ETHIOPATHOGENESIS AND INVESTIGATIONAL TOOLS: A … II/IJPSR... · patients worldwide. Complementary and alternative therapies are available for treatment for arthritis. The therapy

International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619

IJPSR/Vol. II/ Issue II/April-June, 2011

Review Article

ETHIOPATHOGENESIS AND INVESTIGATIONAL TOOLS:

A SHADOW OF RHEUMATOID ARTHRITIS Sumeet Gupta *, Satish Kumar, Aditya

Address for Correspondence Department of Pharmacology, M. M. College of Pharmacy, M. M. University, Mullana, (Ambala)

Haryana, India

ABSTRACT

Early inflammatory arthritis can be self limiting disease, develop into rheumatoid arthritis or differentiate into another form

of chronic arthritis. The current treatment of rheumatoid arthritis is based on the use of synthetic chemical compounds and

natural plants which is having different mechanism of action known or less unknown. Many studies indicate soon after or

during infection elsewhere in body play important role behind it. Due to advances in basic sciences and medicine, the

pathogenetic effective in rheumatoid arthritis are better know today than ever before. This review article is summarized with

pathophysiology and their treatments with latest technology, Genomic Association Studies which help to find out the cause

of rheumatoid arthritis in less time.

KEY WORDS: Rheumatic Arthritis, Mediators, treatments, Genomic Association Study.

INTRODUCTION

Traditional Pain is very common worldwide in

every part of human system. According to the

International Association for the study of pain, pain

is described as “un pleasant sensory and emotional

experience associated with actual or potential tissue

damage (Sowerbutts et al., 2009). Pain is surely the

most common reason people seek medical attention

and this is particularly evident in the field of

rheumatology. The first known clues of arthritis

date as far back as 4500 BC. In 1859 the diseases

got its current name called rheumatoid arthritis.

Pain is the first symptom in the majority of

rheumatic disorders (Montecucco et al., 2009).

Rheumatoid arthritis has 19th

century roots and a

20th

century pedigree. Classification criteria were

only developed 50 years ago (Scott et al., 2010). It

is a disease of joints causes the pain, swelling,

inflammation and deformities. The term “arthritis”

covers more than 100 diseases and conditions

affecting joints, the surrounding tissues, and other

connective tissues (Newell et al., 2005). The

cartilage between two the bones damages due to

which both bones rub on each other and causes the

pain and inflammation. The bones of joints are

enclosed in capsule containing fluid which

provides lubrication to joints different bones are

separated by cartilage in arthritis this cartilage can

be damaged. It is a synovial related disease. Two

type of pain present in arthritis being acute and

chronic related to different causes. Crystal induced

arthritis and osteoporotic fractures are the typical

examples of acute pain and rheumatoid arthritis and

other inflammatory arthritis include osteoarthritis,

rheumatoid arthritis, systemic lupus erythematosus,

juvenile rheumatoid arthritis, gout, bursitis,

rheumatic fever, Lyme arthritis, carpal tunnel

disease and other disorders (Arthritis Foundation.,

1999) are the examples of chronic pain. Pains in

rheumatic arthritis are very serious problem in the

patients worldwide. Complementary and alternative

therapies are available for treatment for arthritis.

The therapy of rheumatoid arthritis has been

revolutionized by advances in the understanding of

disease at a cellular and molecular level

accompanied by the technology to target specific

mediators of disease. With this paper we would like

to focus on the detail study of rheumatic arthritis

which will help for the research graduates for

understanding the latest lacunae about this topic.

Three major types of arthritis in human pathogenesis

Rheumatoid

arthritis

Osteoarthritis Gout

It is auto-immune disorder in which

human immune

system attaches on their own body

andsome alteration

causes the joint pain.

It is condition of wear and tear of

cartilage or joints

bones rub on each other after

cartilage damage.

It is degenerative joint disease, pain

is due to creaking.

Burning sensation in muscles and

tendons

(McAlindon et al., 2007). Due to

Heavy exercise.

May be due the genetic factors.

It is condition of accumulation

of uric acid

crystal and causes the joint hot,

redness, pain and

swelling. It is also called metabolic

arthritis. About

12% of gout patient are

affected due to

the diets (Schumacher et

al., 2008) taken

e.g. - due to alcohol, meat and

sugar etc..

Rheumatic arthritis

Rheumatic arthritis (RA) is chronic and progressive

inflammatory disorder. It is chronic poly arthritis

with unknown and multifactorial etiology and

autoimmune condition that causes synovial cell

proliferation, fibrosis, pannus alteration and

cartilage and bone erosion leads to pain, stiffness,

and swelling of joints which cause the loss of

function of joint (American College., 1996). The

main symptom of rheumatoid arthritis is

inflammation of the synovial membrane (Synovitis)

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with pain, heat, swelling, redness and loss of

function. If left untreated, synovial fluid will

increase, leading to raised pressure in the joint,

creating pain and tenderness.

Most affected area is wrist about 75% of RA

patients showed wrist symptoms (Sung-Jae Kim et

al., 2007, Flatt et al., 1995). This process is

regulated by a network of cytokines, prostanoids

and proteolytic enzymes which depends upon each

other .Pro-inflammatory cytokines such as

interleukin-1 (IL-1)( Lubbertset et al., 2005) and

tumor necrosis factor-alpha (TNF-α) are central

mediators in RA. The concentration of

chromogranin A (CgA) and TNF-α are correlated

with each other (Comite et al., 2006). Also due to

genetic factors (Jorg et al., 2009) but with

involvement of environmental factors (Turesson et

al., 2006). Mainly two type of receptor are involved

Toll-like receptors (TLRs) and NOD-like receptors

(NLRs) (William et al., 2009, Neil et al., 2008).

