Lecture 24 - Rheumatoid Arthritis Flashcards
Arthritis definition
Literally means ‘inflamed joint’
Umbrella term for over 100 joint-inflammation diseases
Number of Australians suffering from arthritis in 2011-2012
~3.3 million
Diseases causing 95% of arthritis cases
Osteoarthritis, rheumatoid arthritis, gout
Cost of arthritis and musculoskeletal condition treatment in 2012
$55.1 bilion
Rheumatoid arthritis
Chronic autoinflammatory disease of unknown aetiology
Associated with articular manifestations
Synovitis
1)
2)
1) A primary manifestation of RA
2) Leads to erosion of bone cartilage and peri-articular structures
Incidence
Number of cases diagnosed in a year
Prevalence
Number of cases within a set period of time
Incidence of RA in adult caucasian populations
8 to 98 cases/100,000 per year
Prevalence of RA in adult caucasian populations
0.5-1%
Which gender is more at risk of RA?
Females 2-3x more likely to develop RA than males
Peak age of RA onset
40 years (40-70 year range)
RA risk factors 1) 2) 3) 4)
1) Genetic
2) Epigenetic
3) Hormonal
4) Stochastic triggers
Most powerful genetic factor in RA
HLA type
HLA types most associated with RA
DRB1 gene of HLA2 locus
DRB1 alleles associated with RA
DRB1 0401
DRB1 0404
Amount that genetics contributes to RA susceptibility
~60%
Proportion of genetic RA cases that are caused by HLA
12.7%
Which chromosome is HLA locus on?
p arm of chromosome 6
Aspect of HLA DRB1 that makes one more susceptible to RA
Encodes shared epitope
What is the shared epitope? 1) 2) 3) 4)
1) Encoded by HLA DRB1
2) Glutamine-leucine-arginine-alanine-alanine motif
3) Occupies position 70-74 of HLA-DRbeta chain
4) Surrounds peptide binding groove
Amino acid sequence of shared epitope
Glutamine-leucine-arginine-alanine-alanine
QKRAA
How does the shared epitope contribute to RA? 1) 2) 3) 4) 5)
1) Efficiently binds citrullinated residues
2) Thymic expression of autoimmune cells (positive, negative selection)
3) Target for T cells (molecular mimicry, EG: EBV)
4) Marker of immunoreactivity (ACPA)
5) Polarises T cell differentiation to Th17
ACPA
Anti-citrullinated protein antibodies
What can be inferred from the presence of shared epitope?
1)
2)
1) Doesn’t necessarily predict RA
2) Could indicate severity of RA - With two copies, increases bone erosion, extra-articular manifestations
HLA-DRB1 RA odds ratio
4-5 fold increase
Gene that is a RA risk factor in Asian populations
PADI4
Gene that is a RA risk factor in caucasian populations
PTPN22
PTPN22
Encodes lymphoid tyrosine phosphatase
RA risk factor in non-Asian populations
An explanation why shared epitope is not a RA risk factor in certain ethnic groups
Microchimerism
Microchimerism
Maternal cells of shared-epitope-expressing women persist in child’s circulation throughout adulthood
Non-inherited maternal antigens
Epigenetic mechanisms that might contribute to RA susceptibility
1)
2)
3)
1) Increased levels of histone deacetylase in RA synovia
2) DNA methylation in fibroblast-like synoviocytes and T cells
3) MicroRNAs (regulate protein expression)
Hormonal risk factor in RA
Oestrogen exposure
How can oestrogen exposure contribute to RA susceptibility?
1)
2)
3)
1) Oestrogen makes B cells more resistant to apoptosis (even if B cell makes autoantibodies)
2) Fibroblast-like synoviocytes increase levels of metalloproteases
3) Macrophages increase production of TNFa
Effect of metalloproteases on RA
Damage synovium, bones, tendons
How is pregnancy a hormaonal risk factor in RA?
1)
2)
3)
1) 1st and second trimerster - Over 75% report improvement in RA
2) 3rd trimester - Remission
3) Postpartum - 90% flare
What is citrullination?
Post-translational conversion of arginine to citrulline.
Catalysed by peptidyl-arginine deiminase
How does citrullination contribute to RA?
1)
2)
3)
1) Citrullinated protein forms a neoepitope
2) Citrulline binds shared epitope more avidly
3) This can lead to autoimmune activation
PADI
Peptidyl-arginine deiminase
Converts arginine to citrulline
Is PADI expression specific to RA joint symptoms?
No
Citrullination occurs in many different settings of tissue stress and inflammation
Number of human PADI isoforms
Four
Human PADI isoforms associated with RA
Isoforms 2 and 4 are abundant in inflamed synovium
RA environmental factors 1) 2) 3) 4) 5)
1) Smoking
2) Bronchial stress
3) Infections
4) TLR activation
5) Microbiome
Infections that can increase RA risk 1) 2) 3) 4) 5)
1) Porphyromonas gingivalis
2) EBV
3) Cytomegalovirus
4) Proteus species
5) E coli
How can TLR activation lead to RA?
