Rheumatoid arthritis: The science Flashcards
Features of a rheumatoid joint? (4)
- erosion into corner of bone
- thinning of cartilage
- inflamed synovial - spreads across joint surface
- inflamed tendon sheath
Define Rheumatoid arthritis
chronic symmetric polyarticular inflammatory joint disease, which primarily affects the small joints of the hands and feet
The rheumatoid synovitis (pannus) is characterised by ?
inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis
What does the joint cavity contain?
synovial fluid
- neutrophils, particularly during acute flares of RA
What causes bone and cartilage destruction (deformities)?
synovial pannus
What can be present in RA many years before the onset of clinical arthritis?
Auto immunity
what Autoantibodies are are commonly associated with RA (2)
as RFs and anti-citrullinated protein antibodies
When do autoantibodies occur in RA?
When either joint antigens, such as type II collagen, or systemic antigens, such as glucose phosphate isomerase are recognised
Describe features of seropositive RA? - what antibody is circulated?
Rheumatoid factor
Anti-citrullinated protein antibody (ACPA)
Diagnostic anti-CCP assays recognise citrullinated self-proteins
α-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin
Patients who have what antibody of seropositive RA will have a ..?
ACPA+ disease
(Anti-citrullinated protein antibody (ACPA)
A less favourable diagnosis
2 types of autoantibody production ?
Seropositive rheumatoid arthritis
Seronegative rheumatoid arthritis
What is rheumatoid factor a auto-antibody to ?
self IgG Fc
What plays a key role in susceptibility to RA and disease severity?
genes
Concordance rates in twins - mono and dizygotic
15-30% among monozygotic (identic) twins
rates 5% among dizygotic twins
RA has an association with what serotype?
what do the alleles contain that confers susceptibility?
Association with HLA-DRB1 locus (HLA-DR4 serotype)
- common amino acid motif (QKRAA – shared epitope) in the HLA-DRB1 region
What do the alleles provide? (2)
- Role in promoting autoimmunity (e.g. altered antigen presentation)
- Molecular mimicry (e.g. with microbial proteins)
What genetic associations are there?
what do they help function ?
polymorphisms in PTPN22, CTLA4, c-REL etc. aggregate
- functionally with immune regulation
There are distinct genetic associations for ?
ACPA-positive and ACPA-negative RA
Environmental factors affecting the chances of developing RA?
GIVE examples of infectious agents (5)
Smoking and bronchial stress (exposure to silica)
Infectious agents have been associated with RA
- Viruses (EBV, CMV)
- E. Coli
- Mycoplasma
- Periodontal disease (Porphyromonas gingivalis)
- Microbiome (gut microbes)
Repeated insults in a genetically susceptible individual would lead to? (2)
Formation of immune complexes and rheumatoid factor (high-affinity autoAb against the Fc portion of Ig)
Altered citrullination of proteins and breakdown of tolerance, with resulting ACPA response
What is Citrullination?
conversion of the amino acid arginine in a protein into the amino acid citrulline
What activation is there in genetically susceptible individuals?
T cell activation
Describe epigenetic modification
- altered post transcriptional regulation
- self protein Citrullination
- loss of tolerance
- transition of arthritis
Coexisting conditions relating to RA (6)
- vascular disease
- osteoporosis and fracture
- metabolic syndrome
- cog dysfunction and depression
- disability and decline
- socioeconomic status
What cells are involved in the loss of tolerance
dendritic B cell T cell autoantibodies sec lymphoid tissues
Cells involved in Synovitis in RA?
Intimal lining hyperplasia and sublining infiltration (migration) with mononuclear cells, especially CD4 + T cells, macrophages, and B cells
In Synovitis what proliferates ?
what are activated ?
what can the lymphocytes do ?
Lining FLS - become aggressive
- macrophages
Lymphocytes
- diffusely infiltrate the sublining
- form lymphoid aggregates with germinal centres
what cells display the memory cell phenotype
Sublining CD4+ T cells
What cells exhibit evidence of antigen-driven maturation and antibody production?
Synovial B cells and plasma cells
How is Neoangiogenesis induced
local hypoxic conditions and cytokines
What is Synovitis
= inflammation of the synovium
Describe the features of Pathogenesis of Rheumatoid Arthritis (6)
- Villous hyperplasia
- Infiltration of T cells, B cells,
macrophages and plasma cells - Intimal cell proliferation (fibroblasts)
- Production of cytokines and proteases
- Increased vascularity
- Self-amplifying process
Low levels of T cell cytokines are present in ?
RA synovium
What is efficacious in RA?
Abatacept (fusion protein CTLA4-IgG1 Fc that blocks T-cell costimulation
Synovial B cells are mainly localised in?
T-cell-B-cell-aggregates
- Ectopic lymphoid follicles
Role of B cells ? (3)
- production of autoAb
- Autoantigen presentation
- Cytokines (IL-6, TNF-α)
What cells are abundant in RA synovium ?
what do they go on to produce?
Macrophage and fibroblast cytokines
Chemokines that recruit inflammatory cells into the joint
Macrophages (M1) are activated by?
TLRs and NLRs
What networks perpetuate synovial inflammation?
Cytokine
What Anti-inflammatory cytokines is produced in rheumatoid synovium ?
IL-10
Describe some features of Inflammatory cytokines? (6)
- Induce expression of endothelial-cell adhesion molecules
- Activate synovial fibroblasts, chondrocytes, osteoclasts
- Promote angiogenesis
- Suppress T-regs
- Activate leukocytes
- Promote autoAb production
IL-6 mediates systemic effects
4
Acute-phase response
Anaemia
Cognitive dysfunction
Lipid metabolism dysregulation
What does Neo-angiogenesis provide?
nutrients to the hyperplastic synovium
What enhances blood vessel proliferation in the synovium (2)
Hypoxic conditions and angiogenic factors such as IL-8 and VEGF
Microvascular endothelia in the synovium express ?
adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants
What regulates cartilage degradation and bone destruction in RA
Distinct mechanisms and cell types
what attaches to and invades cartilage in RA?
Synovial lining cells, especially FLS,
What is bone destruction mediated by?
osteoclasts that are activated under the influence of RANKL produced by RA synovium
Factors that regulate osteoclast differentiation in RA?
RANKL - M- csf
Systemic consequences of RA (GENERAL) (4)
Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
- Lungs (interstitial lung disease, fibrosis)
- Muscles (sarcopoenia)
- Bone (osteoporosis)
- Secondary Sjogren’s syndrome
Systemic consequences of RA (Cardiovascular) (3)
- Altered lipid metabolism
- Elevated acute-phase reactants
- Increased endothelial activation
Systemic consequences of RA (fatigue)
- reduced cognitive function (secondary fibromyalgia)
Dysregulation of the HPA axis
Systemic consequences of RA (liver) (3)
Elevated acute-phase response
Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)
Several genes are implicated in susceptibility to RA and severity of disease, including?
class II major histocompatibility complex genes and PTPN22
Repeated insults (smoking, infectious agents) in genetically susceptible individuals would lead to loss of ?
tolerance and autoimmunity
Evidence of autoimmunity -when can this be present?
including high serum levels of autoAb (RFs and anti-CCP), can be present for many years before the onset of clinical arthritis
What has been implicated in the pathogenesis?
Adaptive and innate immune responses in the synovium
What cytokine networks participate in disease perpetuation (therapeutic targets) (2)
TNF-α, IL-6,
Bone and cartilage destruction are primarily mediated by ?
osteoclasts and fibroblast-like synoviocytes
