Science of RA

Question 1

what is the function of the synovium

Answer 1

maintenance of intact tissue surface, lubrication of cartilage, control of synovial fluid volume and composition (hyaluronan, lubricin), nutrition of chondrocytes within joints

Question 2

breifyly describe a rheumatoid joint

Answer 2

erosion of the corner of the joint, inflamed synovium spreading across the surface of the joint, thinning of the cartilage, inflamed tendon sheath.

Question 3

Define RA

Answer 3

Rheumatoid arthritis is a 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. The synovial fluid in the joint cavity contains neutrophils, particularly during acute flares of RA. The synovial pannus causes bone and cartilage destruction (deformities)

Question 4

what is the role of autoantibodies that occur in RA

Answer 4

they recognise type2 collagen. RF’s and anti-citrullinated protein antibodies too. As well as systemic antigens: glucose phhosphate isomerase.

Question 5

what identifies seropositive RA

Answer 5

rheumatoid factor, anti-citrullinated protein antibody (ACPA), patients with a ACPA positive disease have a less favourable prognosis.

Question 6

what citrullinated self proteins does diagnostic anti-CCP assays recognise?

Answer 6

α-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin

Question 7

what is rheumatoid factor?

Answer 7

an autoantibody to self IgG Fc.

Question 8

describe how genes play a key role in the susceptibility to RA and disease severity

Answer 8

Twins studies implicate genetic factors in RA (Concordance rates 15-30% among monozygotic (identic) twins/ Concordance rates 5% among dizygotic twins)
Association with HLA-DRB1 locus (HLA-DR4 serotype).

Question 9

what are the environmanetla factors for RA

Answer 9

smoking, bronchial stress (silica exposure), EBV, CMV, Ecoli, mycoplasma, peridonal disease, microbiome, repeated insults to a genetically susceptible individual leading to the formation of immune complexes and rheumatoid factor.

Question 10

what is citrullination

Answer 10

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).

Question 11

how does synovitis develop in RA?

Answer 11

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 the lining are 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 is induced by local hypoxic conditions and cytokines. Insufficient. lymphangiogenesis limits cellular egress. Neutrophils are present in synovial fluid

Question 12

what is the pathogennesis of RA?

Answer 12

there is synovitis = villous hyperplasia, infiltration od t cells, b cells, macrophages and plasma cells. Intimal cell proliferation (fibriblasts), production of cytokines and proteases, increased vascularity. Self amplyfying process.

Question 13

t cells and cytokines

Answer 13

there are relativly low levels of t cell cytokines are present in RA synovium. There is a shift from homeostasis to inflammation where there are a lot of t cells present. abatacept (protein that blocks t cell costimulation) is effecious in RA

Question 14

b cells and cytokines

Answer 14

Synovial B cells are mainly localised in T-cell-B-cell-aggregates. 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, TNF-α))

Question 15

stromal cell cytokines

Answer 15

Macrophage and fibroblast cytokines are abundant in RA synovium. Macrophages (M1) are activated by TLRs and NLRs Cytokine networks perpetuate synovial inflammation
Chemokines that recruit inflammatory cells into the joint generally are produced by macrophages and fibroblasts
Anti-inflammatory cytokines such as IL-10 are produced in rheumatoid synovium in amounts insufficient to offset proinflammatory cytokines

Question 16

what do inflammatory cytokines do?

Answer 16

induce the expression of endothelial cell adhesion molecules. Activate synovial fibroblasts, chondrocytes and osteoclasts. They promote angiogenesis. Supress t regs. Activate leukocytes. Promote autoAb production. IL-6 mediates systemic effects. (acute phase response, anaemia, cognitive dysfuntion, lipid metabolism dysregulation).

Question 17

what is the function of neoangiogenesis?

Answer 17

provides nutrients to the hyperplastic synovium, hypoxic condition enhance blood vessel proliferation in the synovium. Microvascular epithelium in the synovium expres adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants.

Question 18

how does joint space narrowing and erosion occur in RA?

Answer 18

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

Question 19

what are the systemic consequences of RA?

Answer 19

vasculitis, nodules, scleritis, amyloidosis. CVS disease (altered lipid metabolism, elevated acute phase reactants, increased endothelial activation), fatigue and reduced cognitive function (2ndry fibromyalgia - dysregulationof the HPA), liver (anaemia), interstitial lung disease, sarcopenia, osteoporosis, 2ndry Sjorgen’s syndrome.