5. Rheumatoid arthritis Flashcards
Do arthritis patients present with pain in their back?
No
Does rheumatoid arthritis affect one or both hands?
Symmetrical - always affects both (same with wrists, knee etc.)
When is stiffness around the joins particularly bad during the day?
In the morning
What usually helps stiffness in the joints
Exercise
What are the key features of RA?
- 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
Is RA more common in males or females?
Females
Describe the genetic component of the pathogenesis of RA
- 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
How is smoking related to RA?
- 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
What are the most commonly affected joints in RA?
- Metacarpophalangeal joint (MCP)
- Proximal interphalangeal joint (PIP)
- Wrists
- Knees
- Ankles
- Metatarsophalangeal joint (MTP)
What type of change will untreated and chronic RA result in?
- Mechanical change
* e.g. change in shape can cause callous formation under the heads of metatarsals
What is Swan-neck deformity?
Hyperflexion at the DIP and hyperextension at the PIP
What is Boutonniere deformity?
Hyperflexion at the PIP
What is a whole swollen digit referred to as?
Dactylitis
Can several fully swollen fingers be explained by RA?
No (as in this case it’s not just the joint affected)
What wraps around the tendons to allow them to move freely?
Tenosynovium
How can you confirm that synovitis is around the tendons and not the joints e.g. extensor tenosynovitis?
- Ask the patient to raise their fingers
* You will see the swelling being pulled back
What are bursars and what happens when they are inflamed?
- Pockets of fluid on the surface of the joints
* Inflammation => bursitis
How are rheumatoid nodules formed?
• 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
Where are rheumatoid nodules commonly seen?
Along the ulnar border of the forearm
Is the patient always ‘rheumatoid factor positive’ if rheumatoid nodules are present?
Yes
Can the test for rheumatoid factor be diagnostic for RA and why?
No, as 1/3 of RA is rheumatoid factor negative
How specific are antibodies against citrullinated peptides in RA?
Highly specific - anti-cyclic citrullinated peptide antibody (Anti-CCP)
What is ‘citrullination’ and which enzymes mediate it?
Post-translational modification of arginine by peptidyl arginine deaminases (PADs)
Why do citrullinated peptide antigens develop in rheumatoid arthritis?
- 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
What are common (and uncommon) extra-articular features of RA?
Common
• Fever
• Weight loss
• Subcutaneous nodules
(Uncommon • Vasculitis • Neuropathies • Amyloidosis • Lung disease)
Why is a citrullinated antigen more likely to elicit an auto-immune response?
- 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
Why are multiple different HLA serotypes associated with RA e.g. HLA-DR4, -DR1, -DR6, -DR10
- 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)
What are the early and later radiographic abnormalities seen in RA?
- Early - juxta-articular osteopenia
* Later - joint erosions at margins of the joint, deformity and destruction
What happens to the synovial membrane in RA?
Thickened and chronically inflamed (pannus)
What is the ‘bare area’ in RA?
- Where erosion if first seen on the bone
- Pannus normally destroys the cartilage before it reaches the bone
- Peri-articular erosions are seen first
How thick is the synovium?
Single cell lining
Which cells produce synovial fluid from within the synovial lining?
- Macrophages and fibroblasts
* Within the synovial lining
What is the consistency of the synovial fluid and why?
- Viscous
* Lot of hyaluronic acid
What is the articular cartilage made up of?
Type 2 collagen (contains a proteoglycan)
What is the main proteoglycan in articular cartilage?
Aggrecan
What is the synovium made up of?
- Type 1 collagen (fibroblast-like, produce hyaluronic acid)
* Macrophage-like cells (clear debris within the joints)
What structural and cellular changes cause the inflammation of the synovium (pannus)?
- Neovascularisation
- Lymphangiogenesis - formation of new lymphatic vessels
- Inflammatory cells activated: B cells, T cells, plasma cells, mast cells, macrophages
Outline the cytokine imbalance in RA?
- 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
Why is TNF-α so significant in the cytokine imbalance and how is this useful in treatment?
- 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
How is TNF-α mainly produced (affecting RA)?
By activated macrophages in the rheumatoid synovium
What is the treatment goal in RA?
- Prevent joint damage
- Multi-disciplinary approach involving physiotherapists, surgery etc.
- Pharmaceutical interventions are necessary
- Treat natural history of the disease, pain and inflammation
What do Disease-Modifying Anti-Rheumatic Drugs (DMARDs) do?
• 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
When is glucocorticoid therapy useful for RA?
- 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
How fast is the onset of action for DMARDs?
Slow i.e. weeks
How are patients monitored whilst on DMARDs and why?
- Regular blood tests
- Significant adverse effects
- Look at LFTs every 6-8 weeks
- Changes in the tests are seen way before people fell unwell
What biological therapy interventions can help RA?
- Anti TNF-α - infliximab, fusion protein
- B cell depletion - rituximab
- Modulation of T cell co-stimulation
- Inhibition of IL-6
How are newer biological therapies for RA different to older therapies?
- Older - mouse antibodies (chimeric) => could trigger a human anti-chimeric response
- Newer - completely human antibodies => no chimeric antibody response
What are the disadvantages of biological therapy?
- 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)
