Background Recent research has shown that response to glucocorticoids (GC) predicts the effectiveness of DMARD induction therapy including methotrexate (MTX). Moreover, GC use has been associated with higher intracellular concentrations of methotrexate-polyglutamates (MTX-PG), and higher MTX-PG concentrations were associated with lower disease activity in rheumatoid arthritis (RA). If GC use is associated with higher MTX-PG concentrations, the association between MTX-PG concentrations and non-response may be modified by GC use.
Objectives The objectives were to investigate whether MTX concentrations are associated with response and whether this association is modified by CG use.
Methods This study included combined data of RA patients treated with MTX from 2 longitudinal cohorts: 285 from the tREACH study and 102 from the MTX-R study. We measured MTX with a tail of 1,2,3,4 and 5 glutamates in erythrocytes after 3 months of therapy using an LC-MS/MS assay. GC use was defined as use of oral or intramuscular GC therapy at start of treatment. As outcome measure for MTX response we defined disease activity score (DAS) 28 at 3 months. GC use, MTX-PG concentrations and their interaction terms (CGuse*MTX-PG concentrations) were tested for associations with DAS28 with an ANCOVA analysis. The analysis was corrected for gender, age, MTX-dose, baseline DAS28, and other DMARD use.
Results Mean DAS28 decreased from 4.76 (SD=1.26) to 3.07 (SD=1.20) after 3 months. 49% of patients used glucocorticosteroids at baseline and the median total MTX-PG was 54 nmol/l (IR=42-70). MTX-PG1 (p=0.012), MTX-PG2 (p=0.001), MTX-PG3 (p=0.006) and total MTX-PG were negatively associated with DAS28. GC use was not associated with DAS28 (p=0.450). Patients with GC use had higher concentrations of MTX-PG3 (p=0.005), MTX-PG4 (p<0.001) and MTX-PG5 (P<0.001) than patients without GC treatment. The interactions between GC use and total MTX-PG was significantly associated with DAS28 (p=0.049). When data were stratified by CG use lower MTX-PG1 (p=0.004), MTX-PG2 (p=0.005) and total MTX-PG (p=0.008) were associated with non-response only in patients who did not use corticosteroids at baseline. In persons who used CGs no association was shown.
Conclusions This study shows that MTX-PG concentrations were related to a lower DAS28. Furthermore we showed that GC use increases the accumulation speed of MTX-PG concentrations and thereby possibly potentiating the efficacy of MTX, resulting in a lower DAS28. The association between MTX-PGs and DAS28 depends on CG use.
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Acknowledgements tREACH: Unrestricted grant from Pfizer bv. (0881-102217). RDJ: Dutch Arthritis Association (06-02-402 and 09-1-402).
Disclosure of Interest None Declared