Rheumatoid Arthritis & Atherosclerosis: Is there a Link?

Recent research in atherosclerosis has yielded surprising results, as more and more dimensions of inflammatory/autoimmune diseases begin to show themselves as essential aspects of the disease. Though this research is in its infancy the prior research on rheumatoid arthritis as well as late coming connections between the incidence of one and the incidence of the former are being found occurring simultaneously between the two disorders, both of which show a higher mortality rate together and when atherosclerosis appears as unstable, i.e. inflammatory in nature. (Margolis, February 2007, NP) Much recent research is indicating the connectivity of the two diseases as well as an essential need to compare contrast and combine research to help determine the extent to which the two are connected. This work will discuss the early findings which demonstrate connectivity between both incidence of rheumatoid arthritis and atherosclerosis and the similarities between the two disorders, both of which serve as a distinctive element of future research and growth of alternative treatments for the previously mysteries outcomes of varied degrees of atherosclerosis and its equally mysterious prognosis based upon the degree of damage done to coronary and circulatory arteries.

Rheumatoid Arthritis & Atherosclerosis: Is there a Link?

The development and extent to which atherosclerosis is linked with morbidity has for some time been a mystery to researchers and clinical specialists, as the variety to which atherosclerosis demonstrates the ability to be lethal has led to the utilization of treatment protocols that are focused upon eliminating the occurrence of plaque build up to the greatest degree possible, with most focusing almost exclusively on reducing known external causes for the buildup, independent of unknown mitigating factors. In other words the focus of treatment for the disease has been on reducing plaque build up by pharmacological means, and then intervening just prior to or following a potentially lethal event by surgical means. The concern for many has always been that intervention in atherosclerosis often comes too late and that narrowing and hardening via plaque buildup often causes outward acute medical crisis prior to detection of the disease process, creating many more mortalities than would seem logical to many who have been treating and researching the disease for years. While more extensive and longstanding research into the immunological and inflammatory aspects of rheumatoid arthritis is proving to be an incremental aspect of research and treatment of atherosclerosis.

The increasing knowledge of the inflammatory and immunological mechanisms of rheumatoid arthritis is leading to the development of new and effective strategies for the treatment of this disease, in particular anti-cytokine strategies, immunological interventions, and modulation of the Th1/Th2 response. The knowledge of the inflammatory and immunological mechanisms of coronary heart disease is still at its beginning and is raising more questions than answers. However, this innovative approach may lead to new discoveries that could improve our understanding of the basic mechanisms of this disease and, possibly, lead to innovative, fascinating strategies for prevention and treatment of atherosclerosis and its complications. (Pasceri & Yeh, 1999, p. 2126)

One thing that researchers and clinicians are intimately aware of is that rheumatoid arthritis frequently presents with atherosclerosis, both coronary and peripheral and that this connection could offer a significant avenue of research for both diseases as the progression of atherosclerosis can be tracked much more effectively due to earlier detection of both conditions in the same person. See Table one for clinical similarities between the two diseases, a significant hint that the two might be related, and more specifically that the inflammation process may be at play in both with regard to progression of atherosclersosis and particualy fatal atherosclerosis.

Table 1. Similarities Between Atherosclerosis and Rheumatoid Arthritis

Atherosclerosis

Rheumatoid Arthritis

Macrophage activation http://circ.ahajournals.org/math/agr.gif

Metalloproteinase expression

Interleukin-6

(UA)

Mast-cell activation

T-cell activation

Soluble IL2 receptor

(UA)

CD3+DR+

(UA)

CD4+CD28-

(UA)

http://circ.ahajournals.org/math/ggr.gif

(UA)

Th1/Th2 balance

Th1

B-cell activation

Autoantibodies (oxLDL, HSP)

http://circ.ahajournals.org/math/uarr.gif

Rheumatoid factor

C-reactive protein

(UA)

Adhesion molecules (VCAM-1, ICAM-1, E-selectin, P-selectin)

Endothelin

Neoangiogenesis

Possible antigens

HSP, Ox-LDL, Infectious agents

Collagen II, Cartilage antigens, HSP, Infectious agents http://circ.ahajournals.org/math/agr.gif indicates tumor necrosis factor-alpha; HSP, heat shock http://circ.ahajournals.org/math/uarr.gif increased; http://circ.ahajournals.org/math/uarr.gif marked increased.

