Rheumatoid arthritis

Question 1

What is rheumatoid arthritis?

Answer 1

Chronic inflammatory condition characterised by pain, stiffness and symmetrical synovitis (inflammation of synovial membrane) of synovial joints

Question 2

What are some key features of rheumatoid arthritis?

Answer 2

• Polyarthritis –swelling of small joints (hand/wrist)
• Symmetrical
• Early morning stiffnes
• May lead to joint damage & destruction

Question 3

What are some extra-articular features of RA?

Answer 3

• Rheumatoid nodules

Question 4

What is rheumatoid factor?

Answer 4

Anti- IgG IgM antibody

Question 5

Describe the epidemiology of RA

Answer 5

1% of population affected

Females affected 3 times more than male

Question 6

Describe the environmental and genetic component of RA

Answer 6

Genetic component:

• Heritability estimates of up to 60%
• The genetic component comes from a specific set of amino-acids in the beta-chain of the HLA-DR molecule
• This specific set is then shared amongst all RA HLA sub-sets –termed “Shared epitope”

Environmental component:
- Smoking contributes

Question 7

What are the most commonly affected joints in RA?

Answer 7

• Metacarpophalangeal joints
• Proximal interphalangeal joints
• Wrists.
• Knees
• Ankles.
• Metatarsophalangeal joints

Question 8

What are some recognizable features of RA in the hands?

Answer 8

Swan-neck deformities–affects ring-finger with hyper-extension of PIP (proximal interphalengeal) joint and hyper-flexion of DIP joint

Boutonnière deformity–affects little finger with hyper-flexion of PIP joint

Question 9

What are the sites of rheumatoid arthritis?

Answer 9

Synovial joints –PIP joint synovitis

Tenosynovium –extensor tenosynovitis (tendons wrapped in tenosynovium)

Bursa –olecranon bursa for example

Question 10

Describe the structure of a rheumatoid nodule

Answer 10

Central area –fibrinoid necrosis surrounded by macrophages

Peripheral area –connective tissue

Question 11

How does RF presence change with onset?

Answer 11

RF is present in 70% at disease onset and a further 10-15% become positive over the first 2 years of diagnosis

Question 12

What are the associations with high RF?

Answer 12

High likelihood of joint damage and patient feels more ill

Question 13

What is anti - CCP?

Answer 13

Cyclic citrullinated peptide antibody

Question 14

What mediates citrullination?

Answer 14

PADs - peptidyl arginine deiminases

Question 15

Where are PADs more active?

What produces them?

Answer 15

PADs are more active at sites of inflammation when they are produced by neutrophils and monocytes

Question 16

What is ACPA associated with?

Answer 16

smoking

Question 17

Citrulline and HLA

What can increase citrulline levels?

Answer 17

Arginine -> citrulline, facilitated by PADs

• 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, anti CCP are more likely to develop among individuals with citrullinated auto-antigens who have the shared epitope

Environmental factors can enhance levels of citrulline (e.g. smoking) so the cause of anti-CCP antibodies could be a combination of genetics and the environment

Question 18

What is citrullination?

Answer 18

During inflammation for example, arginine can be converted into citrulline residues. If their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response

Question 19

What is dactylitis?

Answer 19

Swelling of the whole digit

Question 20

Rheumatoid nodules

Answer 20

• Rheumatoid factor can produce immune complexes that can deposit in any tissue
• They have a tendency to deposit in subcutaneous tissue and cause extra-articular manifestations
• These extra-articular manifestations are relatively rare
• Rheumatoid nodules are sub-cutaneous so you can pick the skin up over the nodule, it is not attached
• Rheumatoid nodules are commonly seen along the ulnar border of the forearm
• Rheumatoid nodules are an important clinical finding because in rheumatoid arthritis, if rheumatoid nodules are present, then the patient is always rheumatoid factor positive

Question 21

Is rheumatoid factor diagnostic test for RA?

Answer 21

NO as 1/3 of patients are negative

Question 22

Pathogenesis of RA - genetic

Answer 22

• An individual may be susceptible if they carry the conserved amino acid sequence in their HLA-DR antigen-binding groove (‘shared epitope’). More likely to present to T cells -> more likely to get auto-immunity.
• Shared sequence in amino acids 70-74 of the HLA-DRβ chain
• This is why multiple different HLA serotypes were associated with disease (HLA-DR4, -DR1, -DR6, DR10)
• This shared epitope preferentially binds non-polar amino acids such as citrulline and citrulline-containing peptide antigens increased during inflammation

Question 23

What are some extra-articular features of RA?

