Flashcards in Lecture 25 - Rheumatoid Arthritis - Introduction Deck (80):
How many different types of arthritis are there?
What is the burden of arthritis?
• approx. 3.3 million
• $55 billion spent
What is the definition of RA?
Chronic inflammatory autoimmune disease of unknown aetiology
Describe the primary manifestation of RA
Synovitis (synovial inflammation)
• Peri-articular structures
What is the incidence of RA?
0.5% - 1%
Is RA more common in males of females?
Females (2-3x more common)
What is the age of onset of RA?
What is the central paradigm of autoimmune disease?
Genetic susceptibility + Environmental trigger
→ Breakdown of immune tolerance
→ Autoimmune disease
Outline the categories of risk factors for RA
Describe the genetic risk factors for RA
1. HLA class II
• DRB1 gene, which encodes HLA-DR
• Allelic variants
2. non-HLA II
What do twinning studies show about genetic risk of RA?
Genetics accounts for 50-60% of disease susceptibility
The remainder is due to other factors
On which chromosome are the genes for HLA class II?
Chromosome 6, p arm
Which alleles of HLA-DR predispose to RA?
What is the 'shared epitope'?
What is its role in RA?
Five aa sequence: QKRAA
Present in the HLA-DR β chain
Surrounds the peptide binding groove; thus determining antigen presentation in the context of HLA II)
Role in RA:
• Efficient binding of arthritogenic peptides
• Thymic selection of autoimmune T cells
What are the proposed roles of the SE?
SE: Shared epitope
• Target for T-cells (molecular mimicry)
• Marker of immunoreactivity
• Polarises T cell differentiation to Th17 (autoimmunity)
List some non-HLA genetic risk factors for RA
There are many other genes that have been identified
• has a role in B and T cell signalling
• Carries a 2 fold risk of RA in caucasians
What is microchimerism?
Give an example of it in RA
What is NIMA?
• the presence of a small number of cells that originate from another individual (usually the mother)
• Genetically distinct from the cells of the host individual
• The cells often come from the mother during gestation
• Maybe responsible for autoimmune disease, however the mechanisms are still unclear
NIMA: Non-inherited maternal antigens
Persistence of maternal antigens in a child throughout life (from gestation)
These antigens are not 'inherited'
Cells expressing SE from mother persist
What is epigenetics?
Modification of chromosome that leads to altered gene expression without changes to the DNA sequence
What are some epigenetic mechanisms seen in RA?
1. Increased histone deacetylase
• In fibroblasts
→ increased cell proliferation
2. DNA methylation
(suppression of gene expression)
• In RA, there is an abnormal pattern of DNA methylation
of genes associated with RA
• Pre-translational modification of genes thought to be associated with RA
List some hormonal risk factors for RA
1. Oestrogen exposure
→ Thus women more prone to RA
• High levels of Oestrogen and Progesterone (as well as IL-10)
• Immune suppressive effect during pregnancy
• Relapse postpartum
Describe how oestrogen exposure predisposes to RA
1. B cells
• Eostrogen exposure makes them become more resistant to apoptosis
• These are the cells that are producing the auto-antibodies
• Eostrogen exposure leads to increased metalloproteinase secretion
→ damage of joints
• Eostrogen exposure to macrophages increases their release of TNF
Describe how pregnancy exposure predisposes to RA
In pregnancy there are high levels of Oestrogen and Progesterone
1st & 2nd trimester: > 75% of the women have improvement of RA
3rd trimester: remission
• Lots of oestrogen circulating
**(is oestrogen beneficial or harmful?)
What is Citrullination?
Post-translational conversion of arginine to citrulline by PADI enzymes
What is the function of PADI enzymes?
Where are they active (on a cellular level)?
Conversion of arginine to citrulline
Active intra- or extracellularly
What is the role of citrulline in RA?
1. Citrulline binds the Shared Epitope (SE) more avidly
2. Break down in tolerance
3. Presence of anti-citrullinated protein Ab
What is ACPA?
What are some of its targets?
Anti–citrullinated protein antibody
• Type II collagen
When is PADI expressed?
Not specific to joint or RA
Happens in many instances:
• Tissue stress
How many isoforms of PADI are there in humans?
Which are abundant in inflamed synovium?
There are four isoforms
Abundant in inflamed synovium:
• PADI -2
• PADI -4
What does PADI stand for?
Describe the citrullination reaction
Arginine → Citrulline
List some environmental risk factors for RA
• increased PADI 2 expression
• Epstein-barr virus (molecular mimicry)
• Porphyromonas gingivitis (increased PADI4 expression)
4. Bronchial stress
• Exposure to silica
5. TLR activation
Describe the features of synovitis
1. Inflammatory cell infiltration
• Mast cells
2. Vascular neogenesis
3. Ectopic lymphoid neogenesis
4. Synoviocyte neogenesis
What are the articular manifestations of RA?
• Morning stiffness
Which joints are most commonly affected by RA?
