inggris 3 denata baru.docx

8/12/2019 inggris 3 denata baru.docx

1/22

1

CHAPTER I

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


2/22

2

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)

.


3/22

3

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. EpidemiologyRheumatoid arthritis has a worldwide distribution with an estimated prevalence of 1 to

2%. Prevalence increases with age, approaching 5% in women over age 55. The average

annual incidence in the United States is about 70 per 100,000 annually. Both incidence and

prevalence of rheumatoid arthritis are two to three times greater in women than in men.

Although rheumatoid arthritis may present at any age, patients most commonly are first

affected in the third to sixth decades.

3. EtiologyThe cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and

infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle

factors (eg, tobacco use, the main environmental risk) may influence disease outcome.


4/22


5/22


6/22

6

b) Morning joint stiffness ( 1 hour)c) Joint swellingd) 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 :

a) 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.

b) 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


7/22


8/22


9/22

9

CHAPTER III

CREACTIVE PROTEIN (CRP) & NITRIT OXIDE (NO)

1. CReactive Protein (CRP)a) DefinitionCRP 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.
http://en.wikipedia.org/wiki/Giant-cell_arteritishttp://en.wikipedia.org/wiki/Giant-cell_arteritis


10/22

10

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

duringinflammatoryprocesses occurring in the body. This increment is due to a rise in the

plasma concentration ofIL-6,which is produced predominantly bymacrophages as well as

adipocytes.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.
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/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


11/22

11

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 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.


12/22

12

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.

STRUCTURE

The three distinct genes for the human neuronal, inducible and endothelial NOS isoforms

exist, with a single copy of each in the haploid human genome (picture 4).

The enzymes exist as homodimers. In eukaryotes, each monomer consisting of two major

regions: an N-terminal oxygenase domain, which belongs to the class of heme-thiolate

proteins, and a multi-domain C-terminal reductase, which is homologous to

NADPH:cytochrome P450 reductase and other flavoproteins. The FMN binding domain is

homologous to flavodoxins, and the two domain fragment containing the FAD and NADPH

binding sites is homologous to flavodoxin-NADPH reductases. The interdomain linker


13/22

13

between the oxygenase and reductase domains contains a calmodulin-binding sequence. The

oxygenase domain is a unique extended beta sheet cage with binding sites for heme and

pterin.

NOSs can be dimeric, calmodulin-dependent or calmodulin-containing cytochrome p450-

like hemoprotein that combines reductase and oxygenase catalytic domains in one dimer,

bear both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), and carry

out a 5`-electron oxidation of non-aromatic amino acid arginine with the aid of

tetrahydrobiopterin.(17)

All three isoforms (each of which is presumed to function as a homodimer during

activation) share a carboxyl-terminal reductase domain homologous to the cytochrome P450

reductase. They also share an amino-terminal oxygenase domain containing a heme

prosthetic group, which is linked in the middle of the protein to a calmodulin-binding

domain. Binding of calmodulin appears to act as a "molecular switch" to enable electron flow

from flavin prosthetic groups in the reductase domain to heme. This facilitates the conversion

of O2 and L-arginine to NO and L-citrulline. The oxygenase domain of each NOS isoform

also contains an BH4 prosthetic group, which is required for the efficient generation of NO.

Unlike other enzymes where BH4 is used as a source of reducing equivalents and is recycled

by dihydrobiopterin reductase, BH4 activates heme-bound O2 by donating a single electron,

which is then recaptured to enable nitric oxide release.

The first nitric oxide synthase to be identified was found in neuronal tissue (NOS1 or

nNOS); the endothelial NOS (eNOS or NOS3) was the third to be identified. They were

originally classified as "constitutively expressed" and "Ca2+ sensitive" but it is now known

that they are present in many different cell types and that expression is regulated under

specific physiological conditions.


14/22

14

In NOS1 and NOS3, physiological concentrations of Ca2+ in cells regulate the binding

of calmodulin to the "latch domains", thereby initiating electron transfer from the flavins to

the heme moieties. In contrast, calmodulin remains tightly bound to the inducible and Ca2+-

insensitive isoform (iNOS or NOS2) even at a low intracellular Ca2+ activity, acting

essentially as a subunit of this isoform.

Nitric oxide may itself regulate NOS expression and activity. Specifically, NO has been

shown to play an important negative feedback regulatory role on NOS3, and therefore

vascular endothelial cell function. This process, known formally as S-nitrosation (and

referred to by many in the field as S-nitrosylation), has been shown to reversibly inhibit

NOS3 activity in vascular endothelial cells. This process may be important because it is

regulated by cellular redox conditions and may thereby provide a mechanism for the

association between "oxidative stress" and endothelial dysfunction. In addition to NOS3, both

NOS1 and NOS2 have been found to be S-nitrosated, but the evidence for dynamic regulation

of those NOS isoforms by this process is less complete. In addition, both NOS1 and NOS2

have been shown to form ferrous-nitrosyl complexes in their heme prosthetic groups that may

act partially to self-inactivate these enzymes under certain conditions. The rate-limiting step

for the production of nitric oxide may well be the availability of L-arginine in some cell

types. This may be particularly important after the induction of NOS2.

