lecture 25 Flashcards
What is arthritis?
- derived from Greek words
- ‘arthron’ = joint
- ‘itis’ = inflammation
- literally means ‘inflamed joint’
- umbrella term rather than a single disease
- > 100 different types of arthritis currently identified
- disability and reduced quality of life (elderly)
What is the prevalence of arthritis in the Australian Population?
- in 2011-12
- approx, 3.3 million (1 in 6; ~15%) had arthritis
- prevalence higher in indigenous than non-indigenous
- 95% of cases due to osteoarthritis
- less commonly rheumatoid arhtritis, gout
- in 2012 total cost of arthritis and musculoskeletal conditions
- $55.1 billion
- based on current trends, by the year 2050, 7 million australians expected to suffer some form of arthritis
What is a definition of rheumatoid arthritis?
- chronic inflammatory autoimmune disease of unknown aetiology
- associated with
- articular manifestations (dominant feature)
- systemic (or ‘extra-articular’) complications
What does RA lead to in the absence of effective treatment?
- progressive locomotor disability within 10-20 years of diagnosis
- reduced life expectancy of up to 10 years
- significant socioeconomic costs - also loss of gainful employment
What is the primary manifestation of RA?
- synovitis
- primary manifestion is synovial inflammation of ‘synovitis’
- -> erosion of bone, cartilage, peri-articular structures
What is the epidemiology of RA?
- in adult caucasian populations
- incidence 8 to 98 cases per 100,000/annum (new cases diagnosed)
- prevalence 0.5 to 1.0% (number of diagnosed patients over a given point in time)
- occurs 2-3x more commonly in females than males
- peak age of onset 40 (range 40 - 70) years
What is the principle of all autoimmune diseases?
cocktail of ingredients before someone gets an autoimmune disease:
- genetic susceptibility
plus
- environmental trigger (not always known)
leads to breakdown of immune tolerance (self-reactive antibody or T cells)
consequence of this is autoimmune disease
What are risk factors for RA?
- multifactorial
i. genetic
ii. epigenetic
iii. hormonal
iv. stochastic (random) environmental triggers
What are genetic risk factors for RA?
- HLA
- studies of identical twins
- genetics accounts for 50-60% of disease susceptibility
genetic risk factors
i. human leukocyte antigen (HLA) ~ 12.7%
ii. non-HLA ~4%
- HLA Class II (most important)
- DRB1 gene
- encodes HLA-DR antigen presenting molecule
- allelic variant
- DRB1*0401
- DRB1*404
What is the location and organisation of HLA complex? What allelic variants contribute to RA?
- chromosome 6
- short arm
- this area can be divided into three broad regions: class II, class III, class I
- within the class II region, it is the DRB1 which has been associated with increased risk of RA
- RA HLA risk alleles: HLA-DRB10401 and DRB10404
- with this allele risk increased approximately 4 fold
What is the shared epitope hypothesis?
HLA-DRB1 alleles (confer RA risk) encode a five amino acid sequence termed a ‘shared epitope’
- glutamic-leucine-arginine-alanine-alanine (QKRAA)
- occupies positions 70 to 74 of the HLA-DRβ chain
- surrounds peptide binding groove (determines antigen-binding specificity and presentation to CD4+ T helper cells)
What is the proposed role of shared epitope?
i. efficient binding of arthritogeneic (citrulline) peptides
ii. marker of immunoreactivity
- anti-citrullinated protein antibodies (ACPA) expression
iii. thymic selection of autoimmune T cells (+ve or -ve)
iv. target for T cells
- molecular mimicry - SE and microbes (e.g. epstein-barr virus)
v. polarises T-cell differentiation to T helper type 17 (autoimmunity)
What is the susceptibility associated with shared epitope in RA?
Does not necessarily predict progression to RA
- cohort with recent-onset undifferentiated (ACPA+) arthritis, progression to RA occured regardless of HLA-DR genotype
May predict RA severity
- increased joint damage e.g. increased erosions (two copies)
- increased prevalaence of extra-articular manifestations
What is microchimerism?
- possible explanation SE not associated with RA in ceratin ethnic and racial groups
- maternal cells of SE-expressing women persist in their children’s circulation throughout adulthood –> confers increased RA risk
- termed non-inherited maternal antigens (NIMA)
What are non-HLA genetic risk factors for RA?
gene, odds ratio for RA, function
- PTPN22, ~2 fold, encodes lymphoid tyrosine phosphatase; role in T and B cell signalling, no role in RA risk in asians
- PADI4, ~2 fold, primarily asian populations
- TRAF1-C5, b/w 1.2 and 2 fold: encodes TNF-associated factor and complement protein 5c
- STAT4, b/w 1.2 and 2 fold: encodes a tf that controls genes involved in Th1 cell responses
- TNFAIP3, b/w 1.2 and 2 fold: encodes TNF-induced protein 3
- IL2/21, b/w 1.2 and 2 fold: –
- CCR6, – , encodes chemokine-receptor 6
- NLRP1, – , encodes inflammasome-related protein (only in Han Chinese)