J Rheum Dis.  2025 Jan;32(1):30-37. 10.4078/jrd.2024.0073.

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

• Baek IW
• Park KS
• Kim KJ

• KMID: 2562657
• DOI: http://doi.org/10.4078/jrd.2024.0073

Abstract

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 antirheumatic 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.

Keyword

Rheumatoid arthritis; Methotrexate; Erythrocyte; Erythrocyte indices

Figure

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  Figure 1 Anemia in patients with red blood cell macrocytosis. (A) Frequency and proportion of anemic and non-anemic patients by sex. Values are presented as number (%). (B) Hemoglobin levels in anemic and non-anemic patients by sex.

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  Figure 2 Factors associated with red blood cell macrocytosis. (A) Multivariate linear regression analysis for development of RBC macrocytosis. (B) Distribution of patients with RBC macrocytosis and normal MCV by MTX dose. ACPA: anti-citrullinated peptide antibody, CRP: C-reactive protein, DAS28: Disease Activity Score 28-joints, ESR: erythrocyte sedimentation rate, LFNM: leflunomide, MTX: methotrexate, OR: odds ratio, RBC: red blood cell, RF: rheumatoid factor, SSZ: sulfasalazine, MCV: mean corpuscular volume.

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  Figure 3 Cumulative incidence of the initiation of biologic or targeted synthetic DMARDs by the presence of RBC macrocytosis. (A) Kaplan–Meyer plot for probability of b/tsDMARDs initiation by RBC macrocytosis. (B) Forest plot of HRs of b/tsDMARD initiation. ACPA: anti-citrullinated peptide antibody, CRP: C-reactive protein, DAS28: Disease Activity Score 28-joints, ESR: erythrocyte sedimentation rate, HR: hazard ratio, CI: confidence interval, LFNM: leflunomide, MTX: methotrexate, RBC: red blood cell, RF: rheumatoid factor, SSZ: sulfasalazine, b/tsDMARDs: biological or targeted synthetic disease-modifying anti-rheumatic drugs, MCV: mean corpuscular volume.

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