Disease related to synovial which causes the

cartilage damage (Fedewa et al., 1998, Andreas et

al., 2008). In RA the immune system attacks the

tissues. RA can affect other organs also like lungs,

heart and blood vessels (Gaffo et al., 2006). RA

may damage bone and cartilage within the joints,

weaken muscles And tendons that support the

joints and which ultimately lead to joint destruction

(Heijde et al., 1995).RA begins in middle age and

occurs more frequently in women than in men. It

can affect any joint in the body, but it most often

affects the wrist and fingers. It is mostly occurs

alternatively in body for example if one hand is

affected other will be affected. Culture of RA

produces IL-17 it is 17 kDa proteins (Lubberts et

al., 2005). In RA loss of regulation of T cell growth

and activation. Patient having RA have the more

risk of myocardial infarction (Giles et al., 2005,

Gonzalez et al., 2005). The disease modifying anti-

rheumatic drug’s (DMARD) therapy is used for RA

(Machold et al., 2006). A new treatment

Immunoablative therapy and hematopoietic stem

cell transplantation (HSCT) (Hügle1 et al., 2008).

Complementary and alternative medicine (CAM)

therapies.

Diagnosis Criteria

Early classifications were designed to distinguish

established rheumatoid arthritis from other types of

established joint diseases. The American College of

Rheumatology (ACR) 1987 criteria is limited by

poor sensitivity and specificity for classification of

patients with early inflammatory arthritis as having

rheumatoid arthritis. New criteria has been

developed (2007) under ACR called Early arthritis

prediction. In the presence of inflammatory

arthritis, evidence of systematic inflammation-

shown by high acute phase reactants and prolonged

morning stiffness and auto antibodies in serum

based on this, the ACR and European League

Against Rheumatism (EULAR) have devised new

classification criteria for early arthritis as shown in

table 1 (Scott et al., 2010).

Table 1: Classification criteria of Rheumatic Arthritis according to symptoms

The American College of

Rheumatology 1987 revised

criteria for rheumatoid arthritis

(Arnett et al., 1988).

Arthritic prediction 2007 American college of rheumatology 2010 criteria

(Aletaha et al., 2010).

1. Morning stiffness of at least 1

hour before maximal improvement

2. Arthritis of three joint areas or more

3. Arthritis of hand joints

4. Symmetric arthritis 5. Rheumatoid nodules

6.Rheumatoid factor positivity

7. Radiographic changes on hand and wrist radiographs (erosions or

decalcification)

1. Age(multiply by 0.02)

2. Sex(female1)

3.Distribution of involved joints

• Small joint hand and feet (0.5)

• Symmetrical (0.5)

• Upper limbs (1) or upper and

lower limbs (1.5) 4. Morning stiffness (visual analogue

scale)

• 26-90 mm(1)

• >90 mm(2) 5. Number of tender joints

• Four to ten(o.5)

• 11 or more(1) 6. Number of swollen joints

• Four to ten(0.5)

• 11 or more(1)

7. C-reactive protein (mg/l)

• Five to 50(0.5)

• 51 or more(1.5) 8. RF positive (1)

9. ACPA positive(2)

1. Joint involved (0-5)

• One medium-to-large joint(0)

• Two to ten medium to large joints(1)

• Four to ten small joints (large joints not counted)(3)

• More than ten joint(at least one small joint)(5) 2. Serology(0-3)

• Negative RF and negative Anti-citrullinated protein/peptide antibodies (ACPA)(0)

• Low positive RF or low positive ACPA(2)

• High positive RF or high positive ACPA(3) 3. Acute –phase reaction(0-1)

• Normal C-reactive protein (CRP) and normal ESR(0)

• Abnormal CRP or abnormal Erythrocyte sedimentation rate (ESR)(1)

4. Duration of symptoms(0-1)

• Less than 6 week(0)

• 6 week or more(1)

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Epidemiology

RA prevalence ranges from 0.33% to 1% in

different countries (Marco et al., 1998, Christian et

al., 2009). Its incidence is worldwide

inhomogeneous, varying among 20 and 50 cases

per 100,000 inhabitants in North American and

Northern European countries. About 42 million

Americans have some form of arthritis. It can affect

people of all ages and races. People the prevalence

of RA are estimated to be 0.5-1.0% worldwide

(Lundkvist et al., 2009). It was estimated 27% of

the population of USA suffers from physician

diagnosed arthritis and India is one of the country

which has been reported sharp increase in the

number of elderly persons between 1992 and 2001.

The diseases are three times more frequent in

women than men. Suggesting hormonal factors

have a pathogenic role (Scott et al., 2010).

In the US, the RA affects 2.5 times more in women

compared to men. In 2050, the number of elderly

persons would rise to about 324 million and 7.7%

population related to more than 60 years. Various

epidemiological studies in India have shown that

musculoskeletal problems are out-numbered. Over

two thirds of people with arthritis are younger than

65 years of age (CDC Targeting Arthritis, 2005).

Throughout the world, ethnic groups like North

America Pima Indians and southeast Alaskan

Indians have much higher incidence of RA.

Causes of arthritis

Mainly it depends upon two type factors Genetic

Factors and Environmental Factors but other

factors are also involved in it.

