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Resistin is an adipokine that may contribute to the link between inflammation and cardiovascular disease.1 In rheumatoid arthritis (RA), resistin forms part of the inflammatory cascade and indeed colocalises with inflammatory cells in synovial tissue and upregulates cytokine production.2–6 Herein, we examined the associations of metabolic risk factors, systemic inflammation and disease characteristics with resistin concentrations as well as the independent relationship of resistin concentrations with endothelial activation in 217 African patients (112 black and 105 white patients) with established RA7 that form part of an ongoing study on cardiovascular risk.8
All patients were employing disease modifying agents for rheumatic disease that included tumour necrosis factor-α inhibition and rituximab in 3.7% and 0.5% of them. The study was approved by the Witwatersrand University Ethics Committee (Human Subjects) and each participant gave informed written consent. Concentrations of interleukin-6, a major circulating cytokine in RA, were quantified using a solid-phase sandwich ELISA (QuantikineHS, R & D Systems, Inc, Minneapolis, Minnesota, USA). The inter- and intra-assay coefficients of variation were 7.8% and 7.4%, respectively.
We measured circulating concentrations of molecules that mediate the early stages of atherosclerosis9 and comprise E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), an essential molecule in atherosclerosis,10 and resistin concentrations employing a solid-phase sandwich ELISA (QuantikineHS). The inter-and intra-assay coefficients of variation were 7.0% and 3.1%, 5.5% and 4.6%, 7.9% and 5.8%, 5.7% and 5.8% and 8.4% and 4.7%, respectively. An endothelial activation score was used to provide a summary measure of endothelial activation and was calculated from SD (z) scores as follows: (z (E-selectin)+z (VCAM-1)+z (ICAM-1)+z (MCP-1)).
Table 1 shows the recorded characteristics. The low C reactive protein concentrations despite an overall restricted access to biologic agents, infrequent use of oral glucocorticoids and ∼78% of patients that test positive for rheumatoid factor may have resulted from the routine application of a treatment strategy of tight disease activity control in our setting.8 In demographic feature and cardiovascular agent use adjusted mixed regression models, waist circumference, C reactive protein and interleukin-6 concentrations and leucocyte counts associated with resistin concentrations (partial R=0.134 (p=0.05), 0.195 (0.005), 0.194 (p=0.005) and 0.317 (p<0.0001)). Since patients with RA experience immune activation, our SD (z) endothelial activation score could conceptually and partly reflect RA disease activity. However, in the present cohort of treated RA patients, neither the Clinical Disease Activity Score nor the Disease Activity Score in 28 joints was associated with the respective endothelial activation score in demographic characteristic adjusted regression models (partial R=0.024, p value=0.7 and −0.012, p value=0.7, respectively).
Table 2 shows the conventional and non-conventional risk factor independent relationship of resistin concentrations with the endothelial activation score in all patients. Further adjustment for leucocyte counts did not materially alter this association (partial R=0.217, p=0.002).
Importantly, inflammation directly increases cardiovascular risk and participates in the atherogenic effects of conventional cardiovascular risk factors.9 We found in sensitivity analysis (table 2) that the resistin concentration–overall endothelial activation relationship was particularly strong in patients with adverse traditional risk factors, long standing disease or clinically evident joint damage and absent in those without the respective characteristics. These results provide additional support for an involvement of resistin in cumulative and high grade inflammation induced enhanced cardiovascular risk in RA.
In conclusion, resistin concentrations are independently related to endothelial activation in RA, particularly among patients with conventional cardiovascular risk factors, long standing disease or clinically evident joint damage. Resistin may enhance cardiovascular risk and its stratification in RA.
We thank Ms Linda Tsang for her invaluable contributions to the data collection and management.
Contributors PHD, GRN, AJW and AS contributed to the design and concept of the study. PHD and AS generated the primary data. GRN and AJW provided the measurements of interleukin-6 and endothelial activation molecule concentrations. PHD performed the data analysis and interpretation and wrote the manuscript in cooperation with GRN and AJW.
Funding The South African Medical Research Council (grant MRC2008_DES) funded the testing kits for determination of interleukin-6 and endothelial activation molecule concentrations.
Competing interests None.
Patient consent Obtained.
Ethics approval The Witwatersrand University Ethics Committee (Human Subjects).
Provenance and peer review Not commissioned; externally peer reviewed.
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