pathophysiology of RA

• intro to RA:

  • Systemic autoimmune disease that is characterised by chronic inflammation of the synovial joints
  • Affect multiple joints symmetrically
  • Leads to progressive destruction of the synovial joints through loss of cartilage and bone
  • Results in loss of function and disability, reduced quality of life, increased comorbidity and often a shortened life expectancy
  • RA is more common in women (3:1 ratio) 
  • Onset most often seen between 30 and 50 years–May develop at any age  
• • healthy synovium
  • synovium - connective tissue between the joint capsule and joint space (excluding the cartilage)
  • has a thin lining facing the joint space made of synovial cells
  • macrophage-like synovial cells (type 1/A)
  • fibroblast-like synovial cells (type 2/B)
  • synovial sublining is loose connective tissue with blood and lymphatic vessels, nerves, scattered macrophages and fibroblasts
• RA synovium

  • the lining becomes thickened 6-8 cells thick from 2-3 cells due to hyperplasia (increased cell proliferation) and hypertrophy (increased cell size)
  • infiltration of the underlying sublining by lymphocytes, macrophages and plasma cells


  here

  
• 4 steps of leukocyte extravasation:

  1. rolling adhesion - mediated by E-selectin ( endothelium ) and its ligand sialyl-Lewis X ( leukocyte )
  2. tight binding - CXCL8 ( endothelium ) binds to CXCR8 ( leukocyte ): LFA-1 ( leukocyte ) and ICAM-1 ( endothelium )
  3. diapedesis - leukocyte crosses the endothelium via PECAM
  4. migration - migration into the cell along a chemokine gradient
• Unknown trigger -> initial inflammation of synovial tissue

  1. Infiltration of synovium by inflammatory cells and proliferation of synovial cells

  –Occurs via trafficking of leukocytes out of blood vessels through a process called leukocyte extravasation

  – inflammatory signals change the adhesiveness of endothelial cells lining blood vessels

  – Leukocytes recruited include neutrophils, monocytes, mast cells, T-cells and B-cells
• 2. Increase in blood vessel formation

  • Synovial hypoxia is a consequence of the hyperproliferative synovium with increased consumption of oxygen in RA and reduced blood flow

  • Response to hypoxia and the increased metabolic demands of the synovial tissue activate hypoxia-inducible factor (HIF), leading to the release of pro-angiogenic factors

  • Pro-inflammatory cytokines (TNF-α and IL-1β) within RA joint are angiogenic • Increased angiogenesis in RA
• 3. Increased chemokine production, upregulate adhesion molecules expression on vascular endothelium

  • CXCL8 , CXCL5 and CXCL1 are important in RA. Abundant in synovial tissue, synovial fluid and blood. Produced by macrophages

  • TNFα activation of vascular endothelium, E-selectin and ICAM expression upregulated, increased leukocyte recruitment

  • CCL2 potent chemoattractant for monocytes via CCR2

  • CCL3 recruits monocytes, lymphocytes, basophils and eosinophils via CCR1,5

  • CCL5 recruitment of lymphocytes and monocytes via CCR1 , 3 and 5
• 4. cytokines and MMPs

  macrophages -> cytokine production ( TNF-alpha , IL-1beta) -> activate chondrocytes to produce MMPs , activate osteoclasts , increase adhesion molecule expression on he endothelium
• 5.  Pannus formation (hyperproliferative, inflammatory invasive vascularised mass, hallmark RA)

  • macrophage-like & fibroblast-like synovial cells in synovial tissue and large number of infiltrating leukocytes (CD4+ T lymphocytes, B cells, plasma cells and dendritic cells)
  • Develops from normal synovium & invades cartilage and bone
  • Fibroblast-like synovial cells and activated chondrocytes produce MMPs, ADAMTS, pro-inflammatory cytokines and prostaglandins -> cartilage degradation
  • Fibroblast-like synovial cells and T-lymphocytes secrete RANKL which activates osteoclasts to destroy bone
• Summary

