Rheumatoid Arthritis

Question 1

What is rheumatoid arthritis?

Answer 1

Chronic autoimmune disease characterised by pain, stiffness (particularly bad in the morning and gets better with exercise) and symmetrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints

• Arthritis patients will not present with pain in their back. This is because this disease affects the SYNOVIUM.

1% of population affected

F:M is 3:1

Question 2

Why can you get extra-articular disease?

Answer 2

e. g Rheumatoid nodules
- Others rare e.g. vasculitis, episcleritis

This is because of rheumatoid factor (autoantibody) forming immune complexes

Question 3

What is rheumatoid factor?

Answer 3

IgM antibody recognises and binds to Fc portion of IgG (rhematoid antibody)

may be detected in blood

• Positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis

Question 4

Is there a genetic component?

Answer 4

Disease concordance rates for twins are 15-30% (monozygotic) and 5% (dizygotic)

• Heritability estimates of up to 60%

specific set of amino acids within the beta chain of the DR molecule conserved among all HLA subtypes that are associated with RA suggesting that it is this particular amino acids sequence in the antigen binding group that is associated with rheumatoid arthritis - shared epitope

Question 5

How does smoking affect RA?

Answer 5

Patients with rheumatoid arthritis, who smoke, generally fare worse than those that don’t smoke - affects susceptibility and severity

Question 6

What are the commonly affected joints in rheumatoid arthritis?

Answer 6

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

Question 7

What are classic deformities in RA?

Answer 7

Swan-neck Deformity: Hyperextension at the PIP and hyperflexion at the DIP

Boutonniere Deformity: Hyperflexion at the PIP (boutonniere means ‘button-like’)

• Synovitis has damaged the joints and the surrounding tendons are pulling on an abnormal joint via damage to articular cartilage -> deformity

Question 8

What is dactylitis?

Answer 8

whole digit is swollen

• several fully swollen fingers can be explained by RA

Question 9

Why are several fingers swollen in RA?

Answer 9

not just the joints that are swollen

tenosynovium wraps around tendons to allow them to move freely - swelling of tenosynovium

• Ask a patient with extensor tenosynovitis to raise fingers -> you will see the swelling being pulled back - confirms that the synovitis is around the tendons and not the joints
• Tenosynovitis can damage the tendons and impair their function

Question 10

What are bursa?

Answer 10

pockets of fluid that are found on surface of joints

• inflammation -> bursitis

Question 11

What are sub-cutaneous nodules?

Answer 11

Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue - rheumatoid factor can produce immune complexes that tend to deposit in sub-cutaneous tissue -> extra articular manifestation

*occurs in around 30% of patients

** Associated with: severe disease, extra-articular manifestations and rheumatoid factor

*** nodule = always rheumatoid factor positive

Question 12

What is cirullination of peptides?

Answer 12

Citrullination of peptides is mediated by enzymes termed: Peptidyl arginine deiminases (PADs)

Citrullination is a post-translational modification of arginine by PADs

occurs frequently in areas of inflammation, and isn’t restricted to the joints

Question 13

What is an ACPA?

Answer 13

Antibodies to Citrullinated Protein Antigens

If someone has RA, we often find RF and anti-CCP antibodies

• Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis (Anti-cyclic citrullinated peptide antibody ‘anti-CCP antibody’)

Question 14

Why do citrullinated peptide antigens develop in rheumatoid arthritis?

Answer 14

PADs are present in high concentrations in neutrophils and monocytes

• there is increased citrullination of autologous peptides in the inflamed synovium
• Citrulline binds much better than arginine to the specific peptide sequence that is conserved in the MHC molecules that are associated with rheumatoid arthritis. So, ACPA are more likely to develop among individuals with citrullinated auto-antigens who have the shared epitope

Question 15

What are some extra-articular features of RA?

