Inflammatory autoimmune disorder characterized by joint pain, swelling, and synovial destruction

Aetiology

• Chronic inflammatory autoimmune disorder of unknown etiology
• Hypotheses suggest the aetiology is multifactorial, with the following factors playing a role:
  • Genetic predisposition - seems to be associated with specific HLA types e.g. HLA DRB1 gene
  • Environmental triggers - infection and smoking increase anti-CCP
  • Hormonal factors - higher incidence in females (3:1)
• Prevalence peaks 35-50 years of age

Pathophysiology

• Initially, non-specific inflammation affects the synovial tissue, which is later amplified by activation of T cells
• Triggers e.g. smoking, infection or trauma have been implicated
• With time it may lead to inflammatory joint effusion and synovial hypertrophy as as well as progressive destruction and deterioration of cartilage and bone
• Inflammatory pannus (inflammatory granulation tissue) forms which produces proteinases that destroy the cartilage extracellular matrix
• Tendon rupture and soft tissue damage can occur leading to joint instability and subluxation
• Chronic phase - fibrosis, deformity

Generation of auto-antibodies and activation of the immune response

• Susceptibility genes lead to the conversion of arginine (A) into citrulline (C) → protein will unfold due to loss of positive charge
• The unfolded protein acts as an antigen - autoimmune response mediated by auto-reactive CD4+ T cells
• Involvement of pro-inflammatory CD4+ Th1 and Th17 effector cells and macrophages
• Driven by a type IV hypersensitivity mechanism, but secondary type III hypersensitivity responses also occur as anti-citrullinated peptide antibodies (can be generated in the lungs from smoking) can form immune complexes with the citrullinated proteins produced in an inflamed synovium → neutophil infiltration and activation

Rheumatoid factor

• IgM or IgA antibody that binds to Fc region of IgG
• Found in ~80% of patients with RA (15% are negative for RF)