Genetic Factors

The results of several studies have shown a higher

disease concordance among monozygotic twins

(12-15%) than dizygotic twins (4%), implying the

influence of genetic factors. The data from the past

few years have indicated that the HLA DRB1

alleles shared epitope and PTPN22 risk alleles are

associated only with a subset of rheumatoid

arthritis by presence of ACPA or rheumatoid factor

or both (Kochi et al., 2009). Finding of the studies

shown that the MHC region harbors the most

important genetic risk factors for the ACPA

positive disease with PTPN22 as the second most

important gene. Several additional risk alleles for

the disease have been identified in gene region

containing TNF-associated signalling pathway

(TRAF1), signal transducer and activation of

transcription factor-4 (STAT4) and OLIG3-AIP3

genes. Many genetic study shows that there are

very much similarities in two or more arthritic

patient in their genetic structure which shows that

genetic factor are involved in arthritis. HLA-DRB1

is a special type of allele subtypes (Stastny et al.,

1976, Gibofsky et al., 1978) are found in most

Yakima and Pima Indians, who have the highest,

reported prevalence of RA in the world. The

different alleles showed the association study in

arthritis (Table 2.)

Table 2: Arthritis susceptible alleles and their

mechanism and their genes

Disease

susceptibility

alleles

Gene product Suggested

mechanism

HLA-DRB1–

shared

epitope alleles

HLA-DRβ chain T-cell selection

and maturation

TNFSR11A RANK (receptor

activator of nuclear

factor)

Osteoclast

differentiation

CRHA2 CRH (corticotropin-

releasing hormone)

Defective HPA

response to

inflammation Slc2F2T

SCL22A4 organic

action transporter

Regulates

lymphocyte activation in

secondary

lymphoid organs and/or

contributes to

local inflammation

Runx1 RUNX1 (Runt-related

transcription factor)

Regulates

expression of SCL22A4

Environmental factors

There are various environmental factors (Figure 2)

due to which arthritis takes place. Like life style

factors e.g. smoking, diet (Deborah et al., 2001),

RA in smokers causes more problems than non-

smokers problems may be like nodules (Masdottir

et al., 2000), Harrison et al., 2001. Smoking is

associated with RF and ACPA production. In

addition, smoking multiplies the adverse effect of

the HLA-DRB1 shared-epitope alleles. Several

causes the infections microorganisms also initiate

the intermediate related to RA. Diet fish oil, olive

oil has the protective action in RA. Omega 3 fatty

acids contents are also protective action in RA. The

best environmental factors associated with arthritis

is smoking seems to be positive relation with HLA-

DRB1 shared-epitope alleles other factors include

fish oil, saw dust and silica gel.

Other factors

Age and sex are also important factor to identify

the cause and prevalence of arthritis. The RA ratio

was reported on age basis in female and male was

3:1 (Tobón et al., 2010). With increasing age the

chances of arthritis increases (Eberhardt et al.,

1990, Pease et al., 1999). Most sensitive age for

arthritis is 20-30 but its symptoms appear mostly

after 35 or 40. Sex hormones are the other factor in

the immune response, with estrogens as enhancers

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at least of the humoral immunity and androgens

and progesterone as natural immune-suppressors In

female’s, estrogen stimulate the immune system

and in males, low level of testosterone was

observed (Barrett et al., 1999), bacteria, virus,

Epstein-Barr virus, parvovirus B-19, rubella and

retrovirus may infect an individual with the

appropriate genetic background through some

mechanism, the inflammatory response becomes

focused on self antigens.

Pathophysiology

Rheumatoid arthritis is called a complex genetic

disease, meaning that several genes, environmental

factors, and stochastic factors act in concert to

cause pathological events. Findings of twin studies

have estimated the relative contribution of genetic

factors to be about 50% for the entire syndrome of

rheumatoid arthritis, leaving the remaining part to

environment and chance (Scott et al., 2010). The

role of the mediators of inflammation, cytokines,

growth factors, chemokines, adhesion molecules

and matrix metalloproteinase has not been clearly

defined in the pathogenesis of RA. These

substances appear to be involved in attracting,

proliferation and phenotypic transformation of

synoviocytes into pannus. Pannus behaves similar

to a locally invasive tumor by invading and eroding

articular cartilage, subchondral bone, tendons and

ligaments.

1. Inflammation through receptor

2. Inflammation through intermediates mediators

Inflammation through receptors

Some of receptors called Pattern recognition

receptors (PRRs) implicated in various

inflammatory arthropathies which leads to

activation of cytokines (figure 1). These receptor

also sense microbes (William et al., 2009).

Microbial molecules are found in joint of RA

patient which activates inflammatory reactions

(Heijden et al., 2000).

1. Toll-like Receptors (TLRs)

2. NOD-like Receptors (NLRs)

Toll-like receptor

There are ten TLRs are known in human but the

function of nine is known (TLR1 toTLR9). e.g.

TLR2 senses lipopeptides from bacteria. TLRs10 is

not determined (Neill et al., 2008). The signaling

pathway of TLR’s involves adapter proteins

Myeloid differentiation primary response gene

(88)(MyD88), Nuclear factor-kB (NFkB) which

makes some nucleic acid change leads to release of

pro-inflammatory cytokines (Kenny et al.

2008).TLRs antagonist having a very improving

effect in RA disease its study had been conducted

on Rats (Joosten et al., 2007).

Figure 2: Picture of factors affecting arthritis (Klareskog et al., 2009)

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Figure 1: Receptors theory involved in pathophysiology of rheumatoid arthritis

NOD-like receptors

These are intracellular receptors. This family

consists of 22 cytoplasmic proteins

including the Nucleotide-binding oligomerization

domain-containing protein (NOD) or NALP. One

nucleotide binding domain and other is leucine rich

C-terminus (William et al., 2009). Using NOD1

and NOD2 knockout mice, Joosten and colleagues

have shown a pro-inflammatory role for NOD2 and

an anti-inflammatory role for NOD1 in a

streptococcal cell wall induced model of arthritis

(William et al., 2009).

