5. Rheumatoid arthritis

Question 1

Do arthritis patients present with pain in their back?

Answer 1

No

Question 2

Does rheumatoid arthritis affect one or both hands?

Answer 2

Symmetrical - always affects both (same with wrists, knee etc.)

Question 3

When is stiffness around the joins particularly bad during the day?

Answer 3

In the morning

Question 4

What usually helps stiffness in the joints

Answer 4

Exercise

Question 5

What are the key features of RA?

Answer 5

• Chronic arthritis - symmetrical polyarthritis, untreated - destruction
• Extra-articular disease can occur e.g. rheumatoid nodules, vasculitis (rare) due to rheumatoid factor
• Rheumatoid factor may be detected in blood - IgM autoantibody against IgG that can form immune complexes

Question 6

Is RA more common in males or females?

Answer 6

Females

Question 7

Describe the genetic component of the pathogenesis of RA

Answer 7

• Specific set of amino acids within the beta chain of the DR molecule
• It is conserved among all HLA subtypes associated with RA
• Suggests that this is the antigen binding group (HLA-DR antigen binding groove) associated with RA
• Referred to as the shared epitope

Question 8

How is smoking related to RA?

Answer 8

• Affects the susceptibility and severity of the disease - smokers with RA are generally far worse than non-smokers
• Interacts with the shared epitope to increase risk

Question 9

What are the most commonly affected joints in RA?

Answer 9

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

Question 10

What type of change will untreated and chronic RA result in?

Answer 10

• Mechanical change

* e.g. change in shape can cause callous formation under the heads of metatarsals

Question 11

What is Swan-neck deformity?

Answer 11

Hyperflexion at the DIP and hyperextension at the PIP

Question 12

What is Boutonniere deformity?

Answer 12

Hyperflexion at the PIP

Question 13

What is a whole swollen digit referred to as?

Answer 13

Dactylitis

Question 14

Can several fully swollen fingers be explained by RA?

Answer 14

No (as in this case it’s not just the joint affected)

Question 15

What wraps around the tendons to allow them to move freely?

Answer 15

Tenosynovium

Question 16

How can you confirm that synovitis is around the tendons and not the joints e.g. extensor tenosynovitis?

Answer 16

• Ask the patient to raise their fingers

* You will see the swelling being pulled back

Question 17

What are bursars and what happens when they are inflamed?

Answer 17

• Pockets of fluid on the surface of the joints

* Inflammation => bursitis

Question 18

How are rheumatoid nodules formed?

Answer 18

• Rheumatoid factor produces immune complexes that can deposit in any tissue
- IgM binds to Fc portion of IgG
• Tendency to deposit in subcutaneous tissue (and cause extra-articular manifestations - rare)
• Effects are outside the synovium
• Associated with severe disease

Question 19

Where are rheumatoid nodules commonly seen?

Answer 19

Along the ulnar border of the forearm

Question 20

Is the patient always ‘rheumatoid factor positive’ if rheumatoid nodules are present?

Answer 20

Yes

Question 21

Can the test for rheumatoid factor be diagnostic for RA and why?

Answer 21

No, as 1/3 of RA is rheumatoid factor negative

Question 22

How specific are antibodies against citrullinated peptides in RA?

Answer 22

Highly specific - anti-cyclic citrullinated peptide antibody (Anti-CCP)

Question 23

What is ‘citrullination’ and which enzymes mediate it?

Answer 23

Post-translational modification of arginine by peptidyl arginine deaminases (PADs)

Question 24

Why do citrullinated peptide antigens develop in rheumatoid arthritis?

Answer 24

• PADs are present in high conc. in neutrophils and monocytes
• Increased citrullination of autologous peptides in the inflamed synovium
• Strongly associated with smoking and the HLA ‘shared epitope’
• Citrulline binds much better than arginine to the specific peptide sequence conserved in the MHC (that is associated with RA)
• The shared epitope preferentially binds non-polar amino acids such as citrulline

Question 25

What are common (and uncommon) extra-articular features of RA?

Answer 25

Common • Fever • Weight loss • Subcutaneous nodules ``` (Uncommon • Vasculitis • Neuropathies • Amyloidosis • Lung disease) ```

Question 26

Why is a citrullinated antigen more likely to elicit an auto-immune response?

