Introduction
Atherosclerosis is a process whose onset can be observed even in the foetal period.
A number of risk factors, such as hyperlipidaemia, hyperhomocysteinaemia, arterial
hypertension, hyperuricaemia, smoking, metabolic syndrome, hypertriglyceridaemia,
and diabetes, accelerate the progression of atherosclerotic lesions leading to the
development of atherosclerotic cardiovascular disease (ASCVD) [1].
Atherosclerotic cardiovascular disease is defined as coronary artery disease (CAD),
cerebrovascular disease, or peripheral arterial disease of atherosclerotic origin.
This disease represents the number one cause of morbidity and mortality worldwide.
The number of patients with cardiovascular diseases in the world in 2019 was 523 million,
while the number of deaths due to them reached 18.6 million [2].
Atherosclerosis – general look on pathogenesis
The pathogenesis of atherosclerosis is a multifactorial process involving large and
medium-sized arteries, the head of the aorta, and coronary vessels, and it occurs
especially in the places of their branches and bifurcations. According to modern concepts,
atherosclerosis is a consequence of a long-term defence reaction of the organism,
which increases with time, in the form of a chronic inflammatory response, leading
to degenerative and productive changes in the inner and middle layers of the arteries.
Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue-healing
responses, which begins with endothelial dysfunction and ends with plaque development,
instability, and rupture, which leads to MI, stroke, or critical ischaemia of the
lower limbs [3].
Atherosclerosis in patients with rheumatological diseases
Many authors indicate that atherosclerosis is an auto-inflammatory disease but also
an autoimmune disease, because it produces antibodies to oxidized low-density lipoprotein
(oxLDL) [4, 5]. It should be noted that the progression of atherosclerosis is particularly
pronounced in patients with autoimmune diseases (Table I).
Table I
The risk of atherosclerotic cardiovascular disease in people with selected autoimmune
diseases
Autoimmune disease – examples
Estimated risk of ASCVD – calculated as OR/HR/RR – from different papers
References
Type 1 diabetes mellitus
9.38 (95% CI: 5.56–15.82)
[6]
Systemic lupus erythematosus
3.39 (95% CI: 2.15–5.35)
[7]
Rheumatoid arthritis
2.97 (95% CI: 1.15–7.68)
[8]
Systemic sclerosis
2.25 (95% CI: 1.59–3.18)
[9]
Psoriasis
1.78 (95% CI: 1.51–2.11)
[10]
Hashimoto’s thyroiditis
1.44 (95% CI: 1.05–1.99)
[11]
Multiple sclerosis
1.28 (95% CI: 1.09–1.51)
[12]
ASCVD – atherosclerotic cardiovascular disease, HR – hazard ratio, OR – odds ratio,
RR – relative risk.
Based on the data presented in Table I, it should be emphasized that autoimmune diseases
are a strong independent risk factor for ASCVD. It should be stressed that the presence
of autoimmune inflammatory diseases (such as rheumatoid arthritis, systemic lupus,
or psoriasis) is an indication for early and regular lipid profile control and should
be included in the cardiovascular risk stratification [13].
Importantly, systemic autoimmune diseases and atherosclerosis share common pathogenic
pathways (chronic inflammatory background mediated by the toll-like receptors and
inflammasome Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin
domain containing 3/interleukin 1 (NLRP3/IL-1) pathways as seen in auto-inflammatory
diseases and endothelial dysfunction) [5]. Moreover, autoantibodies (an essential
component of autoimmune diseases) may ultimately cause structural and irreversible
arterial wall damage with subsequent atherosclerotic plaque development and rupture
[5]. It is worth adding that oxLDL and anti-β2-glycoprotein I (β2-GPI) are both inflammatory
(innate) and immunogenic (adaptive) molecules.
One possible role for these molecules is that they can serve as biological linkers
to link the progression from chronic inflammation to a complete autoantibody response
in the later stages of atherosclerosis. When autoantibodies are present, rheumatoid
arthritis patients have an accelerated atherosclerosis compared to rheumatoid arthritis
patients who do not have these antibodies. Similarly, autoantibodies in systemic lupus
erythematosus exacerbate atherosclerosis [5].
In rheumatic diseases, atherosclerosis can be accelerated by both systemic inflammation
and local vasculitis. Levels of pro-inflammatory cytokines such as TNF-α, IL-6, IL-17,
and IFN1 are often chronically elevated in rheumatic diseases, further exacerbating
endothelial dysfunction, macrophage activation, and thrombosis [3]. A characteristic
feature of rheumatological diseases is the production of autoantibodies, some of which
may be deposited directly in the lesions of the vessel wall, intensifying the progression
of atherosclerosis. T and B lymphocytes play a key role in the pathogenesis of rheumatological
diseases. It is worth mentioning that a specialized population of T lymphocytes, CD4+
CD28- cells, was isolated from inflammatory lesions of the synovium and ruptured plaque
[3].
An important factor contributing to the intensification of atherosclerosis progression
in rheumatological diseases is the presence of various genetic polymorphisms, such
as NFKB1–94ATTG ins/del polymorphism, HLA-DRB1*0404 shared epitope allele, and a TNF-α
rs1800629 gene polymorphism [3].
From a clinical point of view, the influence of rheumatological disease treatment
on the risk of ASCVD is significant. Ideally, such a therapy would work to reduce
the risk of ASCVD. For example, in a study by Ozen et al. [14] was compared the effects
of biologic disease-modifying anti- rheumatic drugs (bDMARD) and conventional synthetic
DMARD (csDMARD) on incident cardiovascular disease in patients with rheumatoid arthritis.
Cardiovascular risk reduction with TNF inhibitors (HR 0.81, 95% CI: 0.71 –0.93) and
abatacept (HR = 0.50; 95% CI: 0.30 –0.83) compared to csDMARD was demonstrated. Also,
it was found that minimizing the use of glucocorticoids and optimizing the dose of
methotrexate may improve cardiovascular outcomes in patients with rheumatoid arthritis
[14].
Moreover, a study by Yang et al. [15] assessed the long-term effect of treating patients
with systemic lupus erythematosus (SLE) with hydroxychloroquine (HCQ) on the risk
of ASCVD. Decreased risk for CAD was found among SLE patients with a high usage of
HCQ for at least 318 days (HR = 0.31; 95% CI: 0.12–0.76). A low risk for CAD was observed
in SLE patients with a high cumulative dose of at least 100.267 mg HCQ (HR = 0.25;
95% CI: 0.09–0.66) [15].
Thus, patients with rheumatological diseases have an increased risk of ASCVD, which
is a result of increased inflammation and autoimmune processes. Treatment of these
conditions reduces the risk of ASCVD in this group of patients.
Conclusions
Atherosclerosis with its background in inflammation and autoimmunity processes is
not only a pathology of the cardiovascular system. Lots of autoimmune and rheumatological
conditions are currently viewed as risk factors for accelerated atherosclerosis. Thus,
cardiovascular check-ups must be included in rheumatology practice. New methods of
treatment and new data on some drugs influencing both cardiovascular and rheumatological
diseases (like statins) are increasing our mutual recognition of both fields of medicine.