Inflammation through intermediates mediators

• Cluster of differentiation (CD4+CD25+T) cells

In human glycoprotein CD4+CD25+ Tregs increases

in peripheral circulation in RA. The CD4+CD25+

T cells might function as potential regulators of

immune responses in RA (Wahl et al., 2005).

CD4+CD25- T cell prevent experimental induced

RA (McHugh et al., 2002, Mottetet al., 2003). First

one is that the CD4 + CD25+ T cell expresses

chemokine receptor in RA. CXCR4, CCR4 are

highly expressed in synovial. CD4 T cells are also

in healthy human but the active retention in RA.

Second is the accumulation of CD4+CD25+ T cells

in synovial related to IL-2 because the synovial

fluid contains high levels of inflammatory

cytokines. Third is that inhibition of T-cell to

undergo apoptosis due to which the T-cell in

synovial increases. Function of CD4+CD25+Tcells

in synovial:- Synovial CD4+CD25+ T cells display

an even increased suppressive capacity compared

with blood CD4+CD25+ T cells in RA.

• Interleukin-17 (IL-17)

It is 17 kDa protein cell cytokine spontaneously

produced by cultures of rheumatoid arthritis (RA)

synovial membranes. IL-17 is a pro-inflammatory

cytokine produced only by cells of the immune

system (Chen et al., 2000, Shi et al., 2000), which

is consider as activator in RA. The concentration of

IL-17 is more in RA than osteoarthritis

(Ziolkowska et al., 2000, Chabaud et al., 1999). It

is a stimulator of osteoclastogenesis which promote

the collagen degradation in synovial. This

ultimately causes the bone destruction (Lubberts et

al., 2001).

• Tumor necrosis factor-α (TNF-α)

TNF has an important role in pathology of RA.

Some evidence shows that RA is a systemic

disease. CgA is correlated with the TNF-α during

disease the concentration of CgA is higher in blood

more than the synovial (Capellino et al., 2008).

TNF-α is used as a target for the treatment RA by

using its antagonist (Maini et al., 2000, Taylor et

al., 2001).

• Chemokines

Chemokines are small chemo attractant proteins

that have a prominent role in leukocyte recruitment

and activation in sites of inflammation. They are

ligands for G-protein-coupled receptors on the

surface of leucocytes. The distribution of

chemokine and receptor expression is variable,

which means that specific leukocyte subsets can be

recruited. Numerous chemokines are thought to be

active in the synovium of patients with rheumatoid

arthritis, but their function with regard to leukocyte

subset recruitment and activation is unknown.

• Matrix metalloproteinase

Metalloproteinase are produced at high levels by

type B synoviocytes in rheumatoid arthritis.

Metalloproteinases are a family of enzymes

required for remodeling and destruction of

extracellular matrix. The activity of the matrix

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metalloproteinases is regulated by molecules such

as tissue inhibitors of metalloproteinases (TIMPs),

serine proteinase inhibitors (SERPINS) and

macroglobulin. In rheumatoid arthritis, high levels

of metalloproteinase activity are thought to

contribute to cartilage and bone degradation

(McCachren et al., 1990, Gravallese et al., 1991).

• Adhesion molecules

Adhesion molecules are thought to have a role in

recruitment of inflammatory cells to the joints in

rheumatoid arthritis. The presence of adhesion

molecules, which confer cells with the ability to

adhere to each other and the extracellular matrix, is

the central to various biological processes

including homoeostasis, vascular and epithelial

integrity, immune responses, and organogenesis.

Analysis of rheumatoid arthritis synovial tissue

indicates that many families of adhesion molecules

are expressed in patterns appropriate for

modulating cell retention in the rheumatoid arthritis

synovium (Hale et al., 1989, Johnson et al., 1993).

• Angiogenesis

Angiogenesis—the process of new blood-vessel

formation—is highly active in rheumatoid arthritis,

particularly early onset disease (FitzGerald et al.,

1991). The newly formed vessels provide oxygen

and nutrients to the hypertrophic synovium, and

provide the means for recruitment of inflammatory

cells to the joint anatomical compartment.

Generally, angiogenesis is tightly regulated by

many inducers and inhibitors. In the basal state,

vascular endothelium is quiescent and fewer than

0·01% of endothelial cells divide (Koch et al.,

1998). In physiological processes such as wound

repair or the female reproductive cycle, and

pathological processes such as tumor growth and

rheumatoid arthritis, this quiescent tissue can be

rapidly stimulated to proliferate. A growing list of

angiogenic factors including cytokines, growth

factors, colony stimulating factors, and soluble

adhesion molecules has been described in the

synovium and synovial fluid of patients with

rheumatoid arthritis (Koch et al., 1998).

NEW INTERMEDIATES INVOLVED IN

ARTHRITIS

• Sphingosine-1-Phosphate (S1P)

Sphingosine-1-phosphate (S1P) is a signaling

sphingolipid and a bioactive lipid mediator. It is

well recognized as a regulator of angiogenesis,

vascular homeostasis and permeability (Alvarez et

al., 2007), the most recent evidence indicated that

S1P was a critical regulator of T-cell and B-cell

trafficking (Melendez et al., 2008) and macrophage

function (Weigert et al., 2009). Thus, the binding

of S1P to its receptors, S1PR1/S1PR2 , triggers and

is required for stimulating the movement of

immune cells from the thymus and lymph nodes

into lymphatic vessels from where they can travel

through peripheral circulation to synovial joints.

Additionally, it was shown that the secreted form

of S1P also regulated cell survival and apoptosis by

its capacity to bind to and activate 5 specific G

protein-coupled receptors, S1P1-S1P15 (Hait et al.,

2006).

