MSK L11 Rheumatoid Arthritis Flashcards
Definition
Autoimmune, chronic inflammatory disease, primarily affects the synovial joints
Clinical signs
➢ Soft tissue swelling • Effusion • Warmth • Erythema ➢ Joint deformity ➢ Reduced range of movement ➢ Muscle wasting
Radiological signs
Erosion of bone
Deformity
Symptoms
- Pain
- Stiffness
- Unpredictable ‘flare’ of inflammation
- Fatigue
- Disability
- Psychological effects
• Anxiety
• Depression
• Helplessness
Epi
Half a million in UK have RA
Prevalence worldwide → 0.5-1% WW
40% of patients are registered disabled within 3 years
Cost of treating RA in the UK is £0.8-£1.3 million
Population
Indians highest prevalence
Causes →
Possible antigenic targets in RA:
Microbial antigens:
Self antigens
Microbial antigens causing RA examples
- Super antigens (doesn’t require processing recognised by T-cell immediately) e.g. staphylococcal toxins
- Epstein-Barr virus antigens
- Heat shock proteins (HSPs)
- Parvovirus antigens
Self antigen associated with RA
- Collagen e.g. type II
- Cartilage link protein
- HSPS
- Aggrecan (cartilage matrix)
- Class II MHC shared epitope
- IgG Fc portion
Pannus: Formed from
Synovial hyperplasia containing many inflammatory cells (pannus) that erodes cartilage and bone.
Pannus function
Main form of joint destruction in RA
Panus contains
Abundant cell population: 1. Lymphocytes 2. Macrophages 3. Fibroblasts* Other cell population: 1. B lymphocytes – antigen processing 2. Dendritic cells 3. Plasma cells 4. Mast cells – pro-inflammatory
*Fibroblast cells →
apoptosis is delayed in RA therefore the fibroblasts continue to produce cytokines and enzymes continuing to erode the joint.
Role of B cells →
Auto antibodies:
- Antibodies to the Fc (Rhuematoid factor), Fac and F(ab)2 of the self IgG molecule
- Antibodies to Cellular antigens histone, ssDNA, RA nucleus antigen etc.
- Anti-collagen antibodies
- Antibodies to HSPs
Role of B cells in pathology→ Rheumatoid factors
- Ig classes of IgM, IgG, IgA and IgE
- RF found in 7-% of RA patients
- Not useful in diagnosis but is a good prognostic marker
B cell functions summary:
- Production of autoantibodies
- Secrete cytokines IL-6, THF-alpha and IL-10
- B-cells; can maintain T-cell activation in the RA synovium
Role of T-cells
- Efficacy of t-cell directed treatment in RA (e.g. Anti-CD4 treatment)
- Beneficial effects of cyclosporine
- Prominence of T-cell in the pannus and expression of IL-2 receptor in RA synovium
- Resolution of RA in patients with developing AIDS and during pregnancy
Small joints →
most of joint damage done by the pannus.
Large joints →
e.g.. Hip or knee → cytokines and enzymes released from cartilage contribute to destruction.
Rheumatoid Arthritis → Joint destruction - cartilage
a. Cytokines and other inflammatory mediators
b. Chemokines – presence augments inflammation
c. Enzymes
Cytokines and other mediators in the joint
- TNF alpha
- IL-1 beta
- Gamma-INF
- IL-6
Chemokines
IL-8 → attract neutrophils
IL-16 → attract eosinophils
Enzymes
Four classes of proteases have been recognised which degrade cartilage in RA:
- Cysteine
- Aspartate
- Serine
- Metallo- proteases (main group)
Role of TNF-alpha:
- Induces production of pro-inflammatory cytokines e.g. IL-1, IL-6, chemokines
- Activates endothelial cells, leading to further recruitment of cell within the joint
- Stimulate cells within the joint to break down the matrix which surround them
- Stimulate macrophages to produce matrix MMPs and free radicals
Metallopreoteases
Collagenase
Stromelysin
Gelatinase
Collagenase
MMP-1,8 and 13 → degrade type II collagen
Stromelysin
MMP-3,10 and 11 → proteoglycan degradation
Gelatinase
MMP-2 and 9 → further degrade the products of collagenase.
Changes in Bone:
- Osteoclasts (multinuclear) bind to bone surface via integrins
- The cells lower the pH of the bone by releasing hydrogen ions
a. Loss of mineral part of bone → hydroxyappetite
b. Organic part → collagen and bone matrix (BSP, osteocalcin etc.) → destroyed by proteolytic enzymes like in cartilage. - Gradually destroy both mineral and organic bone
a. Hydroxyapitite
