The Science of Rheumatoid Arthritis Flashcards
What are the function of the synovium?
- Maintenance of intact tissue surface
- Lubrication of cartilage
- Control of synovial fluid volume and composition (hyaluronan, lubricin)
- Nutrition of chondrocytes within joints
Describe the joint affected by rheumatoid arthritis.
- Erosion into corner of bone
- Thinning of cartilage
- Inflammed synovium spreading across joint surface
- Inflammed tendon sheath
What is rheumatoid arthritis?
Rheumatoid arthritis is a chronic symmetric polyarticular inflammatory joint disease, which primarily affects the small joints of the hands and feet
What is rheumatoid synovitis (pannus) characterised by?
Inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis
In rheumatoid arthritis, what does the synovial fluid in the joint cavity contain?
Neutrophils, particularly during acute flares
What does the synovial pannus cause?
Bone and cartilage destruction (deformities)
When can evidence of autoimmunity be present?
Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis
What autoantibodies are commonly associated with RA?
- Rheumatoid factors
- Anti-citrullinated protein
What do autoantibodies recognise in RA?
Either joint antigens such as type II collagen or systemic antigens such as glucose phosphate isomerase
How can autoantibodies contribute to inflammation?
Through several mechanisms including activation of complement
What autoantibodies are produced in seropositive RA?
- Rheumatoid factor
- Anti-cirtullinated protein antibody (ACPA)
What do diagnostic anti-CCP assays recognise in seropositive antibody production?
- Citrullinated self-proteins
- α-enolase
- Keratin
- Fibrinogen
- Fibronectin
- Collagen
- Vimentin
What seropositive RA patients have a poorer prognosis?
Patients with ACPA disease
What is rheumatoid factor?
An auto-antibody to self IgG Fc
What genetic factors contribute to RA?
- Concordance rates 15-30% in monozygotic twins and 5% in dizygotic twins
- Association with HLA-DRB1 locus (HLA-DR4 serotype)
- Other genetic associations including polymorphisms in PTPN22, CTLA4, c-REL etc. aggregate functionally with immune regulation
What environmental factors contribute to RA?
- Smoking and bronchial stress (exposure to silica)
- Infectious agents (viruses, E.coli, mycoplasma, periodontal disease, microbiome)
What would repeated environmental insults in a genetically susceptible individual lead to?
- 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?
- (Or deimination) is the conversion of the amino acid arginine in a protein into the amino acid citrulline.
- Enzymes called peptidylarginine deiminases (PADs) replace the primary ketimine group (=NH) by a ketone group (=O).
Why does synovitis occur in RA?
- Intimal lining hyperplasia and sublining infiltration (migration) with mononuclear cells, especially CD4 + T cells, macrophages, and B cells
- Lining FLS proliferate, become activated and “aggressive”
- Macrophages in lining activated
- Lymphocytes can either diffusely infiltrate the sublining or form lymphoid aggregates with germinal centres
- Sublining CD4+ T cells mainly display the memory cell phenotype
- Synovial B cells and plasma cells exhibit evidence of antigen-driven maturation and antibody production
- DCs can present antigens to T cells in synovial germinal centres
- Neoangiogenesis induced by local hypoxic conditions and cytokines
- Insufficient lymphangiogenesis limits cellular egress
- Neutrophils in synovial fluid
What is synovitis?
Inflammation of the synovium
What is the pathogenesis of RA?
- Synovitis
- 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
What role do T cells play in RA?
Relatively low levels of T cell cytokines are present in RA synovium
Shift from homeostasis to inflammation
- T-cell cytokines, such as IFN- γ and IL-17, are produced by Th1 cells or Th17 cells
- Regulatory T cell function, which suppresses activation of other T cells, is reduced
T cell mediated B cell activation
Direct cell to cell contact with macrophages
How can T cells be targeted in RA?
- T-cell depleting strategies have limited efficacy
- Abatacept (fusion protein CTLA4-IgG1 Fc that blocks T-cell costimulation) is efficacious in RA
What role do B cells play in RA?
- Synovial B cells are mainly localised in T cell B cell aggregates (ectopic lymphoid follicles)
- Pathogenic role for CD20+ B cells is confirmed by the efficacy of rituximab
- Plasma cells are widely distributed and are not targeted by anti-CD20 antibodies
- Role of B cells goes beyond production of autoAb (autoantigen presentation, cytokines IL-6 and TNFa)
What are abundant in RA?
Macrophage and fibroblast cytokines
What are macrophages activated by?
TLRs and NLRs
What perpetuates synovial inflammation?
Cytokine networks including TNF-α, IL-6, IL-1, IL-15, IL-18, IL-23
What do the macrophages and fibroblasts produce?
Chemokines that recruit inflammatory cells into the joints
What anti-inflammatory response does the synovium have?
Anti-inflammatory cytokines such as IL-10 are produced in rheumatoid synovium but in amounts insufficient to offset proinflammatory cytokines
What do inflammatory cytokines do?
- Induce expression of endothelial-cell adhesion molecules
- Activate synovial fibroblasts, chondrocytes, osteoclasts
- Promote angiogenesis
- Suppress T-regs
- Activate leukocytes
- Promtoe autoAb production
What role does IL6 play in RA?
Mediates systemic effects
- Acute-phase response
- Anaemia
- Cognitive dysfunction
- Lipid metabolism dysregulation
What is the role of eo-angiogenesis?
Provide nutrients to the hyperplastic synovium
What enhances blood vessel proliferation in the synovium?
Hypoxic conditions and angiogenic factors such as IL-8
What does the microvascular endothelial of the synovium express?
Adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants
How does cartilage and bone destruction occur in RA?
- Several classes of proteases, including metalloproteinases and aggrecanases are produced by FLS in the intimal lining layer
- Synovial lining cells, especially FLS, can attach to and invade cartilage in RA
- Bone destruction is mediated by osteoclasts that are activated under the influence of RANKL produced by RA synovium
What does cartilage and bone destruction lead to?
Joint space narrowing and erosions
What factors regulate osteoclast differentiation in RA?
RANKL M-CSF
What systemic consequences are there in RA?
- Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
- Cardiovascular disease
- Fatigue and reduced cognitive function, secondary fibromyalgia due to dysregulation of the HPA axis
- Liver problems
- Lungs (interstitial lung disease, fibrosis)
- Muscles (sarcpoenia)
- Bone (osteoporosis)
- Secondary Sjogren’s syndrome
What cardiovascular involvement can occur in RA?
- Altered lipid metabolism
- Elevated acute-phase reactants
- Increased endothelial activation
What liver problems can occur in RA?
- Elevated acute-phase response
- Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)
