To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA_1c) levels in rheumatoid arthritis (RA) patients.

The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease‐modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA_1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu_1–5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA_1c were compared by paired t‐test. Associations of MTXGlu concentrations with changes in the level of HbA_1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort.

In the derivation cohort, the mean change in HbA_1c level after 3 months of treatment was −1.9 mmoles/mole (−0.18%) (P = 0.001). Levels of HbA_1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, −5.5 mmoles/mole (−0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, –3.7 mmoles/mole (−0.34%) (P < 0.001), for the MTX treatment arm, −0.8 mmoles/mole (−0.08%) (P = 0.018), and for the HCQ treatment arm, −2.0 mmoles/mole (−0.19%) (P = 0.175). Increased levels of MTXGlu₂ (β = −0.20, P = 0.005), MTXGlu₃ (β = −0.31, P < 0.001), MTXGlu₄ (β = −0.33, P < 0.001) after treatment, MTXGlu₅ (β = −0.39, P < 0.001), and total MTXGlu (β = −0.29, P < 0.001) were associated with decreased levels of HBA_1c. In the validation cohort, levels of HbA_1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu₃ was associated with decreased levels of HbA_1c (β = −0.26, P = 0.018).

MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA_1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA_1c levels, and glucocorticoid treatment resulted in increased levels of HbA_1c.