Answer 26

* Binds better to the HLA-DR peptide groove (amino acids 70-74 of the HLA-DRβ chain) * More likely to present to T cells * More like to get auto-immunity

Question 27

Why are multiple different HLA serotypes associated with RA e.g. HLA-DR4, -DR1, -DR6, -DR10

Answer 27

* They all contain the shared epitope (amino acids 70-74 of the HLA-DRβ chain) * Some individuals with HLA-DR4 not at risk (as some don't contain the shared epitope)

Question 28

What are the early and later radiographic abnormalities seen in RA?

Answer 28

* Early - juxta-articular osteopenia | * Later - joint erosions at margins of the joint, deformity and destruction

Question 29

What happens to the synovial membrane in RA?

Answer 29

Thickened and chronically inflamed (pannus)

Question 30

What is the 'bare area' in RA?

Answer 30

* Where erosion if first seen on the bone * Pannus normally destroys the cartilage before it reaches the bone * Peri-articular erosions are seen first

Question 31

How thick is the synovium?

Answer 31

Single cell lining

Question 32

Which cells produce synovial fluid from within the synovial lining?

Answer 32

* Macrophages and fibroblasts | * Within the synovial lining

Question 33

What is the consistency of the synovial fluid and why?

Answer 33

* Viscous | * Lot of hyaluronic acid

Question 34

What is the articular cartilage made up of?

Answer 34

Type 2 collagen (contains a proteoglycan)

Question 35

What is the main proteoglycan in articular cartilage?

Answer 35

Aggrecan

Question 36

What is the synovium made up of?

Answer 36

* Type 1 collagen (fibroblast-like, produce hyaluronic acid) | * Macrophage-like cells (clear debris within the joints)

Question 37

What structural and cellular changes cause the inflammation of the synovium (pannus)?

Answer 37

* Neovascularisation * Lymphangiogenesis - formation of new lymphatic vessels * Inflammatory cells activated: B cells, T cells, plasma cells, mast cells, macrophages

Question 38

Outline the cytokine imbalance in RA?

Answer 38

* Excess of pro-inflammatory cytokines * IL-1, IL-6 and TNF-α mainly involved * TNF-α is the dominant pro-inflammatory cytokine in the synovium * It's pleiotropic actions (multiple effects from single gene) are detrimental

Question 39

Why is TNF-α so significant in the cytokine imbalance and how is this useful in treatment?

Answer 39

* Top of hierarchy in the cytokine system * If you down-regulate TNF-α, you down-regulate lots of other pro-inflammatory cytokines * TNF-α inhibition has excellent therapeutic effects * Administered through parenteral administration (mainly subcutaneous) of antibodies and fusion proteins

Question 40

How is TNF-α mainly produced (affecting RA)?

Answer 40

By activated macrophages in the rheumatoid synovium

Question 41

What is the treatment goal in RA?

Answer 41

* Prevent joint damage * Multi-disciplinary approach involving physiotherapists, surgery etc. * Pharmaceutical interventions are necessary * Treat natural history of the disease, pain and inflammation

Question 42

What do Disease-Modifying Anti-Rheumatic Drugs (DMARDs) do?

Answer 42

• Drugs that control the disease process • Started early (as joint damage = inflammation x time) • 'Steroid-sparing agents' • Safer and more effective long-term treatment than steroids • Do not cure RA - they may induce remission and prevent joint damage e.g. methotrexate

Question 43

When is glucocorticoid therapy useful for RA?

Answer 43

* Useful for short-term use e.g. control an exacerbation of the disease or inflammation of a single joint * Preferred to avoid long-term use due to side effects

Question 44

How fast is the onset of action for DMARDs?

Answer 44

Slow i.e. weeks

Question 45

How are patients monitored whilst on DMARDs and why?

Answer 45

* Regular blood tests * Significant adverse effects * Look at LFTs every 6-8 weeks * Changes in the tests are seen way before people fell unwell

Question 46

What biological therapy interventions can help RA?

Answer 46

* Anti TNF-α - infliximab, fusion protein * B cell depletion - rituximab * Modulation of T cell co-stimulation * Inhibition of IL-6

Question 47

How are newer biological therapies for RA different to older therapies?

Answer 47

* Older - mouse antibodies (chimeric) => could trigger a human anti-chimeric response * Newer - completely human antibodies => no chimeric antibody response

Question 48

What are the disadvantages of biological therapy?

Answer 48

* Expensive * Increased infection risk (side effect) * TNF-α is important in granuloma formation e.g. important in TB, so blocking it could cause death from disseminated TB * TNF-α inhibition is associated with increased susceptibility to mycobacterial infection * B cell depletion can be associated with hepatitis B reactivation, JC virus infection and progressive multifocal leukoencephalopathy (PML)