RA - L1 Flashcards
What is RA?
Chronic inflammatory autoimmune disease
Incidence & Prevelance
8-98/100,00 per annum
0.5 to 1%
1-3x more common in females
Principles of Autoimmune Disease
Genetic Susceptibility + Environmental Trigger
leads to break down of immune tolerance (self reactive anitbody or T cells)
Risk Factors
Genetics - 50-60%
HLA - 12.7%
Non-HLA - 4%
Epigenetic
Hormonal
(Citrullination)
Stochastic Environmental TriggersWhat is HLA?
Region of genes at 6p21.31 that are involved in encoding cell surface molecules (antigen presenting molecules) and proteins involved in immune function
What HLA gene is susceptible?
HLA Class II
DRB1 gene
variants DRB1 *0401 & DRB1 *0404
What is the shared epitope?
The five amino acid sequence that the HLA-DRB1 alleles encode
QKRAA
positions 70-74 of the beta chain
surrounds peptide binding groove (determines antigen binding specificity & CD4 presentation)
What is the significance of the shared epitope?
It is shared by all the DRB1 alleles that have been implicated in RA and is not found in other DRB1 alleles, is said to cause the disease
Proposed roles of shared epitope?
Marker of Immunoreactivity (ACPA)
Efficient binding of arthritogenic (citrulline) peptides
Thymic selection of autoimmune T cells
Target for T cell
Polarises T cell differentiation to TH17 type
Is SE a good predictor is disease severity?
Yes, but not a good predictor of disease progression
What is microchimerism?
The state where maternally-derived cells persist in the offspring
What is the relevance of microchimerism?
May explain variability of RA. T cells from mother expressing SE may have survived in the offspring. Can also work in reverse, non-inherited maternal anitgens (NIMA)
What are non-HLA risk factors?
PTPN22
gene coding for a tyrosine phosphatase found in lympoid tissue that is involved in B and T cell signalling (non Asians)
PADI4
asians
What is epigenetics?
modification of a chromosome that leads to altered gene expression, without changing DNA
What are some epigenetic mechanisms?
Histone deacetylase increased in RA
DNA methylation
microRNAs
all involved in down regulation or silencing of gene expression
What are some hormonal risk factors?
oestrogen exposure B cells more resistant to apoptosis FLS produce metalloproteinases and cause bone degradation bind macrophages and they secrete TNF pregnancy
What is citrullination?
the post-translational conversion of arginine (+ve charge) to citrulline (no charge) by peptidyl-arginine deiminase (PADI) enzymes
Why is citrullination relevant?
new tertiary structure, autoimmune response
citrulline binds SE more avidly
leads to immune tolerance breakdown –> ACPA increased
What isoforms of PADI do humans have?
Four
PADI2 & PADI4 abundant in inflamed synovium
What are some stochastic triggers? (~40%)
new world pathogen
smoking (PADI2)
bronchiol stress
microbiome
What are the articular manifestations of RA?
pain
swelling
morning stiffness
symmetrical distribution
What joints are affected in RA and what are there deformities?
Upper limbs MCP - swan neck deformity PIP - Boutonniere deformity wrist Lower limbs MTP
What are some extra-articular manifestations?
nodules pulmonary ocular vasulitis neurological cardivascular cutaneous malignancy
How is RA diagnosed?
X-ray then blood work
What antibodies are looked for in diagnosis?
Rheumatoid factor and ACPA
antibodies develop before symptoms present
What is RF?
a high affinity antibody against the Fc portion of IgG
What is sensitivity?
patients with the disease that test positive
A/(A+C)
What is specificity?
patients without the disease that have a negative result
D/(B+D)
What is the positive likelihood ratio?
true positives / false positives (high the better)
What is the negative likelihood ratio?
false negatives / true negatives (smaller the better)
How to RF and ACPA compare?
RF more sensitive
ACPA more specific
ACPA better PLR
What are the ACR/EULAR classification criteria?
joint involvement
serology (RF & CCP)
acute phase reactants (CRP & ESR)
duration of symptoms
greater than 6 = RA
How is severity of RA assessed?
DAS28-ESR Calculator
What does the DAS28-ESR consider?
joint counts global assessment pain score morning stiffness laboratory (ESR & CRP) disability fatigue radiologica damage
What are the DAS28-ESR thresholds?
5.1: high disease activity
What are the differences between RA & osteoarthritis?
age at onset predisposing factors early symptoms joints involved physical findings radiological findings laboratory findings
