Pathophysiology of RA Flashcards
What is RA?
Chronic systemic inflammatory condition
What is normally affected first?
Interphalangeal joints of fingers + wrists
What happens to the affected joints?
Become warm, painful + swollen
What causes stiffness (particularly in the morning)?
Increased extracellular fluid
What does RA cause?
Progressive destruction bone/cartilage around joint
What are the comorbidities of RA?
CVD
Inflammation around heart + lungs
What is osteoarthritis?
Degenerated arthritis
= wear in the joints = degeneration of cartilage + bone
Where does osteoarthritis usually affect?
Hands, neck, hip, back + knees
What is protective in osteoarthritis?
Exercise
What is septic arthritis?
Secondary to infection
= invasion of joints by infectious agent = joint inflammation
What is post traumatic arthritis?
Secondary to physical injury
What do autoimmune conditions do?
Body cannot distinguish between self + non-self
= body generates Abs against itself
What mutation increases risk to develop RA?
HLA-DR4
What is RA triggered by?
Exposure of genetically susceptible individual to an arthritogenic antigen = breakdown of immunological self-tolerance = chronic inflammation
Describe the breakdown in tolerance
Initiating event = acute arthritis
CD4+T helper cell activation = autoimmune reaction
Release of inflammatory cytokines + mediators = joint destruction
Describe what happens in RA once mediators are released
Joints infiltrated with CD4+T cells
Macrophages secrete pro-inflammatory cytokines + help B cells produce arthritogenic Abs
Cytokines induce production of MMP + RANK ligand by fibroblasts
MMPs attack tissue
= activation of osteoclasts = joint destruction
What are the 2 autoantibodies in RA?
Rheumatoid factor (RF)
Anti-citrullinated peptide Abs (ACPAs)
What is RF?
Autoantibody specific for Fc portion of IgG
What are ACPAs?
Citrullination increased in inflammation
How are citrullinated proteins produced?
Arginine is converted to citrulline by PAD
PAD destabilises proteins = more prone to proteolysis
How do smoking interact with ACPAs?
Smoking induces expression of PAD
Citrullinated proteins found in respiratory tract
HLA-DR4 mutation can activate CD4+T cells as result
They activate B cells
B cells produce Abs to own citrullinated proteins
= autoimmune response
= autoantibodies
What are the stages of RA pathogenesis?
Pre-articular phase
Initiation phase
Progression
What happens in the pre-articular phase?
Synovial membrane fibrous layer form joint capsule
PAD2 + PAD4 = citrullinate proteins
ACPAs present in blood
What happens in RA initiation?
Initiated by joint damage
Damage = state of inflammation
= further activation of PAD
ACPAs + RF enter joint capsule
Lymphocytes respond to specific antigen
Action of T cells + immune complexes = symptoms of RA
What happens in RA progression?
CD4+T differentiate into TH17 + TH1 = activate macrophages + neutrophils
= produce other pro-inflammatory cytokines
What happens overall in RA pathogenesis?
Autoantibodies against citrullinated proteins present in blood BUT joints normal
Needs triggering - eg. microbial/mechanical
Damage provokes normal inflammatory response + Abs enter joint capsule
Inflammation
Continued = progressive tissue damage = destroys synovial joints
What different drugs are used in RA therapy?
NSAIDs
Glucocorticoids
DMARDS
Biologics
Why give glucocorticoids?
Give till DMARDs kick in
What is the mechanism of action of methotrexate?
Supress neutrophil adhesion to blood vessels = prevention of entry into site of inflammation
Suppresses cytokine production
Reduces macrophage function
Reduces immune function
What is the problem with methotrexate?
Immunological suppression = makes patient more susceptible to infection
What is the mechanism of action of Sulfasalazine?
Supresses signalling pathway involved in synthesis of pro-inflammatory cytokines
What are the side effects of Sulfasalazine?
GI disturbances
Blood dyscrasias
What is the mechanism of action of Leflunomide?
Inhibits pyridine synthesis
= supresses expansion of autoimmune lymphocytes
= supresses autoimmunity
What are the side effects of Leflunomide?
Hepatoxicity
Leucopenia, anaemia + thrombocytopenia
What do biologics do?
Target specific components of immune signalling
When are biologics used?
When conventional DMARDS are ineffective
What is Anakinra?
Ab against IL-1
What is Tocilizumab?
Ab that acts as competitive antagonist against IL-6
