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, but less 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) .

CHAPTER II RHEUMATOID ARTHRITIS 1. Definition Rheumatoid 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% of the population RA affects more woman than man ( ratio 3:1) The age of onset is between 30 55 years

3. Etiology Genetic 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 of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, IL-12, IL-16, IL2

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)

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. Extra articular manifestation : Rhematoid nodule The 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 elbows but 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 a restrictive 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. 4

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

CHAPTER III C REACTIVE PROTEIN (CRP) & NITRIT OXIDE (NO) 1. C Reactive 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 or giant-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

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 during inflammatory processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophages as well as adipocytes. CRP binds to phosphocholine on microbes. It is thought to assist in complement binding 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 in innate 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 and bind 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)

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 properties dependent 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.

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. 9

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, lowdensity lipoprotein; MCP-1, monocyte chemoattractant protein 1; PAI-1, plasminogen activator inhibitor-1

Prevention Corticosteroid 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 10

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 the cardiovascular 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 of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with metaanalysis, Annals of the Rheumatic Diseases, vol. 71, no. 6, pp. 862868, 2012. 16. Palinski W, Napoli C. 2002. Untravelling Pleotropic Effects of Statin on Plaque Rupture. Artherioscler Thromb Vasc Biol, 22: 1745 - 50

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