The Science of Rheumatoid Arthritis Flashcards
what is rheumatology?
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
what is arthritis?
inflammation of a joint or joints
symptoms of arthritis
pain stiffness swelling functional impairment systemic symptoms
signs of arthritis
tenderness swelling restriction of movement (heat, redness) systemic features
name some rheumatic diseases
RA sero-negative arthritis crystal arthritis connective tissue diseases systemic vasculitis bone disease
what are the funcitons 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
what is RA?
chronic symmetric polyarticular 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
during a flare of RA what cell is found in the synovial fluid?
neutrophils
what doe sthe synovial pannus result in?
bone and cartilage destruction resulting in deformities
autoantibodies associated with RA
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
activation of what mechanism may contribute to inflammation as a result of autoantibodies?
activation of complement
autoantibody production in seropositive RA
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
genes and RA
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.
environmental factors and RA
• 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
describe the synovitis 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 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
synovitis causes
- 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
T cells and cytokines in RA
• 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
B cells, cytokines and autoantibodies in RA
• 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)
stromal cell cytokines in RA
- 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
function of inflammatory cytokines
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
neoangiogenesis and RA
- 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
joint space narrowing and erosions in RA
- 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
systemic symptoms of RA
• 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
