Rheumatoid Arthritis Flashcards
what is rheumatoid arthritis (RA)?
Autoimmune, systemic, inflammatory disease.
- Characterised by chronic, persistent synovial inflammation which leads to destruction of articular cartilage and bone
- Causes decline in joint function and progressive disability if untreated
- Bone loss and cartilage loss is irreparable – no recovery, so important to treat patients early
is RA considered fully autoimmune?
A causal antigen has not yet been discovered – so is it definitely autoimmune or is it autoinflammatory?
when is the typical onset of RA?
Typical onset is between 40 and 60 years old, however it can begin at any age – not really an age releated disease. If before 18 – JIA (juvenile idiopathic arthritis), later diagnosed as RA
Between 0.5-1% of adults have RA (Smolen et al., 2016). The severity is highly variable
- common autoimmune disease
what joints can RA affect?
RA can affect any joint but usually initially affects the MCP, PIP and MTP joints, sometimes progressing to the wrists, ankles and knees. - Does not usually affect the axial skeleton (spine).
-Characterised by a symmetrical pattern of joint involvement.
what are the common symptomatic features of RA?
- a symmetrical polyarthritis with pain and swelling affecting the small joints of the hands and feet
- morning stiffness in and around the affected joints which improves with activity and frequently report debilitating fatigue
- swelling due to oedema, which can be dispersed with movement
- fatigue is the most difficult symptom to model and treat - caused by continuous autoinflammatory response
what are the key laboratory features of RA?
Increased level of acute phase reactants (e.g. C reactive protein (CRP) )
Increased level of erythrocyte sedimentation rate (ESR))
Presence of autoantibodies such as Rheumatoid Factor (RF) and Anti-Citrillinated Protein Autoantibodies (ACPA)
what is the normal structure of a joint?
At ends of bone is articular cartilage – crucial for joint function
- glycoprotein rich, so can absorb water
- Smooth tissue – enables smooth movement of join
- Cartilage surfaces are lubricated by synovial fluid, produced by synovial membrane
- This membrane is thin, comprised of fibroblasts and macrophages, producing lubricin – couple of cells thick
how are joints altered in RA?
In RA, there is expansion and thickening of membrane – fibroblast expansion and membrane inflammation
- leukocytes, monocytes invade thin membrane and cause swelling
- This impairs joint movement
- Synovial fluid is filled with leukocytes, so becomes thickened
- Fibroblasts no longer produce lubricin properly
- Swelling, pain, difficulty in movement
- Inflammatory environment: cytokines and destructive enzymes form osteoclasts – bone erosion and irreversible loss of cartilage
what are the types of arthritis and their key features?
- rheumatoid arthritis
- symmetrical - psoriatic arthritis
- asymmetric - Ankylosing spondylitis
- inflammation of axial skeleton - osteoarthritis
- ageing disease, caused by damage to cartilage
all include overactivity of immune system
how can different arthritis be treated?
OA = steroids and hip replacement
RA = DMARDs to block TNFa, joint replacement
how is osteoarthritis different to RA?
Osteoarthritis:
- unclear if damage to joint causes localised inflammation, orif localised inflammation cause damage
- Loss of cartilage first, then bone changes
- OA gets worse with movement
Whereas inflammatory arthritis is characterised by synovial inflammation which then causes damage to bone/cartilage
- RA improves with movement
what are the risk factors for RA?
- increasing age (but not an age-related disease)
- female sex (3:1)
- genetic component - heritability is 53-68%
- environmental risk factors e.g. smoking, dust/silica, P. gingivalis
what are the genetic predispositions for RA?
HLA-DRB1 gene variants - “Shared epitope”
Variants or single nucleotide polymorphisms (SNP) in:
- Protein Tyrosine Phosphatase 22 (PTPN22)
- CTLA4
- STAT4
- IL-6
- NF-Kb
- PAD enzymes
does the genetic risk encompass the entire cause of RA?
There is a genetic component, but this doesn’t explain entirety of risk
- Can have genetic risk factor and not get disease, or may not have any gene risk factor but can get disease
what is rheumatoid factor (RF)?
autoantibodies that recognize the Fc portion of immunoglobulin G molecules
- RFs have numerous causes in addition to RA and therefore have limited specificity for RA
is RF good for RA diagnosis?
no:
- Found in RA patients, but also seen in other diseases and even in healthy people
- RF is not specific to RA, but most RA patients have RF
25% healthy 50 year olds have RF – harmful but not causal
- People with RF may not get RA, but can exacerbate RA
what are ACPAs in RA?
autoantibodies to citrullinated protein/peptide autoantigens
- ACPA is only seen in RA
- But not all RA patients have ACPA: ACPA+ and ACPA- RA may be different diseases
- ACPA are causal antibodies in some patients, while other patients may have other causes
- ACPA can be present in family members of RA patients before they have symptoms – should we treat people who have ACPA and who may be at risk of RA?
how are peptides citrullinated?
- cyclic citrullinated peptide is where arginine is converted to citrulline
- this can happen to any protein - citrullination is non-specific
- This occurs via PAD enzymes
- SNPs in PAD can cover RA risk
- P gingivalis produces PAD enzyme – this is how the pathogen can generate CCPs which lead to autoantibody disease
is ACPA more specific to RA than RF?
yes:
- The anticyclic citrullinated peptide (anti-CCP) assay broadly detects antibodies against citrullinated proteins (ACPAs) and has high specificity and excellent sensitivity in RA
- Anti-CCP/ACPAs precede the onset of clinical RA and are associated with more severe disease, making them useful as diagnostic and prognostic tools
what therapy is currently useful in RA?
anti-TNF to dampen down inflammatory responses against the synovium
- but, toxic effects as patient becomes more susceptible to pathogens
