Rheumatoid Arthritis, Inflammation, and Cardiovascular Risk

Much like HIV/AIDS, rheumatoid arthritis (RA) is associated with a higher risk of cardiovascular disease (CVD) and consequent death.¹ The magnitude of the increase in the risk of death is sobering. The prevalence of CVD in a cohort of patients with RA who did not have diabetes mellitus (DM) was comparable to that in patients who had type 2 DM, 13% and 12%, respectively.² CV risk in patients with type 2 DM is treated as secondary, that is, as if they already had a CV event.

Germane to the discussion of residual CV risk factors, RA-analogous to HIV/AIDS-is a chronic disease with heightened, persistent inflammation, both articular and extra-articular. How might this disease-specific inflammation add to residual risk of CVD?

It is interesting to compare the inflammatory cascade in inflamed synovia and arteriosclerotic plaques.³ Both accumulate inflammatory macrophages, monocytes, and T cells. Both pathologies are characterized by mast cell and T-cell activation, tumor necrosis factor α (TNF-α) and interleukin-6 production, and an increase in metalloproteinases and leukocyte adhesion. Not only do the basic pathophysiologies overlap, but joint inflammation can be so active in RA that inflammatory cytokines “spill over” into the circulation, affecting other sites, vessels included.³

Research on the aggressive inflammation of RA and its impact on CV risk has opened new vistas into RA’s role in arteriosclerosis. TNF-α levels are markers for joint inflammation in RA. TNF-α impairs nitric oxide (NO) availability and blocks activation of endothelial NO. The end result is endothelial dysfunction.³

In another article, I examined C-reactive protein (CRP) level as a marker for pathological inflammation and consequent CV risk in patients with HIV/AIDS. In patients who have RA with increased arterial “stiffness,” the CRP level also is elevated and is suspected to be a risk factor.³

To demonstrate that discussions of inflammation’s robust contributions to CV risk do not disqualify the contribution of dyslipidemia, it has been proved that systemic inflammation can adversely affect the structure of lipoproteins. Patients with long-term RA possess a lower LDL size composed of an increase in small, dense LDL, a potent CV risk factor.³ This alteration is not measured by current cholesterol profiling. The change in structure is presumed to be a consequence of RA’s persistent inflammation. Recent data have even revealed that the reduced LDL size is present in early RA before treatment.⁴ Because inflammation in RA also impairs HDL’s ability to remove cholesterol from plaques, as a disease, it prospers an atherogenic lipid phenotype.³

Although the mechanisms that augment CV risk in RA may appear esoteric, there is a potent message here for primary care physicians. How many times has a clarion call been sounded to diagnose and manage RA as early as possible?

The clock for CV disease is ticking the first time a patient with RA presents to a primary care physician. Once the diagnosis of RA is made, therapy for the disease per se-as well as for its untoward vascular damage-mitigates joint and vessel damage. Methotrexate reduces CV events in patients with RA.⁵ TNF-α–blocking agents lead to a lower risk of a first-time CV event in patients with RA.⁶ Statins not only affect LDL levels in those who are afflicted with RA, but remember their pleiotropism. They also reduce other “bad actors” of inflammation, such as CRP level and the erythrocyte sedimentation rate.⁷

RA and CV risk is not just for rheumatologists any more!   

References
1. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71:1524-1529.
2. van Halm VP, Peters MJ, Voskuyl AE, et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann Rheum Dis. 2009;68:1395-1400.
3. Ozbalkan Z, Efe C, Cesur M, et al. An update on the relationships between rheumatoid arthritis and atherosclerosis. Atherosclerosis. 2010;212:377-382.
4. Rizzo M, Spinas GA, Cesur M, et al. Atherogenic lipoprotein phenotype and LDL size and subclasses in drug-naive patients with early rheumatoid arthritis. Atherosclerosis. 2009;207:502-506.
5. Choi HK, Hernn MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173-1177.
6. Jacobsson LT, Turesson C, Glfe A, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol. 2005;32:1213-1218.
7. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised, placebo-controlled trial. Lancet. 2004;363:2015-2021.