microvascular dysfunction in RA.docx

8/12/2019 microvascular dysfunction in RA.docx

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CHAPTER 1

INTRODUCTION

Patients with Rheumatoid Arthritis (RA) have a reduced life expectancy which is

predominantly due to cardiovascular disease (CVD).(1,2) The reason for this excess risk is not

clear. Evidence supporting an increased prevalence of hypertension and dyslipidaemia in RA

is now available, but when adjustment is made for these risk factors, the risk ratio is only

minimally attenuated , suggesting that mechanisms other than the conventional vascular risk

factors may contribute to this excess CV risk.

Recently, similarities have been found between the inflammatory process seen in RA

and atherosclerosis. These features include raised plasma levels of TNF-_, IL-6,

concentrations of CRP and local expression of adhesion molecules. It is now recognized that

the inflammatory process is a major contributor to the pathological processes seen in CVD,

and may play an aetiopathogenic role. It seems likely therefore that the deleterious effect to

the CV system in RA could be mediated by the inflammation associated with the disease

itself, a process we already know is involved in atherogenesis.

The vascular endothelium plays an essential role in maintaining blood vessel health

by releasing a variety of vasoactive substances and mediators of inflammation and

coagulation. When the endothelial function is impaired, there is an imbalance in these

substances resulting in a vasoconstrictor, pro-inflammatory and pro-coagulant endothelium

that may lead to both thrombosis and atherosclerotic disease. Changes in endothelial function

occur early in the development of CVD and are found in asymptomatic subjects with CV risk

factors. In RA, impaired endothelial function has been observed in the macrocirculation, butless is known about microvascular function. The microvasculature is an important vascular

bed to study as it is affected early in the development of endothelialdysfunction and

abnormalities here have been shown to correlate with CV risk factors and established

coronary artery disease. (3,4)

.


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CHAPTER II

RHEUMATOID ARTHRITIS

1. DefinitionRheumatoid arthritis (RA) is an autoimmune disease that causes chronic

inflammation of the joints. While inflammation of the tissue around the joints and

inflammatory arthritis are characteristic features of rheumatoid arthritis, the disease

can also cause inflammation and injury in other organs in the body. Autoimmune

diseases are illnesses that occur when the body's tissues are mistakenly attacked by

their own immune system. The immune system contains a complex organization of

cells and antibodies designed normally to "seek and destroy" invaders of the body,

particularly infections. Patients with autoimmune diseases have antibodies in their

blood that target their own body tissues, where they can be associated with

inflammation. Because it can affect multiple other organs of the body, rheumatoid

arthritis is referred to as a systemic illness and is sometimes called rheumatoid

disease.(8)

2. Epidemiology Prevalence varies from 0,5% to 1,5% ofthe population RA affects more woman than man ( ratio 3:1) The age of onset is between 3055 years

3. EtiologyGenetic susceptibility:

HLA DR4 with Rheumatoid Arthritis, type I diabetes HLA DR2 with lupus

Environmental Factors:

Infections Overexposure to pesticides and toxins Stress

4. Pathophysiology(6)The autoimmune inflammatory process in RA involves a complex cascade of

cells, including T cells, B cells, macrophages, mast cells, and fibroblasts, that

infiltrate the synovial tissues. Macrophage activation occurs, stimulating the release ofproinflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, IL-12, IL-16, IL-


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18, IL-32, and tumor necrosis factor-alpha (TNF-alpha). These cytokines stimulate

synovial fibroblasts and chondrocytes in the nearby articular cartilage to secrete

enzymes that degrade proteoglycans and collagen, leading to tissue destruction. This

results in inflammation of the synovial membrane, increased vascularity, hyperplasia

of the synovial cells, joint effusion, and the growth of a fibrovascular granulation

tissue called "pannus" which infiltrates contiguous bone and cartilage. Bone erosion

and degradation of the cartilage matrix ensue, due to the activation of osteoclasts and

invasion of aggressive synoviocytes, cytokine-activated chondrocytes, and neutrophils

Picture 1 : patophysiology of rheumatoid arthritis

5. Sign and symptoms(7)


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Rheumatoid arthritis is a long-term disease - a chronic disease. Symptoms can

come and go and each patient is affected differently. While some patents may have

long periods of remission, when the rheumatoid arthritis is inactive and few or no

symptoms are felt, others may have virtually constant symptoms for long periods.

Classic features:

Joint pain, typically symmetric Morning joint stiffness ( 1 hour) Joint swelling Constitutional symptoms (fever, fatigue, weight loss, etc.)

Although the joints are almost always the principal focus of RA, other organ

systems may also be involved. Extra-articular manifestations of RA occur most often

in seropositive patients with more severe joint disease. Extra-articular manifestations

can develop even in disease when there is little active joint involvement.

