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)
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
IJPSR/Vol. II/ Issue II/April-June, 2011
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)
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
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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
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
IJPSR/Vol. II/ Issue II/April-June, 2011
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
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
IJPSR/Vol. II/ Issue II/April-June, 2011
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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IJPSR/Vol. II/ Issue II/April-June, 2011
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).
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
IJPSR/Vol. II/ Issue II/April-June, 2011
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.
International Journal of Pharmaceutical Studies and Research E-ISSN 2229-4619
IJPSR/Vol. II/ Issue II/April-June, 2011
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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