EDITORIAL - The role of inflammatory cytokines in the pathogenesis of SLE-related atherosclerosis

[Guest guest]

The Journal of Rheumatology

March 2006

Editorial

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The Role of Inflammatory Cytokines in the Pathogenesis of Systemic Lupus

Erythematosus-Related Atherosclerosis: A Novel Target for Treatment?

Center for Autoimmune Diseases,

Department of Medicine B, Sheba Medical Center;

BORIS GILBURD, MD, PhD,

Sackler Faculty of Medicine,

Incumbent of the Schwarz-Kipp Chair for Research of Autoimmune

Diseases, Tel-Aviv University;

YEHUDA SHOENFELD, MD, FRCP(Hon),

Head, Center for Autoimmune Diseases,

Department of Medicine B, Sheba Medical Center;

and Sackler Faculty of Medicine, Tel-Aviv University

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Atherosclerosis is a slowly progressive chronic inflammatory disease

characterized by focal arterial lesions that can occlude the entire blood

vessel and lead to sudden death. Lesions associated with cardiovascular

events are those enriched in macrophages and other inflammatory cells.

Activation of inflammatory cells within the lesions induces the release of

substantial amounts of inflammatory factors and cytokines, which promotes

more inflammation and associated tissue damage.

During the last few years it has become clear that several autoimmune

diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis

(RA), antiphospholipid syndrome, and systemic sclerosis are associated with

higher rates of cardiovascular morbidity and mortality secondary to

premature and accelerated atherosclerosis1. Thus, patients with SLE have a

5- to 6-fold increased risk for coronary vascular disease (CVD), and this

excess risk is especially pronounced in younger women2,3. It has been also

demonstrated that about 30% of patients with SLE have subclinical

atherosclerosis4.

Despite a large number of studies, the risk factors and proposed mechanisms

of accelerated and premature atherosclerosis in SLE have continued to be the

subject of investigations. First, atherosclerosis in SLE can be attributed

to an increased frequency of traditional risk factors such as hypertension,

dyslipidemia, obesity, and diabetes mellitus3. Additionally, it has been

shown that atherosclerosis cannot be explained by Framingham risk factors

alone5 and may be associated with a combination of both traditional and

nontraditional risk factors. Some novel or disease-related risk factors that

may account for increased risk of atherosclerosis in SLE include

inflammatory markers and cytokines: C-reactive protein (CRP), fibrinogen,

and interleukin 6 (IL-6); immunological factors: antiphospholipid,

anti-ß2-glycoprotein I, antioxidized low-density lipoprotein, and anti-heat

shock protein antibodies; abnormal coagulation factors: plasminogen

activator inhibitor-1 and homocysteine; lipoprotein and modified lipids:

lipoprotein(a) and high density lipoprotein (HDL).

The possibility that SLE itself may be atherogenic through chronic

activation of the immune system and inflammation is of particular interest

since both these mechanisms are involved in the pathogenesis of

atherosclerosis. Considering the inflammatory nature of atherosclerosis, the

question clearly arises: How is the accelerated arterial disease seen in SLE

related to the interaction between different inflammatory and immune

processes?

In this issue of The Journal, the interesting study of Asanuma and

colleagues6 on patients with SLE examines the association between the

proatherogenic inflammatory cytokines IL-6, IL-8, and monocyte

chemoattractant protein-1 (MCP-1) and risk factors for cardiovascular

disease, as well as coronary artery calcifications. Plasma IL-6, MCP-1, and

serum IL-8 were measured in 74 patients with SLE and in 85 healthy subjects.

Coronary artery calcifications were determined by electron beam computed

tomography. The investigations confirmed that levels of IL-6 and MCP-1 were

higher in SLE patients than in controls and were linked with disease

activity, as measured by the Systemic Lupus Erythematosus Disease Activity

Index. Moreover, after adjusting for confounding covariates, including age,

disease activity, Systemic Lupus International Collaborating Clinics Damage

Index, smoking status, and systolic blood pressure, increased IL-6 levels

were positively correlated with coronary calcifications and with Westergren

erythrocyte sedimentation rate (ESR) and CRP. Of interest, elevated IL-6

levels found in patients with SLE were inversely correlated with HDL,

whereas elevated MCP-1 concentrations were linked with increased plasma

triglycerides.

Several studies have provided data on the multifactorial role in

atherogenesis of numerous proinflammatory cytokines, including promoting

atherosclerosis-related inflammation, altering lipid metabolism7, and

contributing to plaque instability and rupture8. Asanuma, et al6 highlighted

numerous important points regarding the potential relationship in SLE

between IL-6, MCP-1, and atherosclerosis.

IL-6, one of the most potent proinflammatory cytokines, induces acute phase

protein production by hepatocytes. It is involved in the recruitment of

inflammatory cells and lipid homeostasis and is associated with increased

cardiovascular mortality and prognosis in the general population9. As noted

above, IL-6 drives CRP production, which itself plays multiple roles,

influencing key promoters of atherosclerosis; moreover, it appears as an

independent predictor of coronary events10. In the study by Asanuma, et al6

the strong correlation between IL-6 and acute phase reactants such as ESR

and CRP raises the possibility that together these reflect the total

inflammatory response associated with the disease. However, it has also been

proven that the link between calcifications and elevated IL-6 levels remains

significant after adjustment for ESR, and is borderline after adjustment for

CRP. Since CRP production is driven by IL-6, an adjustment for CRP may

camouflage the complete influence of IL-6 on atherogenesis; on the other

hand the interaction between IL-6 and CRP in patients with SLE is

controversial. Thus, several previous studies did not find a significant

correlation between IL-6 and CRP levels in SLE patients in comparison to

healthy subjects and patients with other rheumatic diseases11. Therefore,

the relationship between IL-6 concentrations and the burden of

atherosclerosis in SLE patients represents more than an epiphenomenon, and

we agree with the authors that the measurement of IL-6 provides

supplementary information in this cohort of SLE patients.