• Metacarpophalangeal (MCP)
• Proximal interphalangeal (PIP)
• Metatarsophalangeal (MTP)
• Distal interphalangeal
Compare the following in Osteoarthritis and RA:
• Age of onset
• Predisposing factors
• Joints involved
1. Age of onset:
• OA: 65 +
• RA: Childhood and adults, peak around 50
2. Predisposing factors
• OA: Injury, increased body mass,
• RA: Genetics (HLA-D1, HLA-D4), Smoking
• OA: Pain in moving joints
• RA: Morning stiffness
4. Joints involved:
• OA: Hips, knees (weight bearing joints)
• RA: metacarpophalangeal, wrist,
• OA: asymetrical
• RA: symmetrical
• OA: Bony swelling
• RA: Soft tissue swelling
Describe presence of nodules in RA
• Subcutaneous (e.g. Achilles tendon nodules)
List pulmonary features of RA
• Pleural effusion
• Fibrosing alveolitis
List ocular manifestations of RA
• Keratoconjunctivitis sicca (KJS)
List vascular manifestations of RA
• Mononeuritis multiplex
List neurological manifestations of RA
• Nerve entrapment
• Cervical myelopathy
List cardiovascular manifestations of RA
• Ischemic heart disease (IHD)
• Pericardial effusion
• Conduction defects
List cutaneous manifestations of RA
• Palmar erythema
• Pyoderma gangrenous
• Neutrophilic dermatoses
List haematologic manifestations of RA
• Felty's syndrome
List malignant manifestations in RA
• Lymphoproliferative disease
• Large granular lymphocyte syndrome
• Lung cancer
• Skin cancer
List the autoantibodies seen in RA
What are their specificities?
What is the role of these auto-Abs in RA?
Why are they helpful?
1. Rheumatoid Factor (RF)
• auto-Ab against Fc portion of IgG
2. ACPA: Anti-citrullinated protein antigen
• against citrullinated self proteins
Role in RA:
• Indicate break down in tolerance
• Not part of pathogenesis
• Diagnostic and Prognostic information about the disease
• Not part of treatment
Are autoantibodies present before or after onset of RA?
Both: before and after
Auto-Ab can be present years before onset
Compare sensitivity and specificity
Sensitivity: probability of true positive
• Probability of those who have the disease testing positive
Specificity: probably of true negative
• Probability of those who don't have the disease testing negative
What is the positive likelihood ratio?
Sensitivity ÷ (1 – specificity)
How is RA diagnosed?
Detection of auto-Ab:
• IgM RF (rheumatoid factor)
Compare sensitivity and specificity of the two auto-Ab tests
1. IgM RF:
• More sensitive
• RF: 70
• ACPA: 67
• More specific
• RF: 79
• ACPA: 95
Which auto-Ab test has a higher Positive Likelihood Ratio?
Give the ratios for both
ACPA by a long way
IgM RF: 3.3
What are the two 'sero-' subsets of RA?
• RF / ACPA positive
• RF / ACPA negative
How is RA disease activity assessed?
1. Joint counts
• Tender / swollen
• with DAS28-ESR Calculator
2. Global assessment
3. Pain score
4. Morning stiffness
• Erythrocyte sedimentation rate
• C-reactive protein
8. Radiological damage
What is C-reactive protein?
• Protein made by the liver
• Levels rise during inflammation
• Bind to dying or dead cells
• Triggers C' activation
• Thus, role in clearing apoptotic or necrotic cells
Describe the results given by DAS28
1. < 2.6: remission
2. 2.6-3.2: low disease activity
3. 3.2-5.1: moderate disease activity
4. > 5.1: high disease activity
What may still be occurring in clinical remission?
In a certain subset of patients
List some general extra-arthritic manifestations of RA
• Neurological manifestations
• Pulmonary manifestations
• Cardiovascular manifestations
What are 95% of cases of arthritis due to?
Describe the structure of a synovial joint
• Articular cartilage
• Synovial fluid
• Synovial membrane
Which HLA gene is involved in RA?
Which molecule does the Shared Epitope bind very effectively?
Citrulline (a self peptide)
Describe the results of twinning studies in the context of the contribution of smoking to RA
• Mono-zygotic twins that were discordant for smoking and RA
• The twin who smokes is much more likely to develop RA
• Smoking interacts with PADI2
• Contributes to the citrullination process
Describe the effect of the Industrial revolution on RA
RA not observed before the industrial revolution
Some environmental antigen associated with the new Industries that leads to RA?
Describe the role of EBV and molecular mimicry in RA
SE a target for auto-reactivity itself:
• Similar sequence on EBV peptides to the SE (Shared Epitope)
→ Cross reaction
Discuss the risk factor of the Microbiome in RA
• Germ free mice raised
• Certain bacteria given to mice
• Induction of RA in the mice
• Certain bacteria may play a role in development of RA
Compare pain in OA and RA
RA: morning pain
OA: pain progresses in severity throughout the day. Normally at its worst in the evenings
Which joints are commonly affected in:
• DIP: base of thumb
Weight bearing joints:
What is the strength of ACPA Ab in diagnostics?
It is very specific:
i.e. not likely to give a false negative
Describe how auto-Abs can be used as a prognostic tool
Seropositivity of seronegativity gives prognostic information:
• Radiographic progression
• Extra-articular manifestations
• Functional impairment
What are the parameters of DAS28?
• Joint tenderness
• Joint swelling
• ESR (Erythrocyte sedimentation rate)
What is clinical remission?
The disease is not cured, but the disease process has gone away for the moment
What is the goal of treatment in RA?
Which epigenetic modification is seen in the fibroblasts in the inflamed synovium in RA?
What can this lead to?
In fibroblasts: increased Histone deacetylase
Leads to increased proliferation
What is the effect on gene expression of DNA methylation?
Silencing of the gene
What is the role of metalloproteinases in RA?
Destruction of the joint:
Describe the role of Porphyromonas gingivalis in RA
• This is a pathogen
• Affects the function of PADI 4
• Thus, affects the citrullination process
Describe the risk factor of TLR activation in RA
• TLR activation leads to increased expression of PADI
• Increased citrullination
Why is SE a good marker of immunoreactivity?
Leads to production of ACPA when it binds citrulline peptide
What are some common deformities seen in RA?
Describe the position of the affected joints
1. Boutonniere deformity
• Flexion of PIP
• Extension of DIP
2. Swan neck deformity
• Hyper-extension of PIP
• Hyper-flexion of DIP
3. Ulnar deviation
• Phalanges subluxed from the MCP
• Phalanges drift outwards