An erythrocyte macrocytosis by methotrexate is associated with early initiation of biologic or targeted synthetic agents in patients with rheumatoid arthritis

Objective: An association between increased erythrocyte mean corpuscular volume (MCV) and treatment response in patients with inflammatory arthritis receiving methotrexate (MTX) has been reported. We investigated the frequency of red blood cell (RBC) macrocytosis and its clinical implications regarding the initiation of biological or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in patients starting MTX for rheumatoid arthritis (RA).

Methods: RBC macrocytosis (MCV >100 fL) and clinical characteristics were retrospectively examined in 1,156 patients starting MTX for RA. Multivariable logistic regression analyses were performed to identify the independent predictors of RBC macrocytosis. The initiation of b/tsDMARDs was assessed using a multivariable Cox proportional hazards regression model.

Results: RBC macrocytosis was observed in 21.6% of RA patients over 35 [8, 89] months following MTX initiation and was persistent in 63.6% of the patients during MTX treatment. Anemia coexisted in only 20.0% of the patients with RBC macrocytosis. The occurrence of RBC macrocytosis was independently associated with age, MTX dose, and concomitant use of sulfasalazine or leflunomide (all p<0.001). A higher dose of MTX and double- or triple-DMARDs therapy were more frequently used in the group with RBC macrocytosis than in the group with normal MCV. Patients experiencing RBC macrocytosis were more likely to use b/tsDMARDs (hazard ratio 1.45 [95% confidence interval 1.13, 1.87], p=0.003).

Conclusion: RBC macrocytosis was possibly associated with the use of b/tsDMARD and could be a supplementary marker for assessing MTX resistance.