St Thomas' NHS Foundation Trust, Gastroenterology, London, United Kingdom, 2Purine Research Laboratory, GSTS Pathology, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom

Background

Methotrexate (MTX) is commonly used in patients with inflammatory bowel disease (IBD). Within red blood cells (RBC), MTX is activated by sequential addition of glutamic acid residues to form polyglutamates (MTXPG 1–5). In rheumatoid arthritis, low [MTXPG] has been associated with active disease [1], whereas other studies have demonstrated an inverse relationship [2], including the only published data in IBD [3]. The aim of this study was to determine if RBC [MTXPG] reflect clinical response in IBD patients and whether they are useful in assessing adherence.

Methods

This was a single-centre, retrospective pilot study of 21 IBD patients treated with weekly MTX. RBC MTXPG1–5 was measured using high-performance liquid chromatography. Clinical status (active disease or remission) was assessed by 2 IBD physicians blinded to [MTXPG], using a combination of prospectively recorded clinical activity indices (Simple Colitis Activity Index, Harvey–Bradshaw Index), endoscopy, faecal calprotectin and C reactive protein (CRP). Pearson correlation coefficient, r was calculated to assess the relationship between MTX dose and [MTXPG]. Association between [MTXPG] and clinical response was analysed with unpaired t-test.

Results

Patient demographics are shown in Table 1.

Four of 21 patients (22%) (3 of whom admitted non-adherence) had undetectable MTXPGs and were excluded from further analysis. MTXPG2–4 were detected in all adherent patients. PG3 was the predominant polyglutamate accounting for a mean of 43% of total MTXPG. A linear relationship between dose of MTX and PG1–5 was observed. 12/21 (57%) patients were assessed as having active disease. No significant difference in mean [MTXPGn] was observed between those with active disease and remission. For each MTXPGn, a non-significant trend towards a higher concentration was observed in patients with active disease.

Table 1. Demographics
Median age in years (range)35 (22–59)
Male gender, n (%)12 (57%)
Crohn's disease, n (%)16 (76%)
Ulcerative colitis, n (%)3 (14%)
Inflammatory bowel disease unclassified, n (%)2 (10%)
MTX route of administration (oral/subcutaneous)19/2
Concomitant biologic, n (none/infliximab/adalimumab)6/12/3
Mean±SD MTX dose at time of MTXPG test (mg)17.26±1.21
Median disease duration (years)7
Previous immunomodulators, n (azathiopurine/mercaptopurine/thioguanine)14/5/1
Table 2. Correlation of methotrexate dose to RBC MTXPG concentration and clinical outcome
MTX PGnCorrelation between MTX dose and MTXPG, r, (p)Active disease: [ PGn] (nmol/RBC 8×1012), mean±SDRemission: [PGn] (nmol/RBC 8×1012) mean±SDp value
PG10.96 (p = 0.01)22±1615±100.28
PG20.92 (p = 0.008)24±3.617±2.30.17
PG30.98 (p = 0.003)51±9.836±6.70.26
PG40.94 (p = 0.019)19±4.912±1.70.25
PG50.67 (p = 0.219)4.5±1.51.3±0.730.09

Conclusion

In this study, the largest to date in IBD, measuring RBC MTXPG was useful in assessing adherence to MTX. A trend towards higher PG concentrations was associated with active disease confirming the findings in the only other study in IBD. Whether this is confounded by higher doses being used in patients with more active disease warrants further study in larger, prospective trials.

1. Dervieux T et al, (2005), Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study, Annals of the Rheumatic Diseases, 1180–1185, 64.

2. Stamp LK et al, (2010), Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy, Arthritis Rheumatism, 359–368, 62.

3. Alenka JB et al, (2007), Red blood cell methotrexate polyglutamate concentrations in inflammatory bowel disease, Therapeutic Drug Monitoring, 619–625, 29.