Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis

Abstract

Objective: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated.

Methods: In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers.

Results: In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC.

Conclusion: RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

Keywords: absolute lymphocyte count; biomarkers; cardiovascular disease; immunity; red cell distribution width.

Figure 1.. Lower survival in RA patients with high RDW or low ALC prior to MTX start.

1A: Survival probability in local Cohort patients with high RDW (>14.5%) vs. without high RDW; 1B: Low ALC (< 1.2 K/cmm) vs. high ALC; 1C patients low RDW/high ALC vs. low RDW/low ALC vs. high RDW/high ALC vs. high RDW/low ALC; 1D National Cohort survival by low RDW/high ALC vs. low RDW/low ALC vs. high RDW/high ALC vs. high RDW/low ALC.

Figure 2:. ALC is associated with Age, TNFR2, HLADR expression on monocytes and NK cells, and HLADR/CD38 expression on CD4_CM and CD8_CM, while RDW is associated with Age, CD4%, CD8% and HLADR/CD38 expression on CD4_EM and CD4_TE with.

Heat map representation of spearman rank sum correlations among immunology and clinical parameters. Asterisk represents p<0.05.

Figure 3.. ALC decreases on MTX therapy in those with high baseline ALC, and ALC increases on upon addition of TNF blocker therapy to those on MTX primarily in those with low baseline ALC.

3A: ALC before and after start of MTX overall and in low and high ALC subgroups. 3B: ALC before and after start of TNF blocker therapy in patients on MTX.