Rheumatoid arthritis (RA) is a chronic, destructive, inflammatory arthropathy manifested by articular and

extra-articular features. RA has profound effects on patient function and morbidity and exacts a
substantial economic burden from affected persons. Although the pathology of the synovial inflammation
and cartilage destruction that occurs in patients with RA has been described for decades, many important
developments in the understanding of genetic influences and immunopathophysiologic mechanisms have
recently been defined. Basic research delineating the molecular mechanisms of synovial inflammation
has driven the development of innovative therapies for patients with RA. Hopefully, new genomic and
proteomic information will allow further stratification identification of subsets of RA patients who respond
better, longer, and with fewer adverse reactions to targeted therapies.
Pathogenesis The pathobiology of RA involves a complex interaction of three different scientific
domains:
1. a complex genetic predisposition to the disease plus some environmental stimulus
2. a self-perpetuating, self-amplifying, intra-synovial immune response; and at the final stage,
3. Tissue injury mediated by pro-inflammatory cells, inflammatory effector molecules, and
degradative enzymes.
In individuals with RA, this process is arthrotropic and produces a characteristic pathologic lesion in the
synovium as well as the hallmark erosions of bone and destruction of cartilage at the joint margin.
Pathophysiology of Rheumatoid Arthritis Rheumatoid arthritis is an autoimmune disease of the joints,
consisting of hyperplasia of synovial tissue due to chronic inflammation. This proliferation of tissue,
otherwise known as pannus, invades and erodes cartilage and bone, leading to destruction of the joint.
While the exact pathophysiology is not known, autoreactivity of the immune system is thought to be due
to genetic predisposition along with environmental triggers.
Genetic susceptibility is thought to account for 40 to 60% of people that develop RA.1, 2 Specific genes
located in the major histocompatibility complex (MHC) on chromosome 6 have been implicated in the
predisposition and severity of rheumatoid arthritis. Human leukocyte antigens (HLAs), known to define
tissue types, are cell-surface proteins that are encoded by the MHC. Approximately 70% of Caucasians
with rheumatoid arthritis have the HLA-DR4 (DRB1*0401 and *0404) class II antigen. Caucasians with the
HLA-DR4 and Native Americans with the HLA-DR9 polymorphic genes are 3.5 times more likely to
develop rheumatoid arthritis.1,5 In addition to genetic predisposition, environmental triggers, such as
smoking, alcohol, periodontitis, infectious agents and non-inherited maternal HLA antigens, are thought to
initiate the development of rheumatoid arthritis.
Infectious agents linked to the development of RA include mycoplasma, mycobacterium, parvovirus,
Epstein-Barr virus, and retroviruses. Theories suggest that infectious agents may initiate the disease in
genetically prone individuals through direct synovial infection, molecular mimicry or activation of innate
immunity. Recently, studies have found a link between antibodies produced in response to
Porphyromonas gingivalis (P. gingivalis) and development of RA. Associated with periodontitis, P.
gingivalis antibodies in RA patients have been linked to the production of anti-citrullinated protein
antibodies (ACPAs) known to enhance the autoimmune response seen in RA.
Additionally, new reports suggest that smoking simultaneously increases the production of ACPAs and
pro-inflammatory cytokines responsible for the development of RA. Likewise, recent reports suggest an
association between increased alcohol intake and increased levels of inflammatory markers. However,
once RA has been established, other studies suggest alcohol may decrease severity of disease and joint
destruction. Lastly, non-inherited maternal HLA antigens (NIMAs) have been implicated as a trigger for
the development of RA in offspring. An increased susceptibility to RA may be due to maternal cells

