The Science of Rheumatoid Arthritis

Question 1

what is rheumatology?

Answer 1

Rheumatology is the medical speciality that deals with the investigation, diagnosis and management of patients with arthritis and other related conditions. This incorporates more than 200 disorders including inflammatory arthritis, connective tissue disease and bone disease

Question 2

what is arthritis?

Answer 2

inflammation of a joint or joints

Question 3

symptoms of arthritis

Answer 3

pain 
stiffness
swelling
functional impairment
systemic symptoms

Question 4

signs of arthritis

Answer 4

tenderness
swelling
restriction of movement
(heat, redness)
systemic features

Question 5

name some rheumatic diseases

Answer 5

RA
sero-negative arthritis
crystal arthritis
connective tissue diseases
systemic vasculitis
bone disease

Question 6

what are the funcitons of the synovium?

Answer 6

• Maintenance of intact tissue surface
• Lubrication of cartilage
• Control of synovial fluid volume and composition (hyaluronan, lubricin)
• Nutrition of chondrocytes within joints

Question 7

what is RA?

Answer 7

chronic symmetric polyarticular inflammatory joint disease which primarily affects the small joints of the hands and feet

Question 8

what is rheumatoid synovitis characterised by?

Answer 8

inflammatory cell infiltration
synoviocyte proliferation
neoangiogenesis

Question 9

during a flare of RA what cell is found in the synovial fluid?

Answer 9

neutrophils

Question 10

what doe sthe synovial pannus result in?

Answer 10

bone and cartilage destruction resulting in deformities

Question 11

autoantibodies associated with RA

Answer 11

RFs and anti-citrullinated proteins antibodies, are commonly associated with RA. Autoantibodies occur in RA that recognise either joint antigens, such as type II collage, or systemic antigens, such as glucose phosphate isomerase

Question 12

activation of what mechanism may contribute to inflammation as a result of autoantibodies?

Answer 12

activation of complement

Question 13

autoantibody production in seropositive RA

Answer 13

o Rheumatoid factor
o Anti-citrullinated protein antibody (ACPA)
o Diagnostic anti-CCP assays recognise citrullinated self-proteins
§ 𝛼-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin
o Patients with ACPA+ disease have a less favourable prognosis

Question 14

genes and RA

Answer 14

Twin studies implicate genetic factors in RA. Concordance rates 15-30% in monozygotic twins and 5% in dizygotic twins. There is an associate with HLA-DRB1 locus (HLA-DR4 serotype). Alleles containing a common amino acid motif (QKRAA – shared epitope) in the HLA-DRB1 region confer susceptibility. This has a role in promoting autoimmunity (e.g. altered antigen presentation) and molecular mimicry (e.g. with microbial proteins). Other genetic association including polymorphisms in pTPN22, CTLA4, c-REL etc aggregate functionally with immune regulation. Genetic associations in RA are complex and involve many genes. Distinct genetic associations for ACPA-positive and ACPA-negative RA.

Question 15

environmental factors and RA

Answer 15

• Smoking and bronchial stress (exposure to silica)
• Infectious agents have been associated with RA
o Viruses (EBV, CMV)
o E. coli
o Mycoplasma
o Periodontal disease (porphyromonas gingivalis)
o Microbiome (gut microbes)
• Repeated insults in a genetically susceptible individual would lead to:
o Formation of immune complexes and rheumatoid factor (high-affinity autoAb against
the Fc portion of IgG
o Altered citrullination of proteins and breakdown of tolerance with resulting ACPA
response

Question 16

describe the synovitis in RA

Answer 16

• 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 17

synovitis causes

Answer 17

• 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

Question 18

T cells and cytokines in RA

Answer 18

• Abatacept (fusion protein CTLA4-IgG1 Fc that blocks T-cell costimulation) is efficacious in RA
• Relatively low levels of T cell cytokines are present in RA synovium
• Shift from homeostasis to inflammation
o T-cell cytokines, such as IFN- γ and IL-17, are produced by Th1 cells or Th17 cells
o Regulatory T cell function, which suppresses activation of other T cells, is reduced
• T-cell-mediated B-cell activation
• Direct cell-cell contact with macrophages

Question 19

B cells, cytokines and autoantibodies in RA

Answer 19

• Synovial B cells are mainly localised in T-cell-B-cell-aggregates
o 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
o Autoantigen presentation
o Cytokines (IL-6, TNF-α)

Question 20

stromal cell cytokines in RA

Answer 20

• Macrophage and fibroblast cytokines are abundant in RA synovium
• Macrophages (M1) are activated by TLRs and NLRs
• Cytokine networks including TNF-α, IL-6, IL-1, IL-15, IL-18, IL-23 etc. 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 21

function of inflammatory cytokines

Answer 21

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
o Acute-phase response
o Anaemia
o Cognitive dysfunction
o Lipid metabolism dysregulation

Question 22

neoangiogenesis and RA

Answer 22

• Neo-angiogenesis provides nutrients to the hyperplastic synovium
• Hypoxic conditions and angiogenic factors such as IL-8 and VEGF enhance blood vessel proliferation in the synovium
• Microvascular endothelia in the synovium express adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants

Question 23

joint space narrowing and erosions in RA

Answer 23

• Distinct mechanisms and cell types regulate cartilage degradation and bone destruction 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

Question 24

systemic symptoms of RA

Answer 24

• Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
• Cardiovascular disease
o Altered lipid metabolism
o Elevated acute-phase reactants
o Increased endothelial activation
• Fatigue and reduced cognitive function (secondary fibromyalgia)
o Dysregulation of the HPA axis
• Liver
o Elevated acute-phase response
o Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)
• Lungs (interstitial lung disease, fibrosis)
• Muscles (sarcopoenia)
• Bone (osteoporosis