Answer 15

Common: fever (due to abnormal production of cytokines), weight loss and subcutaneous nodules

• Common features are all caused by an abnormal cytokine response

Uncommon: vasculitis, ocular inflammation (e.g. episcleritis), neuropathies, amyloidosis, lung disease (nodules, fibrosis, pleuritic) and Felty’s syndrome (triad of splenomegaly, leukopenia and rheumatoid arthritis)

Question 16

What are the radiographic abnormalities at each stage of RA?

Answer 16

Early: Juxta-articular osteopenia (bones look a little less dense around the joints)

Later: Joint erosions at margins of the joint

Later still: Joint deformity and destruction

Question 17

Describe the pathology of RA?

Answer 17

• the synovial membrane becomes thickened and chronically inflamed -> joint swelling, (referred to pathologically as a pannus – synovial tissue that is chronically inflamed) -> inflammation starts to eat away at adjacent bone
• There is a small area of bone that is within the synovial membrane but is not covered by articular cartilage - often where erosion is first seen (because the pannus normally has to destroy the cartilage before it reaches the bone) –peri-articular erosions are seen first.

Eventually there will be cartilage damage – this is very difficult to reverse.

Question 18

What can you find in a synovial joint?

Answer 18

• The synovium is normally almost a single cell lining
• The synovium is comprised of type-1 collagen cells
• There are macrophages and fibroblasts (which produce synovial fluid) within the synovial lining
• The synovial fluid is viscous because it contains a lot of hyaluronic acid

Question 19

What makes up articular cartilage?

Answer 19

Articular cartilage is made up of type 2 collagen

The main proteoglycan in articular cartilage is aggrecan.

Question 20

Why does the synovium become proliferated?

Answer 20

• Neovascularisation – formation of new blood vessels
• Lymphangiogenesis – formation of new lymphatic vessels
• Inflammatory cells: activated B and T cells, plasma cells, mast cells, activated macrophage

Question 21

What are the key cytokines in RA?

Answer 21

IL-1, IL-6 and TNF-alpha

• TNF-alpha is the dominant pro-inflammatory cytokine in the rheumatoid synovium

Question 22

How is RA managed?

Answer 22

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)
- Started early in the disease because risk of joint damage increases the longer the inflammation lasts

• Joint damage = inflammation x time
• often referred to as ‘steroid-sparing agents’ since they enable us to avoid long-term steroid or at least use much lower doses of steroids than would be possible in their absence
• safer and more effective long-term treatment than steroids

Biological therapies
- potent and targeted treatment strategies.

Glucocorticoid therapy

• preferred to avoid long-term use of such drugs because of their large side effect profile
• useful for short-term use
• E.g. to control an exacerbation of the disease or to control inflammation of a single joint.

Question 23

What do DMARDs do?

Answer 23

Disease-Modifying Anti-Rheumatic Drug

may induce remission and prevent joint damage by:

• Reducing the amount of inflammation in the synovium
• Slowing or preventing structural joint damage e.g. bone erosions

Question 24

What are some DMARDS?

Answer 24

• Methotrexate – commonly used
• Sulphasalazine – commonly used
• Hydroxychloroquine – commonly used
• Leflunomide – uncommon
• Janus Kinase inhibitors – VERY NEW
• Gold and penicillamine are also DMARDs, but are rarely used now

*All of the DMARDs mentioned have significant adverse effects so they require regular blood test monitoring during therapy

Question 25

What biological therapies are used to treat RA?

Answer 25

Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)

• Antibodies (infliximab, and others)
• Fusion proteins (etanercept)

B cell depletion
- Rituximab – antibody against the B cell antigen, CD20

Modulation of T cell co-stimulation
- Abatacept: fusion protein – extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1

Inhibition of interleukin-6

• Tocilizumab (RoActemra) – antibody against IL-6 receptor
• Sarilumab (Kevzara) – antibody against IL-6 receptor

Question 26

What are the downsides of biological therapies?

Answer 26

• expensive
• side-effects for all include increased infection risk (TNF-alpha is important in granuloma formation – important in host defence against tuberculosis)
• B cell depletion therapy can be associated with hepatitis B reactivation
• B cell depletion therapy has also been associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) - this is very RARE