Extraarticular manifestation :

Rhematoid noduleThe subcutaneous nodule is the most characteristic extra-articular lesion of the

disease. Nodules occur in 20 to 30% of cases, almost exclusively in

seropositive patients. They are located most commonly on the extensor

surfaces of the arms and elbowsbut are also prone to develop at pressure

points on the feet and knees. Rarely, nodules may arise in visceral organs,

such as the lungs, the heart, or the sclera of the eye.

Cardiopulmonary Disease.There are several pulmonary manifestations of rheumatoid arthritis, including

pleurisy with or without effusion, intrapulmonary nodules, and diffuse

interstitial fibrosis. On pulmonary function testing, there commonly is arestrictive ventilatory defect with reduced lung volumes and a decreased

diffusing capacity for carbon monoxide. Although mostly asymptomatic, of

greatest concern is distinguishing these manifestations from infection and

tumor. Atherosclerosis is the most common cardiovascular manifestation in

rheumatoid arthritis. It is also the leading cause of death in the RA patient.

Because chronic inflammation may be the cause of atherosclerosis, it is

possible that early aggressive treatment of RA may reduce the incidence or

severity of heart disease. Pericarditis also seen with RA.


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Eye Disease.Keratoconjunctivitis of Sjogrens syndrome is the most common ocular

manifestation of rheumatoid arthritis. Sicca (dry eyes) is a common

complaint. Episcleritis occurs occasionally and is manifested by mild pain and

intense redness of the affected eye. Scleritis and corneal ulcerations are rare

but more serious problems.

Sjogrens Syndrome.Approximately 10 to 15% of patients with rheumatoid arthritis

develop Sjogrens syndrome. Sjogrens syndrome is an autoimmune condition

that affects exocrine gland function, leading to a reduction in tear production

(keratoconjunctivitis sicca), oral dryness (xerostomia) with decreased saliva of

poor quality, and reduced vaginal secretions.

Rheumatoid Vasculitis. Neurologic Disease.

The most common neurologic manifestation of rheumatoid arthritis is a mild,

primarily sensory peripheral neuropathy, usually more marked in the lower

extremities. Entrapment neuropathies (e.g., carpal tunnel syndrome and tarsal

tunnel syndrome) sometimes occur in patients with rheumatoid arthritis

because of compression of a peripheral nerve by inflamed edematous tissue.

6. Diagnosis


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CHAPTER III

CREACTIVE PROTEIN (CRP) & NITRIT OXIDE (NO)

1. CReactive Protein (CRP)a) Definition

CRP is a protein that produced in the liver as respon from inflammatory

cytokines, but based on recent studies show that CRP can also be produced by

extrahepatic tissues such as adipose cells and vascular smooth muscle cells.

b) Function(5)The acute phase response develops in a wide range of acute and chronic

inflammatory conditions like bacterial, viral, or fungal infections; rheumatic and other

inflammatory diseases; malignancy; and tissue injury or necrosis. These conditions

cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP

and fibrinogen by the liver. During the acute phase response, levels of CRP rapidly

increase within 2 hours of acute insult, reaching a peak at 48 hours. With resolution of

the acute phase response, CRP declines with a relatively short half-life of 18 hours.

Measuring CRP level is a screen for infectious and inflammatory diseases. Rapid,

marked increases in CRP occur with inflammation, infection, trauma and tissue

necrosis, malignancies, and autoimmune disorders. Because there are a large number

of disparate conditions that can increase CRP production, an elevated CRP level does

not diagnose a specific disease. An elevated CRP level can provide support for the

presence of an inflammatory disease, such as rheumatoid arthritis, polymyalgia

rheumatica orgiant-cell arteritis.

picture 2 : Stimulation and synthesis of positive acute-phase

reactants during inflammation. Inflammation caused by

infection or tissue damage stimulates the circulating

inflammation-associated cytokines, including interleukin-1

(IL-1), interleukin-6 (IL-6), and tumor necrosis factor

(TNF)- . These cytokines stimulate hepatocytes to

increase the synthesis and release of positive acute-phase

proteins, including CRP. IL-6 is the major cytokine

stimulus for CRP production
http://en.wikipedia.org/wiki/Giant-cell_arteritishttp://en.wikipedia.org/wiki/Giant-cell_arteritis


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The physiological role of CRP is to bind to phosphocholine expressed on the

surface of dead or dying cells (and some types of bacteria) in order to activate the

complement system. CRP binds to phosphocholine on microbes and damaged cells

and enhances phagocytosis by macrophages. Thus, CRP participates in the clearance

of necrotic and apoptotic cells.

