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
bone erosion
Cytokines including IL-17, RANKL, TNF-alpha, IL-1 and IL-6 promote osteoclast differentiation and activation
Deep bone resorption pits develop, which become filled with inflammatory tissue
Worse at mechanically vulnerable sites, such as the 2nd/ 3rd metacarpal
Little repair as cytokines inhibit the differentiation of osteoblasts
Affects 80% RA patients within 1 year of diagnosis
Clinical markers of RA
Elevated ESR
Elevated CRP
Rheumatoid factor (RF)
Cyclic citrullinated peptide (CCP) antibodies
Rheumatoid factor
Rheumatoid factors are antibodies directed against the Fc portion of another antibody, leading to immune complex formation
Present in 60-70% of patients with RA
Of some use in diagnosis, but:
- Not specific for RA (only 86%), also present in other autoimmune diseases, infectious diseases and some healthy individuals
- Some RA patients are ‘seronegative’
- Levels do not correlate with disease activity
- RF +ve patients have a more severe disease
Role in pathogenesis is unclear
CCP antibody
Also known as ACPA (anti-citrullinated peptide antibodies)
Antibodies directed against CCP are found in 60-70% of patients with RA (anti-CCP +ve)
Very rarely found in healthy people who do not go on to develop RA (high specificity 98%)
Detectable in the blood many years before disease onset
Anti-CCP +ve RA has a more aggressive clinical course of disease
Citrullination
process of replacing protein arginine residues with citrulline residues
Occurs normally in the body but if occurs on an unusual part of the protein, they may be recognised as foreign, leading to an antibody response
Cirullinated self proteins; α-enolase, keratin, fibrinogen, fibronectin, collagen and vimentin are detected in RA patients
Do anti-CCP antibodies have a pathogenic role?
Unable to induce arthritis alone, but can enhances the development and severity of inflammation in mice when a mild synovitis is already present.
Possible mechanisms:
- Activation of inflammatory cells by anti-CCP immune complexes
- Anti-CCP mediated neutrophil cell death producing NETs
- Direct binding of anti-CCPs to drive osteoclastogenesis.
Aetiolofy of RA
Genetics
Immune dysfunction
Environment
polymorphisms associated with RA
HLA-DRB1 SE- Human leukocyte antigen, account for 30-50% of the overall genetic risk
PTPN22 -Regulates T cell activation
CTLA4- co-stimulation suppressor that regulates interactions between T cells and antigen presenting cells
STAT4-Transducer of cytokine signals that regulates proliferation, survival and differentiation of lymphocytes
TRAF1 - Regulator of TNFα receptor superfamily signalling
Genetics: twin study
Monozygotic twins 12-15%
Dizygotic twins 3-5%
Genetics of RA
Susceptibility and severity of disease is determined by a combination of genes
No particular gene is necessary or sufficient for disease
Most genes show a relatively low gene penetrance. Variants are not found in many of the individuals who have RA.
Thus there must be other factors that in addition to genetics that have a role in the susceptibility and severity of autoimmune diseases.
The genes identified as risk factors are likely to regulate the immune response to environmental agents important in the induction of disease
Hormones
Testosterone is considered to protect against autoimmune disease. Men who get RA usually have low testosterone levels
Risk of developing RA is increased during the period just after giving birth
RA risk related to breast feeding after the first pregnancy
RA patients often experience remission during pregnancy. Patients show less disease activity and have increased numbers of T-regulatory cells that can suppress inflammation
However, the risk of developing RA after menopause is not influenced by hormone replacement therapy.
Smoking
Heavy smoking of both sexes increase the risk of RA among persons with susceptibility HLA-DR4 alleles.
Twin studies have demonstrated the gene–environment interaction by showing that the effect of smoking is greater in genetically susceptible individuals, particularly if HLA DRB1+
Smoking and HLA-DRB1 alleles increase the risk of being anti-CCP +ve
2,3,7,8-tetrachlorodibenzop dioxin (TCDD) in cigarette smoke, has been shown to activate synovial fibroblasts to induce pro-inflammatory cytokines.
Suggested infectious trigger of RA
Viral/bacterial infections have been suggested for many decades as an initiating cause of autoimmunity
Evidence has proved difficult to find. The infection may no longer be present once the disease is established
Bacterial components have been identified in joint tissue from RA patients but also in healthy joint tissue
In argument against an infectious trigger, there has been no evidence of a seasonal influence on incidence of autoimmune diseases
Peridontitis
Gum disease bacteria P. gingavitis also has PAD enzymes which cause citrullination and linked to joints