• IL-7 Receptor

Expression of the IL-7 receptor (IL-7R) gene (also

known as CD127) plays a central role in thymocyte

development (Saini et al.,2009), T-cell survival, B-

cell maturation, T-cell-dendritic cell (DC)

interactions (Vogt et al., 2009) as an inducer of

lymphoid tissue development (Schmutz et al.,

2009) as well as being useful for identifying

Tregulatory (Treg) cells producing the FoxP3

phenotype (Banham et al., 2006). To function

normally, the IL-7R requires the presence of the

IL-2 receptor gamma chain (IL-2Rγ) which is the

common γ-chain that is shared by the receptors of

various cytokines including IL-2, -4, -7-, -9, -15

and -21. IL-7R was also found to important in

regulating the accessibility of the T-cell receptor

(TCR) γ locus (TCR-γ) by STAT5 and histone

acetylase (Malemud et al., 2008). Thus, over

expression of IL-7Rα is likely to be highly relevant

to the pathogenesis and even to the progression of

inflammatory arthritis.

• Spleen Tyrosine Kinase

Spleen tyrosine kinase (SyK) and ζ-chain

associated protein-70 (ZAP-70) are non-receptor

kinases that are primarily expressed in hemopoietic

cells, including cells of the spleen, mast cells,

neutrophils and macrophages. Syk and ZAP-70 are

also involved in T-cell and B-cell receptor

signaling potentially making Syk and ZAP-70

enzyme targets for the treatment of autoimmune

diseases (Wong et al., 2004). The reduced

expression of SyK in the R788-treated mice

correlated with an amelioration of clinical arthritis,

a reduction in pro-inflammatory chemokines and

cytokines, including the CXCR2 ligand KC-GRO-

α, macrophage chemo attractant protein-1 (MCP-

1), IL-1, and IL-6, as well as inducing suppression

of cartilage oligomeric matrix protein release, the

latter protein a sensitive in vitro biomarker for

articular cartilage extracellular matrix degradation.

• MEK/ERK 1/2

ERK 1/2 belongs to the SAP/MAPK family of

protein kinases. This must be activated before it

can act as a fully activated protein kinase and the

activation of an MAPK such as ERK 1/2 is

generally carried out by one of at least 7 upstream

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MKK proteins (Malemud et al., 2004). Moreover,

MKK activity is also regulated by further upstream

MKKK and MKKKK activity that are either

tyrosine or serine-binding proteins which may also

require low molecular weight GTP-binding

proteins for MKKK activation. MEK is the key

regulatory protein kinase activation in the

Ras/Raf/MEK/ERK pathway. In that regard, MEK

is critical for the up regulation of several pro-

inflammatory cytokines, including, TNF-α, IL-1β

and IL-6. (Breitkreutz et al., 2007).

• Mitogen-Activated Protein Kinase 5/p38

Kinase Regulated/Activated Protein Kinase

Mitogen-activated protein kinase 5 (MK5) also

known as p38 kinase regulated/activated protein

kinase (PRAK) is a 471 amino acid protein with a

20%-30% sequence identity to the cyclic AMP

responsive element binding protein, CREB-

phosphorylating MAPK-regulated protein kinase

RSK-1, -2 and -3 (New et al., 1998). MK5/PRAK

was found to be expressed in most human tissues

and activated by cell stressors and pro-

inflammatory cytokines in vitro. In turn, PRAK

activity was regulated by p38α and p38β activity.

Once activated, MK5/PRAK was reported to

directly phosphorylate heat shock protein 27

(Hsp27), the latter having been implicated in

several physiologically relevant immune-mediated

inflammatory responses such as CD8+ lymphocyte

subset expansion and apoptosis resistance as well

as in the activation of the Toll-like receptor-4 in

monocytes-derived RA DCs (Roelofs et al., 2006).

• Micro RNAs

Micro- RNAs (miRs) are small non-coding RNA

molecules composed of double-stranded RNAs of

21–25 nucleotides derived from endogenously

expressed transcripts with characteristic hairpin

structures. miRs are known to negatively regulate

gene expression at the posttranscriptional level.

• Inhibition of Proteasome Activity

Proteasomes are large protein complexes that

reside in both the nucleus and cytoplasm of

eukaryotic cells (Peters et al., 1994). A principal

function of the 26S-proteasome is to regulate the

concentration of completed proteins within a cell as

well as to participate in the controlled degradation

of mis-folded proteins that is independent of

enzyme activity within lysosomes. The figure 3

shows the different mediators involved in arthritis.

Various techniques for diagnosis of arthritis

• Rheumatoid factor

It is the mainly used laboratory method used for the

determination. The rheumatoid factors (RF) are

antibodies directed against the fragment

crystallizable region (Fc) portion of the

Immunoglobulin G (IgG) immunoglobulin’s and

are found in 75–80% of patients affected by RA

(Tampoia et al., 2005). For which the result has

been positive in < 5% of normal control subjects. It

is detected by enzyme-linked immunosorbent

assays (ELISAs) for quantitative detection of RF

isotypes IgG, IgA and IgM (Visser et al., 2002).

IgM RF discriminates well between RA and non-

RA conditions (Wolfe et al., 1991).