CRP is a member of the class of acute-phase reactants, as its levels rise

dramatically duringinflammatoryprocesses occurring in the body. This increment is

due to a rise in the plasma concentration ofIL-6,which is produced predominantly

bymacrophagesas well asadipocytes.CRP binds tophosphocholine on microbes. It

is thought to assist incomplementbinding to foreign and damaged cells and enhances

phagocytosis by macrophages (opsonin mediated phagocytosis), which express a

receptor for CRP. It is also believed to play another important role ininnate

immunity,as an early defense system against infections. Serum amyloid A is a related

acute-phase marker that responds rapidly in similar circumstances.

Picture 3 : Key functions of CRP within the innate

immune system include the ability to (1) recognize andbind to phosphocholine exposed in damaged cell walls

and found in many bacteria, fungi, and parasites; (2)

act like an opsonin, marking bacteria, damaged cell

walls, and nuclear debris for phagocytosis; (3) bind to

Cl, the first component of the classical pathway of the

complement system that triggers phagocytic activity;

and (4) bind to polymorphonuclear leukocytes (PMNs)

and monocytes, which stimulate the production of

inflammatory cytokines

CRP rises up to 50,000-fold in acute inflammation, such as infection. It rises

above normal limits within 6 hours, and peaks at 48 hours. Its half-life is constant, and

therefore its level is mainly determined by the rate of production (and hence the

severity of the precipitating cause).

2.

Nitric Oxide (NO)
http://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Interleukin-6http://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/Adipocytehttp://en.wikipedia.org/wiki/Phosphocholinehttp://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Opsoninhttp://en.wikipedia.org/wiki/Innate_immunityhttp://en.wikipedia.org/wiki/Innate_immunityhttp://en.wikipedia.org/wiki/Innate_immunityhttp://en.wikipedia.org/wiki/Innate_immunityhttp://en.wikipedia.org/wiki/Opsoninhttp://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Phosphocholinehttp://en.wikipedia.org/wiki/Adipocytehttp://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/Interleukin-6http://en.wikipedia.org/wiki/Inflammation


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Nitric Oxide is derived endhotelial releasing factor (EDRF) that synthesized and released

by endothelial cells and serves as a potent vasodilator. The release of NO stimulated by

bradykinin. Endothelium derived nitric oxide is synthesised from the amino acid L-arginine

by the endothelial isoform of nitric oxide synthase

NO is isoenzymes in the body and there are 3 types:

Enzyme Endhotelial syntase NO (eNOS), an enzyme that has the propertiesdependent on Ca, the enzyme is found in many types of cells and are responsible for

most of the NO production in healthy blood vessels and released continuously by

arterial and venous endothelial cells and platelets.

Neuronal NO synthase (nNOS), which is a special form of eNOS function of nerves. inducible NO synthase (iNOS), an enzyme that can be induced form, can be found

and removed by myocytes, macrophages and endothelial cells of small blood vessels

that are enabled and can be induced by immunological stimuli by cytokines and

endotoxin.

In normal circumstances, NO produced by eNOS which is activated by blood vessels, but

in a state of inflammation, inducible NO (iNOS) is expressed by macrophages and smooth

muscle cells that affect the production of NO. Increased production of iNOS, leading to

consumption of L - arginine increased so that the substrate for eNOS and iNOS decreased

and resulted in a decrease in the number of endothelial NO and trigger endothelial

dysfunction.

NO is a major factor in maintaining endothelial function. Low concentrations correlated

with decreased endothelial NO endothelial function. NO is an important mediator in

endhotelium dependent vasodilation. In addition, NO also plays a role in platelet aggregation

and regulating the growth and differentiation of smooth muscle cells.


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CHAPTER IV

DISCUSSION

Atherosclerosis is the most common cardiovascular manifestation in rheumatoid

arthritis. Inflammation plays an important role in the development and progression of

atherosclerosis and congestive heart failure (CHF) . The inflammatory process contributes to

the formation of early atherosclerotic plaques in the form of lipid-laden macrophages and

induces plaque weakening and rupture leading to acute coronary syndromes and sudden death

. Furthermore, many circulating markers of inflammation, particularly C-reactive protein

(CRP), are associated with increased morbidity and mortality in asymptomatic individuals

and in patients with cardiovascular disease and CHF .

Picture 5: correlation crp and chf

risk

Picture 4: prevalence atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis is autoimune disease. Autoimmune diseases are illnesses that

occur when the body's tissues are mistakenly attacked by their own immune system.When

antigen entry, it will activate macrophages to secrete inflammatory cytokines. IL6 and TNF-a

will stimulate hepatocyt to secrete CRP, it causes increased levels of CRP in rheumatic

arthritis patients. Rheumatoid arthritis also stimulates limfosit B cells to produce

autoantibody. Autoantibodies to form immune complexes and will attack the target cell,

where that target is their own body tissues.


