The Science of Rheumatoid Arthritis Flashcards
What are the functions of the normal synovium?
Maintenance of intact tissue surface
Lubrication of cartilage
Control of synovial fluid volume and composition
Nutrition of chondrocytes in the joint
What is rheumatoid arthritis?
A chronic, symmetric, poly-articular inflammatory joint disease which primarily affects the small joints of the hands and feet
What is rheumatoid synovitis characterised by?
Inflammatory cell infiltration
Synoviocyte proliferation
Neoangiogenesis
What does the synovial pannus cause?
Bone and cartilage destruction, leading to deformities
When is autoimmunity present in rheumatoid arthritis?
Can be present in RA many years before the onset of clinical arthritis
What antibodies are commonly associated with RA?
Rheumatoid factors
Anti-citrullinated protein antibodies
What do the autoantibodies that occur in RA do?
Recognise either joint antigens e.g. type II collagen or systemic antigens e.g. glucose phosphate isomerase
Have the potential to contribute to inflammation through several mechanisms, including activation of the complement system
What is the autoimmunity of seropositive rheumatoid arthritis?
Rheumatoid factor present
Anti-citrullinated protein antibody (ACPA) present
Diagnostic anti-CCP assays recognise citruliinated self-proteins e.g. alpha-enolase, keratin, fibrinogen, fibronectin
Patients with ACPA +ve disease have a poorer prognosis
What are the concordance rates for RA between monozygotic and dizygotic twins?
15-30% in monozygotic
5% in dizygotic
What genes are associated with RA?
Association with HLA-DRB1 locus (HLA-DR4 serotype)
Alleles containing a common amino acid motif (QKRAA) in the HLA-DRB1 region confer susceptibility
Other genetic associations including polymorphisms in PTPN22, CCTLA4, c-REL etc., which aggregate functionally with immune regulation
Genetic associations in RA are complex and involve many genes
What are the environmental factors that have an influence on RA?
Smoking and bronchial stress e.g. exposure to silica
Infectious agents have been associated with RA
- viruses
- E. coli
- mycoplasma
- periodontal disease
- microbiome
What would repeated environmental insults in an individual genetically susceptible to RA result in?
Would lead to formation of immune complexes and rheumatoid factors and altered citrullination of proteins and breakdown of tolerance with resulting ACPA response
How does synovitis occur in RA?
Intimal lining hyperplasia and sublining infiltration with mononuclear cells, especially CD4+ T cells, macrophages and B cells
Lining FLS proliferate, become activated and aggressive
Macrophages in lining are activated
Lymphocytes either diffusely infiltrate the sublining or form lymphoid aggregates with germinal centres
What do synovial B cells and plasma cells exhibit evidence of?
Antigen-driven maturation and antibody production
What is neoangiogenesis induced by?
Local hypoxic conditions and cytokines
What limits cellular egress?
Insufficient lymphangiogenesis
What is the pathogenesis of rheumatoid arthritis?
Synovitis - inflammation of the synovium
Vilous hyperplasia
Infiltration of T cells, B cells, macrophages and plasma cells
Intimal cell proliferation
Production of cytokines and proteases
Increased vascularity
Self-amplfying process
What is B cell activation mediated by?
T cells
Where are synovial B cells mainly localised?
In T cell-B cell aggregates
What cytokines are abundant in the synovium in RA?
Macrophage and fibroblast cytokines
What do cytokine networks do?
Perpetuate synovial inflammation
Chemokines that recruit inflammatory cells into the joint are generally produced by what?
Macrophages and fibroblasts
Where are anti-inflammatory cytokines, such as IL-10, produced?
In rheumatoid synovium
Produced in amounts insufficient to offset pro-inflammatory cytokines
What do inflammatory cytokines induce?
The expression of endothelial cell adhesion molecules
What do inflammatory cytokines activate?
Synovial fibroblasts, chondrocytes, osteoclasts and leukocytes
What do inflammatory cytokines promote and suppress?
Promote angiogenesis and auto-antibody production
Suppress T-regs
What are the systemic effects that are mediated by IL-6?
Acute phase response
Anaemia
Cognitive dysfunction
Lipid metabolism dysregulation
What does neoangiogenesis provide to the hyperplastic synovium?
Nutrients
What enhances blood vessel proliferation in the synovium?
Hypoxic conditions
Angiogenic factors e.g. IL-8 and VEGF
What molecules are expressed by the microvascular endothelium in the synovium?
Adhesion molecules that guide circulating cells into the joint under the influence of chemo-attractants
What produces proteases e.g. metalloproteinase and aggrecanase?
FLS in the intimal lining layer
What is bone destruction mediated by?
Osteoclasts that are activated under the influence of RANKL produced by RA synovium
What are the systemic consequences of rheumatoid arthritis?
Vasculitis, nodules, scleritis and amyloidosis - secondary to uncontrolled chronic inflammation
Cardiovascular disease
- altered lipid metabolism
- elevated acute phase reactants
- increased endothelial activation
Fatigue and reduced cognitive function and secondary fibromyalgia - due to dysregulation of the HPA axis
Liver
- elevated acute phase response
- anaemia of chronic disease
Lungs - interstitial lung disease, fibrosis
Muscles - sarcopenia
Bone - osteoporosis
Secondary Sjogren’s syndrome