Common and uncommon

Answer 23

Common: fever, weight loss and subcutaneous nodules (caused by cytokines)

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 24

What are some radiographic abnormalities of RA seen at different stages of the disease?

Answer 24

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 25

What is the pathology of RA?

Answer 25

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

Question 26

Describe the structure of the synovium | Describe the synovial fluid and articular cartilage

Answer 26

- The synovium is normally almost a single cell lining - 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 - Articular cartilage is made up of type 2 collagen. The main proteoglycan in articular cartilage is aggrecan

Question 27

What causes the synovium to become a pannus?

Answer 27

Synovial membrane is abnormal in RA. The synovium becomes a proliferated mass of tissue (pannus) due to: 1. Neovascularisation – formation of new blood vessels 2. Lymphangiogenesis – formation of new lymphatic vessels 3. Inflammatory cells: activated B and T cells, plasma cells, mast cells, activated macrophages A cytokine network controls recruitment, activation and effector functions of these cells. There is an excess of pro-inflammatory.

Question 28

What is the involvement of cytokines in RA?

Answer 28

- There is a cytokine imbalance in RA – there is an excess of pro-inflammatory cytokines - The key cytokines involved are: IL-1, IL-6 and TNF-alpha - TNF-alpha is the dominant pro-inflammatory cytokine in the rheumatoid synovium - Its pleiotropic actions are detrimental in this setting

Question 29

What is the effect of a mutation in a pleiotropic gene?

Answer 29

Occurs when one gene influences two or more seemingly unrelated phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously.

Question 30

TNF- a inhibition therapy and administration and success

Answer 30

- There is a hierarchy in the cytokine system and TNF-alpha is at the top - When you down-regulate TNF-alpha, you down-regulate lots of other pro-inflammatory cytokines - TNF-alpha inhibition had excellent therapeutic effects - It’s achieved through parenteral administration (mainly subcutaneous) of antibodies and fusion proteins - Due to success with TNF-alpha inhibition, other cytokines involved in RA became targets for inhibition

Question 31

How is RA managed?

Answer 31

- Aim is to prevent joint damage - Multidisciplinary approach: physio, occupational therapy, hydrotherapy, surgery - Drugs

Question 32

What are the types of drug therapies for RA?

Answer 32

DMARDs –Disease-Modifying Anti-Rheumatic Drugs - Started early in the disease to stop joint destruction - Steroid-sparing agents so are safer and more effective in the long term - Biological therapy: all antibodies - Glucocorticoid therapy –e.g. prednisolone. Avoid long-term use due to side-effects but useful in the short-term to relieve symptoms

Question 33

DMARDs - what do they do and examples of frequently and infrequently used ones What must be done regularly with these medications and why?

Answer 33

- Drugs that induce remission (not cure) and prevent joint damage - They do this by reducing inflammation in synovium & slowing/preventing structural joint damage - Complex mechanisms - Slow onset - Examples: methotrexate, sulphasalazine, hydroxychloroquine(all commonly used) - Leflunomide, gold and penicillamine (rarely used) Everything has significant side effects so require regular blood monitoring

Question 34

Give examples of biological therapies

Answer 34

Rituximab & Infliximab are chimeric antibodies with Fab mouse regions and human constant regions Adalimumab & Golimumab are full human antibodies TNFR-Fc is a fusion protein example of TNF-a: Etanercept

Question 35

What are the downsides of biological therapies for RA?

Answer 35

- Expensive and limited by NICE - Side effects from biological therapy include an increased infection risk chance - Particularly in TB as TNF-alpha is important in granuloma formation. Patients could die from desseminated TB - Increased risk of TB from TNF-a inhibition so patients must be screened before and perhaps prophylactic treatment for susceptible patients - B cell depletion therapy can be associated with hepatitis B reactivation - So need to screen all patients for hepatitis B before treatment - B cell depletion therapy has also been associated with JC virus infection and progressive multifocal leukoencephalopathy