Rheumatoid arthritis Flashcards
RA and autoimmuniy
RA is an autoimmune disease
Autoimmunity (or autoreactivity)= immune responses to self-antigens
Represents a breakdown of immunological tolerance
Immune reactions to ‘self’ can occur as part of a controlled inflammatory reaction e.g. tissue repair
Acute cytokine effect vs chronic cytokine effect
Acute: removal of pathogen
tissue repair
chronic: tissue destruction
Goal of RA treatment
Inflammation naturally fluctuates over time
Goal of treatment: restore natural fluctuations below threshold
Effect of chronic inflammation
tissue damage
Inflammation associated with autoimmunity is chronic, unregulated and persistent.
Autoimmune diseases are often complex and can involve a specific site on the body or can be systemic.
Characteristics of RA
Inflammation of the synovial joints 3x more women than men with RA Affects 1% of the worldwide population Diagnosis most commonly around age 40-50 Systemic inflammation Reduced quality of life Disability Increased mortality – decreased life expectancy
Long term complications in patients with RA
Bone: Low bone mineral density and fractures
Muscle: insulin resistance
Fat: free fatty acid, adipocytokines
Liver: acute phase response (CRP), iron redistribution (hepcidin)
Blood vessels: ahterogenesis, MI, stroke
Brain: fatigue, low stress toelrance, depression
Joint damage in RA
Usually multiple joints in a symmetrical fashion
- Morning stiffness
- Swelling, heat, redness and pain
- Loss of function
Destructive process
- Bone erosion
- Synovial and cartilage damage
Synovitis
Swelling over extensor tendons, wrist and MCP joints
Synovium hyperplasia (an increase in cell numbers)
Synovial fibroblasts have reduced apoptosis, enhanced anchorage, upregulated adhesion molecules and increased proliferation
Rheumatoid arthritis pathology
Pannus (inflammed synovial membrane) synovial fluid rich in neutrophils synovitis cartilage erosion bone erosion cartilage loss
Composition of synovial tissue
macrophages (40%)
fibroblast and endothelial cells (10-15%)
B lymphocytes and plasma cells (5%)
T lymphocytes (40%)
Disequilibrium in inflammation
Pro-inflammatory cytokines: IL1 TNF-alpha IL-6 IL-17
Innate immune cells
Infiltrating macrophages, mast cells, NK cells in synovium
Infiltrating neutrophils in synovial fluid (enhanced NETosis)
Macrophages appear to be key effectors:
- Phagocytosis
- Antigen presentation
- TNF, IL-1 and IL-6
Most therapies decrease macrophage cytokine production
Decreased macrophage infiltration strongly correlates with the degree of clinical improvement to therapies
T cells
Human leukocyte antigen (HLA) associations suggest T cell role
RA synovium is rich in activated T cells
- Th17 cells and Th1 cells predominate
Increasingly, Th17 cells have been suggested as a major pathogenic subset. IL-17 is known to:
- Activate synovial fibroblasts and osteoclasts
- Favour cartilage resorption
T regulatory cells are enriched in the RA joint but appear to be have a defect that can be reversed by blocking TNF
B cells
Auto-antibodies associated with disease are usually present before onset of symptom
B cells form diffuse or follicular infiltrates in the RA synovium
B cell depletion using monoclonal anti-CD20 is effective treatment
B cells also produce cytokines and are important for antigen presentation
Cartilage erosion
Fibroblasts make matrix metalloproteases (MMPs) which break down the collagen network in the cartilage
Chondrocytes undergo apoptosis
Fibroblasts adhere to and invade the cartilage
Leads to biomechanical dysfunction and joint space narrowing