The Science of Rheumatoid Arthritis Flashcards
what does a normal joint look like?
2 bone ends
Covered by tissue that has no vascular and neuro called articular cartilage, made of one cell type the chondrocyte
Synovial fluid filled cavity made by the synovial membrane covering the joint capsule
what does the normal synovium look like?
Key tissue
Thin membrane covering inner tissue of joint
2 layers
Thin layer of lining consisting of fibroblasts and macrophages, just 2 types
Underneath there is the subintimal tissue
Lubrication happens as the synovium produces 2 main lubricants
articular cartilage is devoid of blood vessels or nerve fibres
what are the functions 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 does a rheumatoid joint look like?
In RA there is expansion of the synovium
Causes expansion of tissue
Destruction of cartilage and bone can be seen on x- ray, joint space narrowing
what is the definiton of RA?
- 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)
how is autoimmunity involved?
- Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis
- Autoantibodies, such as RFs and anti-citrullinated protein antibodies, are commonly associated with RA
- Autoantibodies occur in RA that recognise either joint antigens, such as type II collagen, or systemic antigens, such as glucose phosphate isomerase
- The autoantibodies potentially can contribute to inflammation through several mechanisms, including activation of complement
Autoantibody production - what is the difference between Seropositive and seronegative rheumatoid arthritis
Seropositive:
- Rheumatoid factor
- Anti-citrullinated protein antibody (ACPA)
- Diagnostic anti-CCP assays recognise citrullinated self-proteins - α-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin
- Patients with ACPA+ disease have a less favourable prognosis
Negative if autoantibodies are not detectable
Rheumatoid factor: an auto-antibody to self IgG Fc
Genes play a key role in susceptibility to RA and disease severity, such as what?
- Twins studies implicate genetic factors in RA - Concordance rates 15-30% among monozygotic (identic) twins and Concordance rates 5% among dizygotic twins
- Association with HLA-DRB1 locus (HLA-DR4 serotype)
- Alleles containing a common amino acid motif (QKRAA – shared epitope) in the HLA-DRB1 region confer susceptibility - Role in promoting autoimmunity (e.g. altered antigen presentation), Molecular mimicry (e.g. with microbial proteins)
- Other genetic associations 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
what Environmental factors are involved in causing RA?
- Smoking and bronchial stress (exposure to silica)
- Infectious agents have been associated with RA -Viruses (EBV, CMV), E. Coli, Mycoplasma, Periodontal disease (Porphyromonas gingivalis), Microbiome (gut microbes)
- Repeated insults in a genetically susceptible individual would 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 the ACPA response in RA?
The most specific autoimmunity known for rheumatoid arthritis (RA) is reflected by generation of anti-citrullinated protein antibodies (ACPA). Presence of ACPA in established RA is associated with disease severity, while generation of ACPA at early developmental phases of RA can have a strong predictive value for progressing to the full-blown disease. Hence, development of ACPA may be of crucial importance to the pathogenesis of RA
what is the process of Development of Rheumatoid Arthritis?
Interplay between genetic and environmental factors that can lead to autoimmunity with immune mediated synovitis leading to arthritis and bone and cartilage destruction
how does Synovitis happen 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
Pathogenesis of Rheumatoid Arthritis
Synovitis = inflammation of the synovium
what effects odes this cause?
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
how are T cells and cytokines involved?
- T-cell depleting strategies have limited efficacy
- 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
- 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-cell contact with macrophages
Diagram showing Factors that regulate osteoclast differentiation in RA
What are Systemic consequences of RA?
- Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation
- Cardiovascular disease - Altered lipid metabolism, Elevated acute-phase reactants, Increased endothelial activation
- Fatigue and reduced cognitive function (secondary fibromyalgia) - Dysregulation of the HPA axis
- Liver - Elevated acute-phase response, Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)
- Lungs (interstitial lung disease, fibrosis)
- Muscles (sarcopoenia)
- Bone (osteoporosis)
- Secondary Sjogren’s syndrome
