Rheumatology 2 - Rheumatoid Arthritis
Anil Chopra
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Historical
Epidemiology
Disease Pathogenesis
Clinical Considerations
Clinical Case Study
Epidemiology
North
America
1.0%
Inuit
Canada
0.6%
England
0.9%
Denmark
0.8%
Finland
2.0%
Sweden
0.9%
Bulgaria
0.8%
Pima &
Chippewa
Indians
USA 5.3%
Japan
0.6%
China
0.3%
Netherlands
0.9%
Liberia &
Nigeria
0.1%
S. Africa
Soweto 0.9%
Rural 0.1%
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Prevalence : 0.5-1% of population
Incidence : 40-50 per 100,000/year
Sex : F:M 3:1
It is the most common cause of inflammatory arthritis in people
of 20-30 years of age.
Rheumatoid arthritis is a chronic, systemic, inflammatory disease
which targets the synovium of diarthrodial joints.
The causes of rheumatoid arthritis are shown to be:
Genetic ~ 15 to 30%
Non-genetic ~ 70 to 85%
Disability in rheumatoid arthritis occurs from the oneset and is
progressive (by 2 yeards). It reduces the work employment
capacity and manifests itself in other co-morbidities.
Genetic ~ 15 to 30%
N = 68
It results in:
• Pain & destruction
• Loss of function
• Systemic disease
• Work disability
• Economic losses
• Premature death
The disease itself is caused by an imbalance of homeostasis.
• Antigen presenting cells promote autoimmunity
• The immune response from Th1 is more than Th2
• There is a Loss of regulatory T cells and an increase in B cell autoimmunity.
• Cytokines and chemokines are produced in response to the autoantigens.
• There is an increased matrix turnover with more enzymes than inhibitors.
• This all leads to inflammation (particularly of the synovial membrane) and
tissue damage.
• Inflammatory cells are recruited
• These destroy the synovial membrane and accumulate in the synovial fluid
• Rheumatoid factors are released and bound by antibodies
• The complexes formed can be deposited in certain joints
• Immune complexes activate complement cascade leading to chronic joint
inflammation.
There are a number of different mediators in rheumatoid arthritis, often imbalanced
between pro and anti inflammatory:
Pro-inflammatory
e.g. IL-1, IL-6, TNFa, IL-12, IL-15, IL-17, IL-18, GM-CSF
Anti-inflammatory
e.g. IL-10, IL-1RA, TGFb, IL-11, IL-13
Chemokines
e.g. IL-8, MIP-1a, MCP-1, RANTES, ENA-78, GROa
Growth Factors
e.g. VEGF, PDGF, FGF
Presenting Symptoms of Rheumatoid Arthritis
• Complain of symptoms
– pain in joints
– stiffness of: hands, in and around joints and neck
– fatigue
• Problems in coping with activities related to :
– daily living
– social, sport, travel
– work
Diagnosis is made on the presence of 4 out of 7 of the following:
• Morning Stiffness more than 1 hour
• Rheumatoid nodule present on
• Arthritis at least 3 joints
bones
• Arthritis hand joints
• Rheumatoid factor in the serum
• Symmetric arthritis
• Joint erosion X-ray
Other features of rheumatoid arthritis include
 Respiratory
 Pleural effusion M>F (need to exclude other causes)
 Rheumatoid nodules (Caplan’s syndrome)
 Interstitial lung disease (fibrosing alveolitis/fibrosis)
 Bronchiolitis obliterans (small airway disease)
 Pericarditis/pericardial effusion
 Neurological
 Most commonly carpal tunnel syndrome
 Peripheral neuropathy (stocking and glove)
 Mononeuritis multiplex e.g. foot drop
 Haematological
 Anaemia common
 Neutropaenia + splenomegaly +RA = Felty’s syndrome
 Amyloidosis (amyloid proteins found in organs)
 Atlanto-axial subluxation – endangers spinal cord
The serological criteria for classification of RA
 RA is linked to HLA DR4.