  1.Infiltration of synovium by inflammatory cells and proliferation of synovial cells

  2.Increase in blood vessel formation

  3.Increased chemokine production and upregulation of adhesion molecules expression on vascular endothelium

  4.Cytokine production initiates matrix metalloproteinases (MMPs) release leading to degradation of matrix

  5.Pannus formation
• RF in RA is characterised by its high affinity for IgG

  RF are IgM / IgA / IgE / IgG class antibodies with a specificity for the Fc region of IgG antibody
• •Rose-Waaler test

  –using sheep RBCs- sensitised by IgG from rabbit 

  –RF reacts with reagent causing haemogglutination
• Rheumatoid factor:

  • produced in joint by B-cells  
  • IgM major RF in RA
  • RF associated with severity, erosions, extraarticular manifestations & poor prognosis (esp. high levels)
  • present in 70% of RA patients; specificity 60-80%

  • RF also found in 5% of healthy individuals. 

  –Aid immune complex clearance and the uptake and processing of immune complexes by B cells
• • Anti-citrullinated protein antibodies (ACPA) - aka anti-CCP (anti-cyclic citrullinated peptide antibodies)

  • ACPA recognise modified proteins containing non-standard amino acid citrulline:

  …examples include keratin, filaggrin, fibrin/fibrinogen, histones and type II collagen

  • Citrulline created by post-translational modification: PADI catalyse deamination of the amino acid arginine -> citrulline. These enzymes cause the local citrullination of synovial proteins, such as fibrin.
• genetics of RA:

  • cause unknown

  • Initiating events stimulate a complex interaction between innate and adaptive immune systems -> breaks tolerance and leads to autoreactivity (autoimmunity)

  • Genetic factors account for 30-50% of total risk

  • The strongest association is with the Major histocompatibility complex region (HLA in humans)
• MHC:

  • Class 1 all cells but RBCs

  • Class 2 can be all but APCs mainly
• •The human leukocyte antigen (HLA) system or complex is a group of related proteins that are encoded by the major histocompatibility complex (MHC) gene complex in humans
• •RA is associated with the HLA-DRB1 gene. In particular, with DRB1 alleles encoding the shared epitope (SE)

  • the SE is a sequence of 5 amino acids common to HLA-DRB1 alleles known to confer increased risk of RA…….QKRAA, QRRAA or RRRAA

  •The amino acid side chains are important in the context of antigen binding and TCR interaction
• Environmental factors  in RA

  • Smoking, likely the best defined environmental factor in RA

   i. increases the odds ratio for developing RA

  ii. the risk persists for up to 20 years after a person quits smoking

  iv. smoking has been associated with multiple parameters in RA:

  – Risk of disease  – Mortality

  – X-ray damage  – Nodular disease

  – Disease severity  – Rheumatoid factor/CCP
• Environmental factors in RA

  Silica/asbestos

  • Pollutants

  • Diet

  • Role of gut microbiome in RA development

    (gastrointestinal dysbiosis)

  • Peridontal disease (Porphyromonas gingivalis)

  • Infections – viral (e.g. Epstein-Barr virus, Cytomegalovirus ) or bacterial (e.g E.coli)
• • Anti-CCP produced in the joint by B-cells

  • PADI abundant in RA synovium

  • ACPA associated with erosions, joint destruction, and poor prognosis, but not extra-articular manifestations

  •often detectable years before onset of clinical synovitis

  •present in 80 % of RA patients; specificity 90-95%

  •ACR/EULAR criteria for diagnosis of RA
• Summary

  • cause is unknown, complex interplay between genetic and environmental factors -> breach of immunological tolerance

  • Hallmark pathology of RA is cartilage degradation and bone erosion

  • Inflammation is chronic through persistent activity of immune/inflammatory cells and the abundance of mediators they release

  • Multiple cell types, mediators, pathways and processes are all actively involved and co-ordinately drive joint pathology

  • The disease likely arises through non-identical mechanisms in different patients, which instructs the disease course individual patients