entering the child either during or shortly after childbirth, remaining in the offspring for several years
thereafter.
The inflammatory process of RA is complicated by many factors. The synovial joint is infiltrated with T
cells, B cells, macrophages, plasma cells along with cytokines, fibroblasts, growth factors, chemokines,
adhesion molecules and matrix metalloproteinases. Arithrogenic T cells are activated when presented
with antigenic peptides, initially resulting in joint swelling and pain. Two sets of CD4+ T cells are known to
exist based on the cytokines they produce. Activation of CD4+ T-helper 1 cells (Th1) produce proinflammatory molecules (interleukin-2, interferon , tumor necrosis factor , granulocyte-macrophage
colony-stimulating factor) responsible for delayed-type hypersensitivity reactions that are commonly seen
during early-onset RA. T-helper 2 cells (Th2) produce interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin 6
(IL-6) and interleukin 10 (IL-10) known to affect B cell differentiation and activation. Bone and cartilage
destruction seen later in the course of the disease are caused by IL-1, TNF-, IL-6 and IL-8.
Cytokines (responsible for intercellular communication during immune system activation) implicated in
pro-inflammatory responses in rheumatoid arthritis include IL-1, IL-6, IL-8, IL-17 and TNF-.2,5,8
Interleukin-1 is released by macrophages, monocytes, activated T and B cells, stimulating the release of
matrix metalloproteinases; thereby, causing cartilage destruction. Interleukin-6, produced by T cells,
fibroblasts, monocytes and macrophages, promotes B cell differentiation and maturation, causing
increases in the production of rheumatoid factor.5,8 While the role of rheumatoid factor in RA is unknown,
theories suggest that it may cause the formation of immune complexes, leading to the activation of the
complement immune response.8 Additionally, IL-6 enhances bone resorption, induces the acute-phase
response (erythrocyte sedimentation rate, C-reactive protein), and stimulates the proliferation of synovial
fibroblasts that cause tissue and cartilage destruction by releasing matrix metalloproteinases.
Interleukin-8, produced by macrophages, is thought to promote bone and cartilage destruction by causing
recruitment of inflammatory cells such as neutrophils. While B cells, T cells and fibroblasts produce TNF, the primary producers include monocytes and macrophages. The actions of TNF- in RA include
proliferation of synovial tissue, release of metalloproteinases, increased fibroblast expression of
adhesion-molecules to allow the transport of leukocytes into the synovium, secretion of other cytokines
(IL-1, IL-6, IL-8, granulocyte-monocyte colonystimulating factor) as well as prostaglandin production, all
resulting in cartilage and bone destruction. IL-17, now emerging as an important cytokine related to joint
inflammation and destruction, is a product of Th17 T cells increased in the synovial joints of RA patients.
However, the low production of IL-17 from CD4+ cells in the synovium prompts theorists to suggest an
alternative source for the production of IL-17, primarily mast cells. Additionally, the Th17 phenotype may
be able to convert to Th1 cells in response to inflammation, promoting the production of well known proinflammatory cytokines.
Fibroblasts play an important role in the amplification of inflammation in rheumatoid arthritis by promoting
chemotaxis, increasing inflammatory cytokines, matrix metalloproteinases and adhesion molecules.1,6
Recent studies report an increase in fibroblast-like synoviocytes (FLS) may cause hypoxia, leading to the
development and necessity of angiogenesis for the continuation of rheumatoid arthritis. Moreover,
fibroblasts may perpetuate RA by invading unaffected joints through vascular migration.6 Angiogenesis is
another highly occurring phenomenon of RA, especially during the early-onset of disease. While allowing
for the recruitment of inflammatory cells to the synovium, angiogenesis supplies oxygen and nutrients to
the proliferating synovial tissues. Generally, angiogenesis is highly regulated with rapid vascular
endothelial cell division occurring during wound repair and menstruation. However, theories suggest that
stimulation of angiogenesis in RA may be due to an abundance of cytokines, growth factor and adhesion
molecules promoted by fibroblasts, or a lack of inhibiting cytokines, chemokines, and cryptic cleavage
products.

RF TEST
How is it used?
The rheumatoid factor (RF) test is primarily used to help diagnose rheumatoid
arthritis (RA) and to help distinguish RA from other forms of arthritis or other
conditions that cause similar symptoms.
While diagnosis of RA relies heavily on the clinical picture, some of
the signs and symptoms may not be present or follow a typical pattern, especially
early in the disease. Furthermore, the signs and symptoms may not always be
clearly identifiable since people with RA may also have other connective
tissue disorders or conditions, such as Raynaud phenomenon,scleroderma,
autoimmune thyroid disorders, and systemic lupus erythematosis, and display
symptoms of these disorders as well. The RF test is one tool among others that can
be used to help make a diagnosis when RA is suspected.
When is it ordered?
The test for RF may be ordered when a person has signs and symptoms of RA.
Symptoms may include pain, warmth, swelling, and morning stiffness in the joints,
nodules under the skin, and, if the disease has progressed, evidence on X-rays of
swollen joint capsules and loss of cartilage and bone. An RF test may be repeated
when the first test is negative and symptoms persist.
A cyclic citrullinated peptide (CCP) antibody test can help diagnose RA in someone
who has joint inflammation with symptoms that suggest but do not yet meet the
criteria of RA and may be ordered along with RF or if the RF result is negative.
The RF test may also be ordered along with other autoimmune-related tests, such
as an antinuclear antibody (ANA), and other markers of inflammation, such as a Creactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as
acomplete blood count (CBC) to evaluate blood cells.
What does the test result mean?
The RF test must be interpreted in conjunction with a person's symptoms and
clinical history.In those with symptoms and clinical signs of rheumatoid arthritis, the
presence of significant concentrations of RF indicates that it is likely that they have
RA. Higher levels of RF generally correlate with more severe disease and a
poorer prognosis. A negative RF test does not rule out RA. About 20% of people with
RA will have very low levels of or no detectable RF. In these cases, a CCP antibody
test may be positive and used to confirm RA.