1)
2)
1) TLR activation can lead to increased peptidyl-arginine deiminase expression
2) TLR2 activation can directly lead to arthritis (EG: TLR2 activation by strep)
Contributors to synovitis in RA
Macrohpages and fibroblasts erode bone in joints
Articular manifestations of RA 1) 2) 3) 4)
1) Pain
2) Morning stiffness (over an hour each morning, for over 6 weeks)
3) Swelling
4) Distribution
Distribution of affected joints in RA
1)
2) a,b,c
3) a
1) Symmetrical
2) Upper limb joints most affected
a) Metacarpolphalangeal (MCP)
b) Proximal interphalangeal (PIP)
c) Wrist
3) Lower limb joints most affected
a) Metatarsophalangeal (MTP)
Deformity caused by proximal interphalangeal swelling
Boutonierre deformity
Deformity caused by metacarpophalangeal swelling
Swan neck deformity, subluxation, ulnar deformity
Ulnar deformity
Bending of the hand towards ulna bone because of metacarpophalangeal swelling
Boutonierre deformity
Caused by proximal interphalangeal swelling
Features by which to distinguish between RA and osteoarthritis 1) 2) 3) 4) 5) 6) 7)
1) Age of onset
2) Predisposing factors
3) Early symptoms
4) Joints affected
5) Physical findings
6) Radiological findings
7) Lab findings
Difference between RA and OA in age of onset
RA onset is childhood, adulthood
OA risk increases with age
Difference between RA and OA in predisposing factors
RA - Susceptibility epitopes (HLA-DRB1)
OA - Trauma, congenital abnormalities
Difference between RA and OA in early symptoms
RA - Morning stiffness
OA - Pain increases during the day
Difference between RA and OA in physical findings
RA - Soft tissue swelling, warmth
OA - Bony osteophytes (bony swelling), minimal soft tissue swelling early
Difference between RA and OA in lab findings
RA - Increased C-reactive protein, rheumatoid factor, anti-citrullinated protein antibodies
OA - Normal
Difference between RA and OA in affected joints
RA - Wrist, MCP, PIP, symmetry. Distal interphalangeal joint is almost always spared
OA - Distal interphalangeal joint, base of thumb. Can affect the lumbar spine
Ways to diagnose RA
1)
2)
1) Physical analysis
2) Presence of autoantibodies (RF, ACPA)
Rheumatoid factor
High-affinity autoantibody against Fc portion of IgG
Prior to RA onset, increases in IgM or IgA isotype of RH
Anti-citrullinated protein antibodies
1)
2)
1) Before onset of RA, increase in titre, avidity, epitope spreading, isotype change
2) Against citrullinated self proteins
Way to detect presence of anti-citrullinated protein antibodies
Anti-cyclic citrullinated peptide assay
Potential targets of anti-citrullinated protein antibodies
Alpha-enolase, keratin, fibrinogen, fibronectin, type II collaged, vimentin
How long before infection can autoantibodies appear?
Several years
Anti-citrullinated protein antibodies appear ~14 years before symptoms
IgM rheumatoid factor antibodies appear ~10 years before symptoms
SpIn
When a test has a high specificity (EG: over 95%), a positive result is taken as a diagnosis
SnNout
When a test has a high sensitivity, a negative result rules out a diagnosis
Positive likelihood ratio
Sensitivity/(1-specificity)
Negative likelihood ratio
(1-specificity)/sensitivity
IgM rheumatoid factor sensitivity
70%
ACPA specificity
95%
Positive likelihood ratio
Chance that a person with a condition will receive a positive result, compared to someone without the condition.
EG: ACPA has a positive likelihood ratio of 14.4, so someone with RA is 14.4x more likely to receive a positive result than someone without RA
Two subsets of RA
1) Seropositive for RF and ACPA
2) Seronegative
Implications of seropositive RA
More aggressive disease
Worse radiographic impressions, extra-articular manifestations, functional impairment
DAS28 ESR calculator
1)
2)
1) Give scores for things such as joint soreness
2) Program calculates a score to measure severity of RA at time of testing
Factors used to calculate DAS28 score 1) 2) 3) 4) 5)
1) Lab results (C-reactive protein, erythrocyte sedimentation rate)
2) Count of sore joints
3) Pain score
4) length of morning stiffness
5) Radiological damage
Das28 cutoffs for either C-reactive protein or erythrocyte sedimentation rates 1) 2) 3) 4)
1) Remission - Under 2.6
2) Low - 2.6 - 3.2
3) Moderate - 3.2 - 5.1
4) High - Over 5.1
What can persist during clinical remission?
Subclinical inflammation, that can only be viewed using MRI or other imaging techniques
What can and can’t autoantibodies be used to determine in RA?
Can be used to diagnose RA
Can’t be used to determine disease activity