• The filagrin–citrulline protein system

First Nienhuis and Mandema described the anti-

perinuclear factor (APF) discovered by Nienhuis

and Mandema (Nienhuis et al., 1964). This test is

very less use in laboratories although, it is specific

for RA. APF are reported to be present in 40–90%

of patients with established RA. Determination of

protein (pro) filaggrin in buccal mucosa cells by

means of the indirect immunofluorescence test

(IIF). It is confirmed and extended by the

biochemical characterization of (pro) filaggrin as

the antigen in both the APF test and the related so-

called anti-keratin antibody (AKA) test. The

APF/AKA antibodies are therefore, more correctly

referred to as ‘anti-filaggrin’ antibodies (Sebbag et

al., 1995, Schellekens et al., 1998).

Figure 3:- Pathophysiology of Arthritis

involving various mediators

• Conventional X-rays

It is imaging technique used for the diagnosis of

RA. It shows the deformities in joints on a X-ray

(figure 4).

Figure 4: Deformities of joints after arthritis

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Early erosion in foot or hand can be detected by

conventional X-ray method. In the Leiden early

arthritis clinic, 15% of the 524 early arthritis

patients had erosions on X-rays of hands or feet at

the first visit (Visser et al., 2005

• Ultrasound and magnetic resonance imaging

It is more effective than the conventional X-rays

method detect more erosion (Ostergaard et al.,

2003). It less used due to its high cost and more

examination time. Another disadvantage of

ultrasound is dependency on skills of operator. It is

more sensitive tool of assessing inflammation than

physical examination (Tampoia et al., 2005).

• Detection of Presence of autoantibody

A) Anti-SA antibodies (Despres et al., 1994).

B) Anti-RA33 antibodies (Hassfeld et al., 1993).

C) Anti-p68 nucloeporin 68 (BiP) antibodies (Blass

et al., 2001).

D) Autoantibody profiling: proteomics (Tampoia et

al., 2005).

• Erythrocyte sedimentation rate

Erythrocyte sedimentation rate (ESR)

determination is one of the method tells about the

settlement of red blood cells rate in ESR tube

which is used for the Arthritis (Green et al., 2002).

• Cytokine determination

One more method to assess the arthritis is the

determination of the pro-inflammatory cytokines.

Several cytokines which function as immunological

mediators of inflammation may also cause joint

destruction in rheumatoid arthritis (RA).

Interleukin 1 stimulates the secretion of

prostaglandin E2, platelet derived growth factor,

and collagenase by fibroblasts and chondrocytes,

and the proliferation of fibroblasts and their

production of fibronectin, type I collagen, and

proteoglycans (Kahle et al., 1992).

A new way investigation through

pharmacogenomics study

Genome wide association studies are the most

comprehensive and straight forward approach to

teasing out the identity of genetic polymorphisms

associated with any given disease or characteristic.

The capacity to detect very small differences

between disease and control populations and the

reporting of such associations clearly demonstrates

that the low-hanging fruit of genetic disease

associations has been picked and we are now

harvesting the fruit from the top of the tree. (HLA)-

DR4 gene is less specific for RA encodes a special

sequence of amino acid called shared epitope (SE)

of the human leukocyte antigen (Kim et al., 2000).

DQ alleles, another HLA class II region, were also

found to predispose to RA. The RA-predisposing

alleles DQ3 and DQ5 are referred to as DQRA.

DR/DQ model is used for the determination DQ

allele are highly specificity (Wagner et al., 2003).

Prevention before treatment

• By changing life style.

• By taking healthy diet.

• By doing weight losing exercise (Khurana

et al., 2005).

• By Stop smoking for those who smoke

(Daniel et al., 2008).

Previously known SNPs associated with rheumatoid arthritis risk in Europeans (Stahl et al., 2010)

SNP

Locus ID Gene(s) Minor allele

1p36 rs3890745* TNFRSF14 C

1p13 rs2476601 PTPN22 A

1p13 rs11586238 CD2, CD58 G 1q23 rs12746613* FCGR2A T

1q31 rs10919563* PTPRC A

2p16 rs13031237 REL T 2q11 rs10865035* AFF3 A

2q32 rs7574865 STAT4 T 2q33 rs1980422 CD28 C

2q33 rs3087243 CTLA4 A

4q27 rs6822844 IL2, IL21 T 6p21 rs6910071 HLA-DRB1 (*0401 tag) G

6q21 rs548234 PRDM1 C

6q23 rs10499194 TNFAIP3 T 6q23 rs6920220 TNFAIP3 A

6q23 rs5029937 TNFAIP3 T

6q25 rs394581* TAGAP C 8p23 rs2736340 BLK T

9p13 rs2812378* CCL21 G

9q33 rs3761847 TRAF1, C5 G 10p15 rs2104286 IL2RA C

10p15 rs4750316 PRKCQ C

11p12 rs540386* TRAF6 T 12q13 rs1678542* KIF5A, PIP4K2C G

20q13 rs4810485 CD40 T

22q12 rs3218253* IL2RB A

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Duration of anti arthritis Treatment

The total duration of treatment normally 3-12

months this includes prescribed by different

combination of anti arthritis drugs as shown in

figure 4

Figure 4: Duration of anti-arthtits treatment

Figure 5: Picture shown in types of drugs acts on different sites

Established treatments

The key aim of treatment for established

rheumatoid arthritis is minimization of disease

activity. There are different drugs which act on

various receptors and mediators to treat

inflammation as figure 5.

Another alternative treatment

Immunoablative therapy and hematopoietic

stem cell transplantation (HSCT)

Hematopoietic stem cells (HSCs) are progenitor

cells of platelets, erythrocytes, granulocytes, B and

T lymphocytes, monocytes, tissue macrophages.

Various animal studies show that these cells play

an important role in RA. European Group for

Blood and Marrow Transplantation/European

League against Rheumatism (EBMT/EULAR)

working on RA collects the data on 1000 patient

which were treated with (HSCT). In this therapy

the aggressive immune modulating cells are

replaced by non aggressive cells. An effective

transfer prevents the symptoms and cures the RA

(Tyndall et al., 2002).

