Rheumatoid Arthritis Flashcards by Robert Ingram

Define Rheumatoid Arthritis

Chronic autoimmune disease characterised by pain, stiffness and SYMMETIRCAL SYNOVITIS of synovial (diarthrial) joints

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When is the stiffness in the joints particularly bad in rheumatoid arthritis and what can make it better?

In the morning It gets better with exercise

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What is a relatively common extra-articular manifestation of rheumatoid arthritis?

Rheumatoid nodules

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What causes the extra-articular manifestations?

Rheumatoid factor produces immune complexes that can go anywhere

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What type of antibody is the rheumatoid factor?

IgM antibody that binds to the Fc portion of IgG

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Is rheumatoid arthritis more common in males or females?

More common in females (3:1)

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What is the important genetic component that predisposes to Rheumatoid Arthritis?

The genetic component comes down to a specific set of amino acids within the beta chain of the DR molecule (amino acids 70-74 of the DR Beta1-chain) This set of amino acids is conserved among all HLA subtypes that are associated with rheumatoid arthritis – it is called the shared epitope

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What important environmental factor can affect the susceptibility and severity of Rheumatoid Arthritis?

Smoking

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State some joints that are commonly affected in Rheumatoid Arthritis.

Metacarpophalangeal joint (MCP) Proximal interphalangeal joint (PIP) Wrists Knees Ankles Metatarsophalangeal joint (MTP)

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Name and describe some deformities that are indicative of Rheumatoid Arthritis.

Systemic polyarthritis, joint damage and deformity leading to: 1)Swan-neck deformity  Hyperextension of PIP  Hyperflexion of DIP 2)Boutonniere deformity (button-like)  Hyperflexion at PIP

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What is the term given to fingers that are completely swollen, not just around the joints?

Dactylitis – this can’t be explained by Rheumatoid Arthritis because it is not just the joints that are inflame

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Describe the appearance of extensor tenosynovitis.

There will be swelling around the extensor tendon that is inflamed When the fingers are extended, the swelling will move showing that the inflammation is around the tendon and not the joint

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Other that joints and around tendons, where else can synovium become inflamed?

Bursae –> Bursitis

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What are sub-cutaneous nodules?

Central area of fibrinoid necrosis surrounded by histiocytes and a peripheral layer of connective tissue

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Why are rheumatoid nodules an important clinical finding?

Patients with rheumatoid nodules are always rheumatoid factor positive

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Where are rheumatoid nodules commonly seen?

Along the ulnar border

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What proportion of cases of Rheumatoid Arthritis is rheumatoid factor negative?

70% of disease onset and a further 10-15% become positive over the first 2 years of diagnosis

Name another autoantibody that is very specific for Rheumatoid Arthritis.

Anti-cyclic citrullinated peptide antibody

Which enzymes are responsible for the citrullination of peptides?

Peptidyl arginine deaminases (PADs

Why do antibodies to citrullinated peptide antigens develop in rheumatoid arthritis?

PADs are present in high concentrations in neutrophils and monocytes so there is increased citrullination of autologous peptides in inflamed synovium Citrulline binds much better than arginine to the shared epitope (specific peptide sequence that is conserved in all MHC molecules that are associated with Rheumatoid Arthritis) So Antibodies to citrullinated protein antigens (ACPA) are more likely to develop in individuals with citrullinated autoantigens and those that have the shared epitope

State some common extra-articular manifestations of Rheumatoid Arthritis.

Rheumatoid nodules Fever Weight loss Cytokine driven feeling of malaise (feeling ill) and lethargy (feeling tired)

What is an early radiographic abnormality in Rheumatoid Arthritis?

Juxta-articular osteopenia

What are some later radiographic abnormalities in Rheumatoid Arthritis?

Joint erosion and, subsequently, joint destruction and deformity

What is the name given to the thickened, chronically inflamed synovial tissue in Rheumatoid Arthritis?

Pannus

Which area of bone tends to be eroded first in Rheumatoid Arthritis?

Bare area of bone – this is within the synovial membrane but is not covered by articular cartilage (periarticular erosion)

How thick is the normal synovial membrane?

It is normally almost a single cell lining

What is found within the synovium?

Synovial fibroblast-like cells that produce synovial fluid and hyaluronic acid Macrophage-like phagocytic cells Type I collagen

Why is synovial fluid viscous?

It contains hyaluronic acid

What type of collagen is present in articular cartilage?

Type 2 collagen

What is the main proteoglycan in articular cartilage?

Aggrecan

What three main things are responsible for the synovium becoming a proliferated mass (pannus)?

Neovascularisation Lymphangiogenesis Inflammatory cell recruitment:  Activated T and B cells  Plasma cells  Mast cells  Activated macrophages

What are the three main cytokines involved in this disease process?

IL-1 IL-6 TNF-alpha

What is the dominant cytokine and which cells produce it?

TNF-alpha Produced by activated macrophages

What is the main treatment goal for Rheumatoid Arthritis?

Prevent joint damage

What class of drugs are commonly used in Rheumatoid Arthritis to modify the natural history of the disease?

Disease-modifying anti-rheumatic drugs (DMARDs)

When are glucocorticoids used and why are they not used long term?

They are used in the short-term to control, for example, exacerbation of the disease They are not used long-term because of their large side effect profile

Describe the onset of action of DMARDs.

Slow onset and complex action

Give some examples of DMARDs.

Methotrexate Sulphasalazine Hydroxychloroquine Leflunomide Janus kinase inhibitors - Tofacitinib, Baricitinib

What are the shortcomings of DMARDs?

They have significant adverse effects and require regular blood test monitoring

What are the major risks with biological therapy?

EXPENSIVE All biological therapies are associated with an increase infection risk TNF-alpha inhibition is associated with increased susceptibility to mycobacterial infections (TUBERCULOSIS) So all patients must be screened for TB before starting treatment B cell depletion is associated with HEPATITIS B activation so patients need to be screened for this as well B cell depletion is also associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) – RARE

Why are some people more likely to get rheumatiod arthritis than others?

They have the 'shared epitope' gene associated with rheumatoid arthritis in their HLA-DR antigen binding groove This preferentially binds non-polar amino acids such as citrulline which is incresed in inflammation This causes antibodies to develop for citrulline This combined with environmental factors (e.g. smoking) that increase inflammation and subsequently increase citrulline levels makes someone more likely to develop rheumatoid

What are 4 methods of treating rheumatoid arthritis with biological therapy

Inhibition of TNF-alpha B cell depltion Inhibition of IL-6 Modulation of T cell co-stimulation