UA indicates systemic markers found increased in patients with unstable angina. Other factors are expressed in atherosclerotic plaques. (Vincenzo & Yeh, 1999, p. T1)

Rheumatoid arthritis on the other hand has been well documented and at least somewhat well treated for many years as disease symptoms occur much more rapidly and create situations where individuals seek treatment for pain and possible disfigurement long before symptomology becomes a lethal factor associated with cardiovascular disease. Then the most logical observation is that due to the fact that Rheumatoid arthritis is a markedly painful and debilitating disease, where as atherosclerosis can go undetected for years the later should and is more likely to be fatal than the former, as when the disease presents early screening for the lethal aspects of disease, which have always been linked to coronary valve malformations can be screened for. Atherosclerosis on the other hand is not as easily identified by the patient until the disease demonstrates marked, slowly progressing, deterioration of coronary circulation, which can and eventually does cause symptoms of fatigue and acute blockages, often in the form of myocardial infarction. MI being one of the first symptoms, only linked with general fatigue in cases where such limitation causing fatigue has not occurred over such a long period of time to have allowed the coronary arteries to form collateral circulation can and often is essentially fatal.

This disease progression, as it has been identified over the years has demonstrated that atherosclerosis can go undetected for many years and without direct cause to look at the disease process, i.e. known risk factors for the disease (many of which as has been stated demonstrate the potentiality for lethality) there are only limited known factors for intervention. One of which is cholesterol screening and reduction, as old school standards have demonstrated increased incidence of high LDL cholesterol and atherosclerosis but have in the long-term seemed to create more controversy and variation than preventative intervention as correlations between the extent of atherosclerosis and LDL are sometimes considered weak, at best because essentially they are far from direct correlates, even though it is very unlikely to see one completely absent of the other, but more recent studies have been even less able to provide predictive results of elevations of both LDL and atherosclerosis. The former of which seems to be more predictive of overall cardiovascular disease incidence than atherosclerosis progression. (Ravinskov, 2002, pp. 397-403) Ravinskov, stresses that there has even been some research that supports the fact that increases in cholesterol actually mitigate some factors of atherosclerosis, rather than increasing its progression and that only in studies where familial high LDL (non-dietary LDL) is the only predictor of advanced atherosclerosis and as such may not be correlation but may be collaborative with other disease and mitigating processes to cause advanced atherosclerosis. (pp. 402-403)

It has been known for some time that atherosclerosis is a common occurrence among patients with rheumatoid arthritis and more recently such a connection has been postulated to associate preclinical carotid atherosclerosis, which indicates for some the need to advance research toward the direction of seeking an inflammatory causal association for atherosclerosis. (Roman, et. al. 2006, pp. 249-257) See Table 2 and Figure 1 for description of increased incidence of rheumatoid arthritis and atherosclerosis. This incidence is mitigated for as many known contributing factors as possible but still shows a significant increase in the rate of preclinical carotid atherosclerosis (PCA) among patients with Rheumatoid arthritis as apposed to a control group without it. The really interesting facts of this particular study are that the development of PCA in patients who Table 2

Preclinical Carotid Atherosclerosis in Rheumatoid Arthritis or Control

RA Control

Adjusted with Age, Serum Cholesterol, Smoking History an Hypertensive Status

RA Control

38.5% (25.4% -53.5%) 7.4% (3.4%-15.2%) (+- 0.001)

Series 1 incidence less control for known mitigating factors Series 2 incidences with control of mitigating factors see table 1. (+- 0.001) (Roman et. al. 2006, p. 249 were of advanced age, were smokers (currently) and were clinically hypertensive was significantly higher than the rate among those who were not in the control groups, while in the Rheumatoid Arthritis group these factors only mitigated a few points of difference between occurrence or non-occurrence of PCA. Additionally, when the figures were factored utilizing information about cholesterol, high LDL did not create a significant difference for either group, with regard to incidence of PDA. (Roman et. al. 2006, p. 249)

What these findings suggest is that some aspect of RA is a more important factor for the development of atherosclerosis than any of the environmental or genetic risk factors that have been identified already, though this does not negate the fact that in non-RA patients there is a significant risk increase with smoking and age. Another interesting finding of this particular research study, is that use of tumor necrosis factor an…