Gene Therapy

The first human gene transfer is held in 1989.

Rheumatoid arthritis (RA) had become an early

target for gene therapy in the early 1990s and

beginning clinical trials in 1996. The first

International Meeting on the Gene Therapy of

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Arthritis and Related Disorders (GTARD) was held

at the National Institutes of Health (NIH)

(Bethesda, MD, USA) in 1998. In this therapy the

gene is transferred in target cell by the help of any

viral and non viral vectors (Evans et al., 2009).

Oncoretroviruses, such as the moloney murine

leukemia virus was first used vector for RA gene

transfer, other vectors used are Adenovirus vectors.

Complementary and alternative Medicines

(CAM)

In India 33% patient are found to be used CAM

therapies [71]. CAM therapies are safer and more

natural. These may be botanical, dietary (Berman et

al., 2004) and other mineral preparations.But these

treatments are without preclinical studies hence

less faith on these drugs. e.g.:- Fish oil, Valerian,

Ginger, Curcumin, Boswellia etc.

Nutraceutical used as therapeutic agents in

Arthritis

It is interesting to see the increasing use of

nutraceutical in the treatment of various diseases

because of their presumed safety and potential

nutritional and therapeutic effects. Some time it

also called functional food. Functional food

provides the body with the required amount of

vitamins, fats, proteins, carbohydrates necessary

for healthy survival but when it is given for the

treatment of any disease or prevention of any

disease it called as Nutraceutical (Rajasekaran et

al., 2008).

Omega-3 and Omega-6

The important role in treating the Arthritis by

generating potent modulatory molecules for

inflammatory responses, including eicosanoids

(prostaglandins, and leukotrienes), and cytokines

(interleukins) and affecting the gene expression of

various bioactive molecules. Gamma linolenic acid

(GLA, all cis 6, 9, 12-Octadecatrienoic acid, C18:3,

n-6), is produced in the body from linoleic acid (all

cis 6, 9-octadecadienoic acid), an essential fatty

acid of omega-6 series by the enzyme delta-6-

desaturase. Preformed GLA is present in trace

amounts in green leafy vegetables, nuts, vegetable

oils, such as evening primrose (Oenothera biennis)

oil, blackcurrant seed oil, borage oil and hemp seed

oil, and from spirulina, cyanobacteria. It is a

nutraceutical used for treating problems with

inflammation and auto-immune diseases (James et

al., 2003).

Glucosamine

This naturally occurring substance, found in high

concentrations in joint structures, is a rate-limiting

step in glycosaminoglycan (GAG) synthesis and

joint cartilage repair. Thus, when given as a

supplement it is said to stimulate the manufacture

of cartilage components and the incorporation of

sulphur into cartilage, thereby producing the

substances necessary for proper joint function and

for stimulating joint repair (as far as this is

possible); This therefore addresses the cause rather

than suppressing symptoms (Ritchie et al., 2005).

Chondroitin sulphate

These are long chain polymers, which are the major

GAGs found in cartilage. Oral administration of

this as a supplement has been found to have similar

results to Glucosamine. It is said to be an effective

and direct inhibitor of degradative enzyme activity

and long term trials have shown supplementation to

slow the progression of Osteoarthritis, to improve

joint mobility, reduce pain and radiographic

evidence of reversal has been seen. This is often

given in combination with Glucosamine (Ritchie et

al., 2005).

MSM (Methylsulfonylmethane)

MSM is a source of organic sulfur found naturally

in the human body and in many foods. Sulfur is

well known in maintaining the connective tissue.

MSM provides additional elemental sulfur to aid

the body in the repair process of these tissues.

MSM may support the body in regulating insulin

production, improving skin smoothness and

elasticity, regulating environmental and allergic

sensitivities. Lastly sulfur is a key element

necessary in the detoxification processes which is

highly valuable in many patients with arthritis

(Usha et al., 2004).

Bromelain

Bromelain is a proteolytic enzyme complex derived

from the stalk of the pineapple plant which

demonstrates anti-edematous, anti-inflammatory,

anti-thrombotic and fibrinolytic activities.

Bromelain’s therapeutic actions are only partially

due to its enzymatic activity and were able to

induce increased natural killer cell activity in

immunocompromised individuals Studies

comparing bromelain’s anti-inflammatory effects

against pharmaceuticals demonstrate greater levels

of improvement and decreased dependency on

analgesics (Usha et al., 2004, Cohen et al., 1964).

GLA

The most significant source of GLA for infants is

breast milk. GLA is further metabolized to

dihomogamma linlenic acid (DGLA) which

undergoes oxidative metabolism by

cyclooxygenases and lipoxygenases to produce

anti-inflammatory eicosanoids.

Elements and miscellaneous

Selenium: This is a antioxidant that may be

deficient in rheumatoid arthritis patients (Rotruck

et al., 1973).

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Vitamin E: Vitamin E is a antioxidant that works

with selenium.

Zinc: Zinc is a powerful antioxidant and is

generally deficient in those suffering from

rheumatoid arthritis.

Vitamin C: This is an antioxidant and many who

suffer from rheumatoid arthritis are deficient

(Zhong Fang et al., 2002).

Pantothenic acid: A deficiency may cause a

failure in the growth of cartilage produce arthritis

like symptoms.

Calcium and Magnesium: These can help to

prevent bone loss.

Methionine: This is an essential amino acid that is

important to the structure of cartilage and can act as

a natural anti-inflammatory.