Positive RF test results may also be seen in 1-5% of healthy people and in some
people with conditions such as: Sjgren syndrome, scleroderma, systemic lupus
erythematosus
(lupus), sarcoidosis, endocarditis, tuberculosis, syphilis, HIV/AIDS,hepatitis, infectiou
s mononucleosis, cancers such as leukemia and multiple
myeloma, parasitic infection, or disease of theliver, lung, or kidney. The RF test is
not used to diagnose or monitor these other conditions.
Is there anything else I should know?
The 2010 Rheumatoid Arthritis Classification Criteria from the American College of
Rheumatology (ACR) includes cyclic citrullinated peptide (CCP) antibody testing,
along with RF, as part of its criteria for diagnosing rheumatoid arthritis. According to
the ACR, CCP antibodies may be detected in about 50-60% of people with early RA,
as early as 3-6 months after the beginning of symptoms. Early detection and
diagnosis of RA allows health practitioners to begin aggressive treatment of the
condition, minimizing the associated complications and tissue damage.
ANTI CCP TEST
How is it used?
A cyclic citrullinated peptide (CCP) antibody test may be ordered along with or
following a rheumatoid factor (RF) test to help diagnose rheumatoid arthritis
(RA) and to assess the severity and probable course of the disease (prognosis).
Inflammatory markers may also be measured at this time, such as ESR and Creactive protein (CRP).
Cyclic citrullinated peptide antibodies are autoantibodies produced by the immune
system that are directed against cyclic citrullinated peptides (CCP). (See the "What
is being tested?" section for more.)
CCP antibody testing may also be ordered to help evaluate the likely development
of RA in people with undifferentiated arthritis those whose symptoms suggest but
do not yet meet the American College of Rheumatology (ACR) criteria for RA.
According to ACR, approximately 95% of those with a positive CCP antibody will
meet the criteria of RA in the future. Early detection of RA is essential for guiding
treatment decisions.

When is it ordered?
A CCP antibody test is primarily ordered along with an RF test when someone
has signs and symptoms that may be due to previously undiagnosed
inflammatory arthritis or has been diagnosed with undifferentiated arthritis. It may
be ordered as a follow-up test to a negative RF test when clinical signs and
symptoms lead a health practitioner to suspect RA. RA usually affects
multiple joints symmetrically. Signs and symptoms may include:

Painful, warm, swollen joints of

the hands and wrists most
commonly
Pain sometimes affecting
elbows, neck, shoulders, hips,
knees, and/or feet
Stiffness of affected joints in the
morning that improves during the
course of the day

Fatigue
Fever
Development of nodules under
the skin, especially at the elbows
A general feeling of being
unwell (malaise)

What does the test result mean?

When people with signs and symptoms of arthritis are positive for both CCP
antibody and RF, it is very likely that they have RA and it is likely that they
may develop a more rapidly progressive and severe form of the disease.
When people are positive for CCP antibody but not RF, or have low levels of
both, and have clinical signs that suggest RA, then it is likely that they have
early RA or that they will develop RA in the future. When individuals are
negative for CCP antibody but have a positive RF, then the clinical signs and
symptoms are more vital in determining whether they have RA or some other
inflammatory condition. When someone is negative for both CCP antibody
and RF, then it is less likely that the person has RA. It must be emphasized,
however, that RA is a clinical diagnosis and may be made in the absence of
positive tests for autoantibodies.

Is there anything else I should know?

The CCP antibody test is relatively new. It is becoming more widely used but
is still less frequently ordered than the RF test. CCP antibodies are rarely
found in other autoimmune conditions, such as lupus, Graves
disease and Sjogren syndrome, and may be detected in infections such
as tuberculosis.