Patients with SLE have been described as having a lupus pattern of

lipoproteins, including high levels of very low-density lipoprotein and

triglycerides and low levels of HDL cholesterol, which represent a risk

factor for CVD12. A number of mechanisms associated with the production of

inflammatory cytokines may exacerbate atherogenic lipid profiles in SLE.

Thus, IL-6 mediates inhibition of lipoprotein lipase (LPL)7, as well as

elevated circulating levels of anti-TNF-a, which are associated with high

triglycerides and low HDL, contribute to the pattern of hyperlipidemia13.

Identifying coronary artery calcifications is an established method for the

detection of atherosclerosis, but as discussed above, proinflammatory

cytokines could be involved early in atherogenesis, and their concentrations

might play a special role before the development of a detectable plaque.

Evaluation of the predictive value of the proinflammatory cytokines in

SLE-related atherosclerosis will be a subject for further prospective

investigations.

It may emerge that one of the important preventive measures to reduce

cardiovascular complications in rheumatic diseases will be effective

suppression of the underlying inflammatory rheumatic disease. This may have

direct antiinflammatory actions on atherosclerotic lesions, but may also

suppress the disease activity and indirectly improve the profile of

inflammation-related risk factors. For some drugs, such as corticosteroids,

these potential benefits need to be set against possible untoward effects on

the cardiovascular system. Thus, it has been recently reported that SLE

patients with evidence of carotid atherosclerosis are less likely than those

without evidence of atherosclerosis to have received prednisolone,

cyclophosphamide, or hydroxychloroquine, suggesting that disease suppression

may protect against atherosclerosis14. When treating patients with SLE, it

is important to pay attention to a close monitoring of traditional risk

factors, and guidelines for the treatment of hypercholesterolemia and

hypertension should be reset in these patients.

Relatively little is known about the role of other treatments in SLE in

relation to CVD. In this respect, the link between proinflammatory cytokines

and atherosclerosis as well as some traditional risk factors allows

additional opportunities for therapeutic interventions.

The reason for anticytokine therapy in SLE is based on the major role of

cytokines in propagating the inflammatory processes responsible for tissue

damage. Thus, IL-6 is instrumental in maintaining the autoinflammatory loop

in SLE, and a rationale for IL-6 blockade has been recently demonstrated15.

Notably, IL-6 has been shown to promote experimental lupus nephritis in rats

that may be delayed by rat anti-IL-6 antibodies16 or rat anti-IL-6 receptor

antibodies17. Therefore, blockade of the IL-6 cascade may represent a novel

target for prevention and therapy in SLE-associated atherosclerosis.

Inhibitors of tumor necrosis factor-a (TNF-a) have demonstrated efficacy in

many inflammatory diseases including RA, ankylosing spondylitis, and Crohn's

disease; but whether anti-TNF-a treatment also modulates atherosclerosis is

still a mystery. The effect of this treatment on congestive heart failure

(CHF) in RA patients is controversial and has been a subject of

discussion18. By analogy with CHF, the importance of TNF-a blockade in SLE

is also ambiguous, since TNF blockade may induce production of antibodies to

double-stranded DNA and lupus-like disease in RA19. Nevertheless, the

efficacy of anti-TNF-a in patients with SLE has been shown in an open-label

study of infliximab in 6 patients with SLE20. In this trial, 3 patients with

arthritis and 4 with nephritis (one with both clinical features) refractory

to standard therapy were treated with infliximab, with a significant

improvement in clinical manifestations. This observation suggests that

uncoupling between autoantibody formation and inflammatory activity was

found with TNF-a blockade, leading to a significant reduction of disease

activity despite continuous production of anti-DNA autoantibodies20.

Blockade of other inflammatory cytokines, which are directly involved in

atherogenesis, may inhibit progression of atherosclerosis in SLE. For

instance, the Th2 cytokine IL-4 may serve as a target for immunomodulation.

Its potential involvement in atherogenesis has been implicated by the

observation that fatty streak formation in IL-4 knockout mice immunized with

HSP65 or Mycobacterium tuberculosis was significantly reduced when compared

with lesions in wild-type controls21.

Greater understanding of the mechanisms underlying accelerated

atherosclerosis may not help to manage rheumatic disease but might provide

some clues to the pathogenesis of atherosclerotic process in the general

population. In the course of SLE, a variety of cytokines are dysregulated,

several of which likely influence SLE-related atherosclerosis through

propagating the immune and inflammatory response as well as altering lipid

metabolism. Further studies are needed to understand more completely the

mechanisms by which proinflammatory cytokines may influence the development

of accelerated and premature atherosclerosis in SLE. Novel therapeutic

approaches will be developed that target the causes of the inflammatory

process in atherosclerotic plaques.

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