Rheum - RA Flashcards
RA?
Rheumatoid Arthritis
Define RA
Chronic inflammatory condition characterised by
• PAIN
• STIFFNESS
&
• SYMMETRICAL SYNOVITIS (inflammation of synovial membrane) of synovial joints
Key features of RA?
o Chronic arthritis
• Polyarthritis – swelling of small joints (hand/wrist)
• Symmetrical
• Early morning stiffness
• May lead to joint damage & destruction
o Extra-articular disease (may occur)
• Rheumatoid nodules – SC swellings (immune complexes and RF)
o Rheumatoid “factor” (Anti-IgG IgM-auto-antibody)
• IgM auto-Ab against IgG
Epidemiology of RA?
1% of population affected
F:M = 3:1
Genetic component of RA?
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 of RA?
Smoking
• interacts with shared epitope to increase risk!
Most common affected joints of RA?
o Metacarpophalangeal joints (MCP). o Proximal interphalangeal joints (PIP). o Wrists. o Knees. o Ankles. o Metatarsophalangeal joints (MTP).
My Poor Willy Knows All Mothers.
Features of RA?
SYMMETRICAL POLYARTHRITIS
• symmetrical!!
Swan-neck deformities
• affects ring-finger with HYPER-extension of PIP join
AND
• HYPER-flexion of DIP joint
Boutonniere deformity
• affects little finger with HYPER-flexion of PIP joint
Where is the 1o site of pathology of RA?
In the SYNOVIUM, located at:
• Synovial joints - PIP joint synovitis
• Tenosynovium - extensor tenosynovitis
- tendons wrapped in Tenosynovium
• Bursa - olecranon bursa for e.g.
What then develops after the 1o site of pathology and explain this
Sub-cutaneous nodules!
Nodule structure:
• Central area – fibrinoid necrosis surrounded by macrophages
• Peripheral area – connective tissue
o Occur in ~30% patients.
o Associated with – severe RA, extra-articular manifestations, RF
Explain the influence RF has on RA
RF - rheumatoid factor
These are Abs that recognise the Fc portion of IgG as their target antigen!
• typically IgM Abs i.e. IgM anti-IgG Abs
RF is present in 70% at disease onset and a further 10-15% become positive over the first 2 years of diagnosis
Correlations:
o High RH alpha with likelihood of joint damage.
o High RH /alpha/ with how ill the patient feels.
Explain the influence of ACPA on RA
ACPA - anti-cyclic citrullinated peptide Ab
Abs to citrullinated peptides are HIGHLY SPECIFIC for RA
• mediated by PADs (enzymes)
• PADs are MORE active at sites of inflammation when they are produced by neutrophils & monocytes
ACPA is strongly associated with:
• smoking (more citrullination in lungs)
• HLA - ‘shared epitope’
Why might an individual be more susceptible to RA in regards to ACPA?
An individual may be susceptible if they carry the specific amino-acid sequence in their HLA-DR antigen-binding groove – “Shared epitope”
- Shared sequence in amino-acids 70-74 of the HLA-DRbeta- chain
- Hence, multiple serotypes of HLA are associated with RA (HLA-DR1, 4, 6, 10) – all have “Shared epitope”
This shared epitope preferentially binds non-polar substances such as CITRULLINE
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.
Extra-articular features of RA - both common and uncommon?
Common:
Pyrexia, weight loss
SC nodules
Uncommon: Vasculitis Episcleritis – ocular inflammation Neuropathies Amyloidosis Lung disease – fibrosis, nodules Felty’s syndrome – (3) triad of – splenomegaly, leucopenia, RA
Radiographic abnormalities of RA?
Early
• juxta-articular osteopenia (low bone density juxta-articular bone)
Later
• joint erosions at margins of joints
Later still
• joint deformity and destruction
What do you normally find in the synovial joint?
Synovium:
• 1-3 cells thin.
• Contains – type-A synoviocyte (phagocytic), type-B synoviocytes (produce hyaluronic acid) and T1 collagen
Synovial fluid:
• Hyaluronic acid
Articular cartilage:
• T2 collagen
• Proteoglycan – mainly aggrecan
What happens to the synovial membrane in RA?
Synovium becomes a proliferated mass of tissue (pannus) due to:
Neovascularisation.
Lymphangiogenesis.
Inflammatory cells – B/T-cells, plasma cells, mast cells and activated macrophages
- Due to excess, pro-inflammatory cytokine imbalance.
- Mainly due to actions of TNF-a.
- Therapy for RA – TNF-a can be inhibited by SC antibodies/fusion proteins.
Pathology of RA?
In rheumatoid arthritis, the synovial membrane becomes thickened and chronically inflamed
• It will also cause joint swelling, which is referred to pathologically as a pannus (synovial tissue that is chronically inflamed)
The inflammation then starts to eat away at adjacent bone
•There is a small area of bone that is within the synovial membrane but is notcovered by articular cartilage - this bare area of bone is often where erosion is first seen (because the pannus normally has to destroy the cartilage before it reaches the bone) -‐periarticular erosionsare seen first
Eventually there will be cartilage damage -‐this is very difficult to reverse
What is the basis of biological therapy often given to people with RA?
Alongside TNF-a:
• IL-6 and IL-1 can also be blockaded
We can also deplete B-cells in RA by IV anti-CD20 antibodies
o Rituximab
What is the treatment goal for RA?
To PREVENT DAMAGE
How is the treatment goal for RA achieved?
Multidisciplinary approach
• physio, occupational therapy, hydrotherapy, surgery
Medication including:
• Drugs – DMARDs – Disease-Modifying Anti-Rheumatic Drugs.
- Started early in the disease – joint destruction = inflammation x time
- DMARDs (“steroid-sparing agents”) are safer and more effective in the long term than steroids since they avoid the long-term side-effects of steroids
• Biological therapy
• Glucocorticoid therapy – e.g. prednisolone.
- Avoid long-term use due to side-effects but useful in the short-term to relieve symptoms.
DMARDs?
Disease-Modifying Anti-Rheumatic Drugs
Drugs that
• INDUCE REMISSION (NOT cure)
&
• PREVENT joint damage
How do DMARDs fulfil their functions?
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.
What has changed about the biological therpaies over time?
The older biological therpaies were mouse Abs
• so WOULD trigger an IR
• e.g. Rituximab & Infliximab
The newer therpaies are completely human Abs
• so do NOT trigger at IR
• e.g. Adalimumab & Golimumab