Cat’s claw is a rich source of phytochemicals: 17

alkaloids, along with glycosides, tannins,

flavonoids, sterol fractions, and other compounds

(Zhang et al., 2005).

Herbal plants extract treatment

Various well established pre-clinical models of

arthritis which are used to studying the effect of

anti-arthritic activity of herbal extracts

Collagen type II induced hyperimmunised

arthritis in rats

It is widely used method to induce the arthritis in

animal models. When collagen is introduced, it is

immediately captured by antigen presenting cells

(APCs).Disease involves activation of both T & B

cells that are antigen-specific & auto reactive. T

cell & T cell-derived cytokines promote

differentiation & activation of macrophages,

osteoclasts & fibroblast, leading to arthritis

(Doncarli et al., 1997). 2.0 mg/ml collagen is

dissolved in 0.1 M acetic acid and placed at 4 °C

overnight. This solution is added to chilled

incomplete Freund’s adjuvant drop wise. 1 ml of

the above solution is given to the rats on the five

different sites which contains the 0.5ml of collagen

and 0.5 ml of incomplete Freund’s adjuvant in

equal amount. Control animals receive only

incomplete Freund’s adjuvant in 0.1 ml acetic acid.

On 20th

day the hind limbs measured

plethysmographically. The animals with paw

volume of 1.8 ml or more are used for further

testing.20-40 days animal receive the test drug on

day 41 the paw volume is measured again and

compared with the above (Doncarli et al., 1997).

Complete Freund’s adjuvant induce arthritis in

rat

It is the best and most widely used method for the

arthritis produces the symptoms of arthritis. It is

sensitive for both immune system inhibiting and

anti-inflammatory activity. On day zero rats are

injected on the sub planter region on left hind paw

with 0.1 ml of complete freunds adjuvant. This

consists of 6mg Mycobacterium butyricum

suspended in heavy paraffin oil at a dose of 6

mg/ml. Both standard and test are administered on

the same day and dose is given for 12 days

(Kannan et al., 2005).

Streptococcal cell wall method for Arthritis: -

The streptococcal cell wall model of arthritis in

female Lewis rats is one of the most reliable and

best characterized experimental models of RA.

Schwab and colleagues described SCW arthritis in

the 1970.A single injection of streptococcal can

produce severe and erosive arthritis. As in human

RA, female rats develop arthritis more readily than

male rats which show the factor that female human

is more susceptible to arthritis (Kannan et al.,

2005). The high female susceptibility is due to high

estrogen level in the blood.

Cartilage oligomeric matrix protein (COMP)

induced arthritis

Immunization with COMP in IFA induces severe

arthritis in susceptible rat strains, such as DA and

LEW. Although the peripheral joint arthritis

clinically resembles RA, COMP-induced arthritis,

however, does not result in the permanent

destruction of joints. Disease development appears

to be dependent on an immune response to

autologous COMP and not on cross-reactivity to

other cartilage rat collagens (Newbould et al.,

1963, Di Rosa et al., 1972).

Effect on T cell response (T cell activation, T cell proliferation, ratio of

CDa4/CD8 cells, etc.) e.g.- Pterodon pubescens etc.

Induction/expansion of regulatory T cells e.g.- Chelidonium majus etc.

Cellular and humoral

responses

Change in antibody/B cell response e.g.- Camellia sinensis etc. Affecting major cytokines produced by macrophages/ antigen-presenting

cells (TNF-α, IL-1, IL-6, etc.) and/or deviation of the response to Th2 type

e.g.- Swertia chirayita etc.

Cytokine response/balance

Inhibiting the pathogenic cytokine IL-17 and related cytokines e.g.-

Tripterygium wilfordii etc.

Affecting the expression of chemokines and adhesion molecules in the blood vessels or joint tissues e.g.- Fumigant I etc.

Cellular migration into the

target organ Altering the migration of leukocytes into the tissues-monocytes,

macrophages, neutrophils, lymphocytes, etc.e.g.- Curcuma longa etc.

Mechanisms of

immunomodulation by

herbal products

(Shivaparasad

et al.2010)

Mechanism of action not yet

determined

e.g.- Chlorophytum borivilianum, Ocimum sanctum etc.

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DISCUSSION AND CONCLUSION

With the evolution of industrialization,

globalization and economic liberalization with the

Technology Up gradation of the individual life of

style was changing. People with the type of

inheritance are predisposed to certain diseases

triggered by factors existing lifestyle.

Food, style of life and environment are three

important determinants related to the cause of the

disease. An inadequate intake of nutrients,

consumption junk food and beverages such as tea,

coffee, alcohol decreased strength and energy to the

defense mechanism of the body. Environmental

pollution is the result of industrialization and

deforestation, threatening the health of residents.

People engaged in long hours night shifts, and

physical inactivity has led to sedentary lifestyle.

This paper is focused on etiology of arthritis

through different pathophysiology, investigation

techniques and their allopathic treatments. Already

new insights into the various molecular pathways

have been used to develop new and very efficient

treatment approaches for the patients. Apart from

this, natural products can contribute to the

suppression of inflammation and artistic processes.

Despite making major progress in rheumatoid

arthritis research, still genetically this disease is not

in control. So, with new investigation tool called

pharmacogenomics studies which will help to find

out the allele which is responsible for arthritis in

different races, population and ethnicity. On the

basis of pharmacogenomics studies, we need to

find out how the best target these drugs to the right

individuals at the right time. Finally it is concluded

that with pharmacogenomics study we can treat and

minimize the prevalence rate of rheumatoid

patients at globally.

CONFLICT OF INTEREST

There are no conflicts of interest

ACKNOWLEDGEMENT

The authors are thankful to managing committee

for facilities and moral support.

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