Hydroxychloroquine is associated with lower platelet activity and improved vascular health in systemic lupus erythematosus

Abstract

Objective: Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE.

Methods: Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose.

Results: Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056).

Conclusion: HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

Keywords: cardiovascular diseases; inflammation; lupus erythematosus; systemic.

Figure 1

Associations between HCQ use and dose and platelet function, transcriptomics and vascular function. Comparison of HCQ and non-HCQ groups of subjects with SLE examining (A) platelet count and size (Mean PLT Volume). (B) Aggregation in response to ADP and AA with and without in vitro aspirin (ASA). (C) Spearman correlation of daily HCQ dosing and aggregation in response to 1 µM ADP as measured by the area under the curve (AUC). The respective pairwise comparison of no HCQ versus HCQ is also noted with a Wilcoxon p value. (D) Heatmap depicting the correlation and p value between the sample eigengene values associated with platelet pathways and HCQ use, dose and dose-adjusted for weight. (E) Scatterplot showing the eigengene values for the positive regulation of platelet activation gene set compared against HCQ dose/weight for each patient. (F) Scatterplot showing the normalised transcript level of SELP compared against HCQ dose/weight for each patient. (G) Comparison of P-selectin (PSEL) surface expression fold change in subjects on and off HCQ as measured by flow cytometry and a Spearman correlation of HCQ dose and P-selectin fold change. Mean Fluorescence Intensity (MFI) values are reported. Spearman correlations of daily HCQ dosing and PBR (H), RBC filling (I) and BART (J) were also examined, shown here with 95% CI bands. The respective pairwise comparisons of no HCQ versus HCQ are also noted with a Wilcoxon p value. AA, arachidonic acid; BART, brachial artery reactivity testing; HCQ, hydroxychloroquine; PBR, perfused boundary region; RBC, red blood cell; SELP, P-selectin.