Background/Purpose: Peripheral blood red cell distribution width (RDW) and absolute lymphocyte count (ALC) are associated with aging, cardiovascular disease (CVD), and mortality in the general population, and in rheumatoid arthritis (RA) with disease activity. Little is known whether RDW or ALC are associated with specific parameters of inflammation or mortality in the setting of RA. We evaluated relationships between RDW, ALC, CVD, mortality, and plasma markers of systemic inflammation in persons with RA.

Methods: In a retrospective cohort of RA patients treated with methotrexate (MTX) since 2006 at a single VA Rheumatology Clinic with complete blood count lab results available prior to or during treatment (n = 499), we evaluated RDW and ALC prior to and over the course of MTX therapy, with and without the addition of TNF blocker. We further examined the associations between pre-treatment lab values and subsequent mortality. In a subset of these patients (n=64), and in non-RA general medicine clinic controls (n=37) we evaluated relationships between plasma levels of soluble tumor necrosis factor receptor II (sTNF RII), C-reactive protein (CRP), interleukin-6 (IL-6), soluble cluster of differentiation 14 (sCD14), sCD163, Pentraxin 3 (PTX3), Mac-2 binding protein (Mac2BP), and Monocyte Chemoattractant Protein-1 (MCP-1) by ELISA, and RDW and ALC.

Results: High RDW and Low ALC prior to treatment were both associated with increased mortality (log-rank test p< 0.001 for RDW > 14; p=0.018 for ALC < 1.2). Patients with both low ALC and high RDW had higher mortality than patients with neither or either alone (p< 0.001). After adjusting for age and co-morbidities, high RDW remained significantly associated with mortality (Cox regression model p< 0.001). In the sub-cohort sCD14, sCD163, TNFRII, IL-6, and MCP-1 plasma levels were higher in participants with RA than controls, and RDW levels correlated with PTX3 and MCP-1 levels, while ALC levels negatively correlated with RDW, sCD14, TNF RII, and sCD163 levels. Given these associations between levels of inflammatory markers, ALC and RDW, we evaluated the effect of in vivo MTX and TNF blocker therapy on RDW and ALC levels using longitudinal modelling adjusting for correlated results within patient. We observed MTX to result in increased RDW and lower ALC levels (pre-treatment vs. MTX, p< 0.01 for each), and this was partially reversed by the addition of TNF blocker therapy (MTX vs. MTX + TNFa, p< 0.01 for each).

Conclusion: These findings are consistent with a model wherein inflammatory pathways associated with RA alter erythropoiesis (reflected by RDW) and drive lymphopenia (before and/or after starting DMARD therapy) in association with specific biomarkers of monocyte/macrophage activity. Partial reversal with TNF blockade implies mechanistic/causal linkages. Together, these data suggest immunohematologic dysfunction in the context of RA identifies a poor prognosis, but may be reversible with TNF inhibition.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/red-cell-distribution-width-and-absolute-lymphocyte-count-associate-with-biomarkers-of-inflammation-and-subsequent-mortality-in-rheumatoid-arthritis/