Picture 4 : Table of differentiation between iNOS, eNOS, and nNOS

Human NOS

isoform

Gene structure

and size

Chromosom

al location

Number of

amino acids

(aa) in

predominant

form,

protein size

location function


15/22

15

nNOS (NOS-

1)

29 exons, 28

introns,complex

structural

organization,

locus over region

of "200 kbp

12q24.2-

12q24.3 of

chromosome

12

1434 aa, 161

kDa

Nervous

tissue,

skeletal

muscle type

II

Cell

communicatio

n

iNOS (NOS-2) 26 exons, 25

introns, 37 kbp

17cenq11.2

of

chromosome

17

1153 aa, 131

kDa

Immune

system,

cardiovascu

lar system

immune defens

e against

pathogens

eNOS (NOS-

3) 1203 aa,

133 kDa

26 exons, 25

introns,

2122 kbp

7q357q36

of

chromosome

7

1203 aa, 133

kDa

endhotelium vasodilatation
http://en.wikipedia.org/wiki/Immunehttp://en.wikipedia.org/wiki/Immune


16/22


17/22

17

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.

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


18/22

18

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 reducing

RA inflammation, MTX may also reduce collateral damage such as atherosclerosis. (11)

Picture 5 : prevention of cardiovascular disease in rheumatoid arthritis patients

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


19/22

19

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)


20/22

20

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.


21/22

21

REFERENCES

1. Wolfe F, Mitchell DM, Sibley JT et al. The mortality of rheumatoid arthritis. ArthritisRheum 1994;37:48194.

2. Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJ. Rheumatoid arthritis andmacrovascular disease. Rheumatology 2003;42:2927.

3. Celermajer DS, Sorensen KE, Gooch VM et al. Non-invasive detection of endothelialdysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340:1111

5.

4. Khan F, Green FC, Forsyth JS, Greene SA, Morris AD, Belch JJ. Impairedmicrovascular function in normal children: effects of adiposity and poor glucose

handling. J Physiol 2003;551:70511.

5. Pepys MB, Hirschfield GM (June 2003). "C-reactive protein: a critical update".J.Clin. Invest.111(12): 180512

6. Rheumatoid arthritis. Available at http://www.medscape.org/viewarticle/745566 .accessed on 4 december 2012.

7. Reumatoid Artritis Sign and Symptoms. Available at :http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/ .

Accesed on 4 december 2012.

8. All About Rheumatoid Arthritis. Available at :http://www.medicalnewstoday.com/info/rheumatoid-arthritis/rheumatoid-arthritis-

diagnosis.php . Accesed on 4 december 2012
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161431/http://www.medscape.org/viewarticle/745566http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/http://www.medicalnewstoday.com/info/rheumatoid-arthritis/rheumatoid-arthritis-diagnosis.phphttp://www.medicalnewstoday.com/info/rheumatoid-arthritis/rheumatoid-arthritis-diagnosis.phphttp://www.medicalnewstoday.com/info/rheumatoid-arthritis/rheumatoid-arthritis-diagnosis.phphttp://www.medicalnewstoday.com/info/rheumatoid-arthritis/rheumatoid-arthritis-diagnosis.phphttp://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/http://www.medscape.org/viewarticle/745566http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161431/


22/22

22

9. Vaudo G, Marchesi S, Gerli R et al. Endothelial dysfunction in young patients withrheumatoid arthritis and low disease activity. Ann Rheum Dis 2004;63:315.

10.Dessein PH, Joffe BI, Singh S. Biomarkers of endothelial dysfunction, cardiovascularrisk factors and atherosclerosis in rheumatoid arthritis. Arthritis Res Ther

2005;7:R63443.

11.Boots JM, Christiaans MH, van Hoof JP. 2004. Effects of immunosupresive agents onlong term survival of renal transplant recipients; focus on the cardiovascular risk.

Drugs, 64; 204773

12.Ridker PM, Cannon CP, Morrow D, et al. 2005. C Reactive Protein levels andoutcomes after statin therapy. N Eng J Med, 352: 20-8

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: 174550

17. Chinje EC, Stratford IJ (1997). "Role of nitric oxide in growth of solid tumours: abalancing act".Essays Biochem.32: 6172.

inggris 3 denata baru.docx

Documents