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Increased CRP levels is important in endothelial dysfunction because CRP can reduce

the synthesis of Nitric Oxide. NO is a major factor in maintaining endothelial function. Low

concentrations correlated with decreased endothelial function. NO is an important mediator in

endhotelium dependent vasodilation. Beside that, it can stimulate secretion of CD4 from T

lymphocytes to damage endothelial cells. In addition, CRP also stimulates LDL to get into

the macrophages forming foam cells that will eventually become atherosclerotic plaques. (9,10)

Picture 6 :Mechanisms relating C-reactive protein (CRP) to the development and progression

of atherothrombosis. eNOS, endothelial nitric oxide synthase;ET-1, endothelin 1;LDL, low-

density lipoprotein;MCP-1, monocyte chemoattractant protein 1;PAI-1, plasminogen

activator inhibitor-1

PreventionCorticosteroid are often used in the treatment of SLE. RA and other inflammatory

disorder. High dose treatment with corticosteroid has adverse effect on the cardiovascular

system, including endothelial dysfunction, hypertension, and dysregulated glucose

metabolism. But, there is no evidence for similiar clinical effects in patients treated with

low dose (< 7,5 mg/day). In the other hand, a protective effect from CVD ( cardiovascular

disease) could be postulated based on control inflammation, so it has been suggested that

corticosteroid treatment may be associated with a reduce risk of atherosclerosis. MTX

(methothrexate) is today the anchor DMARDs for RA treatment; this suggests that


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reducing RA inflammation, MTX may also reduce collateral damage such as

atherosclerosis. (11)

Recently, treatment with TNF inhibitors was associated with a lower risk of CVD

agents in a study of community based RA registers in Sweden. These drugs act through

the inhibition of TNF alpha, a

proinflammatory cytokine

playing a primary role in RA

appearance, however, as

previously described, TNF

alpha has been implicated

also in the pathogenesis of

RA related atherosclerosis.

The cardioprotective effect of

TNF inhibition in RA may be

related to several factors, as,

for example, the increase of

HDL levels; therefore, these

drugs do not affect LDL

levels or atherosclerotic index

(i.e., TC/HDL ratio). On the other hand, these drugs may reduce significantly insulin

levels and the insulin/glucose index, as well as improve insulin resistance and also a

dramatic reduction of resistin, an adipokine that showed strong correlation with C

reactive protein, was observed following infliximab infusion in RA patients undergoing

this therapy because of severedisease Likewise, improvement of endothelial function

following anti-TNF-alpha administration has been observed in RA patients with severe

disease refractory to conventional DMARDs therapy.(13,14,15)

Statin reduce CVD morbidity and mortality. although they were originally used in

this contect because of their effect in lipid level, it has become increasingly evident that

they have other actionswhich may diminish CVD risk.(12) The anti inflammatory and

immunomodulating effects of statin include supression of leucocyte cytocine release.

Reduce MHC class II expression and reduced production of reactive oxygen species.(16)


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CHAPTER V

CONCLUSION

Systemic inflammation (CRP) is associated with microvascular dysfunction in

patients with RA. Rheumatoid arthritis and atherosclerosis are strictly linked, this link is so

strong that atherosclerosis may be considered an extra-articular manifestation of the

disease, leading to an increased risk of CVD. Moreover, the impact of this extra -articular

manifestation on patients survival is of primary importance, being in fact CVD, the

main prognostic factor in this setting. So it is important to screen and monitor RA patients

to reduce the impact on cardiovascular system. To prevent the occurrence of atherosclerosis

in patients with rheumatoid arthritis, the pateints can do traditional form like physical

exercise and for medikamentosa treatment can use anti inflamatory drugs for decrease CRP

serum, like methotrexate low dosage and TNF alfa inhibitor.


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13.F. Atzeni, M. Turiel, R. Caporali et al., The effect of pharmacological therapy on thecardiovascular system of patients with systemic rheumatic diseases, Autoimmunity

Reviews, vol.9, no. 12, pp. 835839, 2010.

14.M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, T. R. Vazquez- Rodriguez, J. A.Miranda-Filloy, and J. Llorca, Insulin resistance in rheumatoid arthritis: the impact

of the anti- TNF- therapy: annals of the New York Academy of Sciences, Annals of

the New York Academy of Sciences, vol. 1193, pp. 153159, 2010.

15.C. I. Daen, Y. Duny, T. Barnetche, J.-P. Daur`es, B. Combe, and J. Morel, Effect ofTNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-

analysis,Annals of the Rheumatic Diseases, vol. 71, no. 6, pp. 862868, 2012.

16.Palinski W, Napoli C. 2002. Untravelling Pleotropic Effects of Statin on PlaqueRupture. Artherioscler Thromb Vasc Biol, 22: 1745 - 50

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