Rheumatoid Arthritis

• Rheumatoid Arthritis


  A chronic inflammatory disorder that attacks synovial joints (synovitis), initially affecting the small joints
• Rheumatoid Arthritis


  • Genetic and environmental risk factors
  • A systemic autoimmune disease
  • Autoreactive helper T-cells induce B-cells to make pathogenic autoantibodies
• Common Autoantibodies to (Neo) Antigens in RA

  • RFs (rheumatoid factor, antibodies directed to the Fc region of IgG molecules)
  • Anti-CCP (anti-cyclic citrullinated peptide-a standard cyclic peptide recognised by a range of RA autoantibodies)
• Rheumatoid Factor (RF)


  Antibodies of the IgG class that have a self-binding capacity, forming large immune complexes that can further activate the immune system
• Citrullination


  Conversion of the basic amino acid arginine to the neutral residue citrulline, catalysed by the enzyme peptidylarginine deiminase (PADI)
• Smoking increases citrullination of proteins and the generation of citrullinated peptide-specific antibodies
• Only patients with RA develop antibodies to citrullinated synovial proteins
• Development & Selection of T Cells in Thymus

  1. Precursor thymocytes develop as 'double-positive' cells expressing both CD4 and CD8

  2. Undergo positive selection for weak, low affinity, interaction with self MHC

  3. Unselected cells undergo programmed cell death by apoptosis

  4. Cells undergoing positive selection lose one or the other of their co-receptor molecules

  5. Cells that interact with MHC class I become CD8+ cells, and those that interact with MHC class II become CD4+ cells

  6. Self-reactive cells that react strongly to self antigens are eliminated by apoptosis (negative selection)
• The mature T-cell pool contains T-cells able to react to foreign proteins and also those that are able to react weakly to self antigens or react strongly to self antigens that they have not seen, for example antigens in peripheral tissues, including the joints
• Defective Positive and Negative Selection in the Thymus in RA

  • Defects in negative selection would bias the TCR repertoire towards autoreactivity
  • Defects in positive selection may cause lymphopenia, which has been shown to be a risk factor for autoimmunity
• A Model of T Cell Repertoire Selection in RA

  1. Individuals develop RA through a stage of accelerated self-replication of peripheral T cells, compensating for a premature decline in thymic output

  2. Peripheral T-cell homeostasis is maintained through positive selection and the replication of naïve T-cells that recognise self antigens

  3. With peripheral selection being prominent, the T-cell repertoire loses diversity and is biased towards autoreactivity

  4. The disease reflects a breakdown in tolerance to common antigens that are preferentially recognized in the synovium and clonal expansion of autoreactive T-cells
• The best characterised autoimmune responses in patients RA are directed at neoantigens
• Regulatory T-cells (Tregs)


  • A natural T-cell subset generated in the thymus that regulate peripheral immune responses
  • Patients with RA have a deficiency in Treg function, and limited ability to suppress antigen presentation and T-cell activation
• Synovial Joint


  A joint with a synovial cavity between the articulating bones, allowing free movement (diarthrosis)
• Synovial Joint


  • Bones covered by articular cartilage, which reduces friction and absorbs shock
  • Articular joint capsule surrounds the joint, with an outer fibrous membrane and inner synovial membrane
  • Synovial fluid lubricates the joint surfaces and provides nutrients to the cartilage
• CD4+ T Cell Subsets

  • Th1
  • Th2
  • Tregs
  • Th17
• Th17 cells


  Secrete IL-17, important in modulating the immune inflammatory response in RA
• IL-17


  Increases production of MMPs by synoviocytes and chondrocytes, inducing matrix degradation, and inhibits collagen and proteoglycan synthesis by chondrocytes
• IL-17


  Induces expression of RANKL, essential for osteoclast differentiation and bone resorption
• Osteoblasts


  Cells responsible for bone formation, making collagen I which becomes mineralized
• Osteoclasts


  Large multinucleated cells that break down bone matrix, their differentiation and activity is dependent on RANKL and IL-6
• RANKL


  • Essential for the differentiation of osteoclasts
  • Direct cell-cell contact between osteoblasts and osteoclast precursors is needed for RANKL effects on osteoclast differentiation
• IL-17 stimulates


  PGE2 production by osteoblasts
• PGE2 production by osteoblasts

  Induces RANKL expression
• Osteoblasts


  Cells responsible for bone formation
• Osteoblast function


  1. Make collagen I (osteoid)

  2. Osteoid becomes mineralized

  3. Osteoblasts become trapped within the bone matrix and become osteocytes

  4. Stop making osteoid

  5. Number of osteoblasts decreases with age, regeneration of bone becomes limited
• Osteoclasts


  • Formed by the fusion of cells of the monocyte/macrophage cell-line
  • Large multinucleated cells containing 15-20 nuclei
  • Differentiation dependent on RANKL
  • Activity enhanced by IL-6
• Osteoclast function


  1. Release hydrogen ions through the action of carbonic anhydrase

  2. Acidify and aid dissolution of the mineralized bone matrix

  3. Hydrogen ions pumped against high concentration gradient by proton pumps

  4. Release hydrolytic enzymes such as cathepsin and matrix metalloprotease to digest organic components of matrix
• Cathepsin K is the most important of the hydrolytic enzymes released by osteoclasts
• Prostaglandin synthesis


  Chondrocytes and synovial fibroblasts produce PGE2, 2α, and 6-keto-1α, with PGE2 being the major PG synthesized
• IL-1 and TNF-α


  Increase the synthesis of PGs
• Effects of PGE2 on articular tissues

  • Induces cartilage degradation
  • Inhibits collagen synthesis in growth plate chondrocytes
  • Increases metalloprotease production in chondrocytes and synovial fibroblasts
  • Promotes IL-1 expression, amplifying local inflammatory process
  • Stimulates osteoclast formation from precursor stem cells
  • Promotes apoptosis of chondrocytes, limiting cartilage synthesis
  • Promotes angiogenesis and neovascularisation
• COX-1


  Constitutively expressed in all cells, inhibitors associated with unwanted side effects, especially in the gut
• COX-2


  Induced in inflammatory cells when activated, responsible for increased PGE2 in inflammatory disease including RA
• COX-2 inhibitors


  • Celecoxib
  • Rofecoxib (Vioxx)
• COX-2 inhibitors are effective in RA but have some concerns over prothrombotic cardiovascular side effects
• NSAIDs reduce the symptoms of RA but do not slow or reverse the disease process or alter the immunologic abnormalities
• The aim is to preferentially target COX-2 to reduce the synthesis of PGE2
• Use of COX-2 inhibitors

  May be associated with increased numbers of heart attacks due to parallel decrease in PGI2 (prostacyclin)
• Disease-modifying anti-rheumatic drugs (DMARDs)


  Relieve symptoms and may halt or reverse the disease process in RA