 Although many antibodies have been linked to RA, IgM RF remains the sole
serological parameter in the widely used 1987 ACR classification criteria. IgM
RF is an auto-antibody which binds to the FC region of IgG.
 RF’s are found in 75-80% of RA patients at some time during their disease
course.
Note: RA has an unknown aetiology, but we know that it is an autoimmune disease.
Twin studies in RA tell us that genetic factors are clearly important, but there is also a
basis for nurture (i.e. environmental factors) to be considered a causative factor in
RA.
Diagnosis of Rheumatoid Arthritis
Looking for the presence of:
– nodules, vasculitis
– pleural-pericardial disease
– organ involvement ; e.g. lungs, eyes
Laboratory tests for:
• anaemia, leucocytosis, thrombocytosis
• Acute phase response: ESR, CRP
• Rheumatoid factor: these are antibodies that recognise the Fc portion of IgG (can
be IgM, IgG, IgA, IgE) – the majority of rheumatoid arthritis patients are positive
for rheumatoid factor.
X-rays: hands and feet for joint space narrowing, osteopenia (lower bone density) and
bone erosions. X-rays of joints affected by RA show the distribution of joints
affected:
 In the hands: MCP and PIP joints and the wrist joint are affected.
 There will be narrowed joint spaces due to the loss of cartilage. This is
particularly prevalent in weight-bearing joints such as the knee.
 Erosions of the bone are also present (such as in the bones of the hand and the
bones associated with the knee joint).
 Around synovial joints, you will be able to see thinning of bones (this is
periarticular osteoarthritis).
Treatment Of Rheumatoid Arthritis
RA has a good prognosis if referral and management of the condition is done in the
early stages of the disease.
Pharmacology
NSAIDs: non-steroidal anti-inflammatory drugs, used in the control of symptoms.
Should be used with gastro-protective agents in patients with ulcers.
Glucocorticoids: these are injected intra-articular
• Pulse : during induction period of DMARDS or for significant disease flare
• Low-dose, long-term : for severe disease, control of symptoms, function, slows
radiographic damage
DMARDs: Disease Modifying Anti-rheumatic Agents, used in the control of the
actual disease. They stop structural damage as well as control of symptoms. Examples
include:
– salazopyrine
– methotrexate
– gold
– azathioprine
– cyclosporine
– leflunomide
Biologics: these are protein-based drugs designed to target specific aspects of the
inflammatory process.
 Anti TNF therapy: block the action of TNF, these include Infliximab,
etanercept, adulimulab. These control symptoms and signs; improve function;
quality of life; and prevent joint damage.
Problems with therapy include:
• Limited efficacy
• No effect on long term
• Diminishing effect over time
mobility, mortality
• Unacceptable toxicity
• High cumulative cost
As we know, in a chronic inflammatory response, the accumulation of large numbers
of activated macrophages is responsible for much of the tissue damage caused. These
immune cells release various hydrolytic enzymes and reactive oxygen and nitrous
intermediates which damage the surrounding tissue (as occurs in RA).
One of the principal cytokines released by activated macrophages is TNF-α. This
cytokine has a direct cytotoxic effect on tumour cells but not on normal cells.
However, several lines of evidence indicate that TNF-α also contributes to much of
the tissue wasting that characterises chronic inflammation (i.e. in RA, for example).
Activation of macrophages by IFN-γ promotes an
increased transcription of the TNF-α gene and increases
the stability of TNF-α mRNA. Both effects result in an
increased TNF-α production. TNF-α acts synergistically
with IFN-γ to initiate a chronic inflammatory response.
Both cytokines together induce a much greater increase in
ICAM-1, E-selectin, and class I MHC molecules than
either cytokine alone. The increase in these intercellular
adhesion molecules facilitates the recruitment of large
numbers of cells in a chronic inflammatory response.
Thus the use of TNF-α inhibitors have a great scope in
RA to treat the disease and stop the chronic inflammation
that occurs.
Other aspects of Management
• Patient education about the disease is key
• Physical Therapy for stretching and range of motion exercises
• Occupational Therapy for splints and adaptive devices
• Surgery