Rheumatoid arthritis Flashcards
Outline type II hypersensitivity and give 2 examples
Type 2
- Involves antibodies binding to antigens on surface of a cell.
- can lead to 3 things: cell destruction, inflammation, dysfunction.
Cell destruction
-> antibody binds to cell surface antigen
-> activates NK cells -> cell death via cytotoxicity
-> activates phagocytes -> cell death via phagocytosis
Inflammation
-> antibody binds to cell surface antigen
-> activates the complement system -> FC mediated inflammation
Dysfunction
-> binding of antibody to cell surface antigen prevents normal functioning of the cell
Examples:
Transfusion reaction
Myasthenia gravis
Transplant rejection
Outline type 1 hypersensitivity and give example
Type 1
- “First and Fast”
- involves IgE, mast cell and allergen.
*First phase (within minute)
-> antigen cross-links IgE on mast cell leading to immediate degranulation and release of histamine, tryptase , leukotrienes
*Second phase (hours)
-> mast cell releases chemokines + other inflammatory mediators which attract eosinphils
-> leads to further inflammation and tissue damage.
Example: anaphylaxis/ allergic asthma
Outline type III hypersensitivity and give examples
Type III
- Involved immune complexes composed of 3 things: Antibody-antigen-complement.
-antibody is usually IgG
The complex attracts neutrophils which release lysosomal enzymes and can damage tissue.
Examples
Rheumatoid arthritis
Reactive arthritis
Systemic lupus erythematosus
Outline the main steps in the pathophysiology of RA
- Citrullinated proteins associated with synovial joints, seen as autoantigens, are presented to T cells by antigen presenting cells
- T cells are activated, proliferate and release IL-4.
- IL-4 activates B cells which change to plasma cells and produce 2 main autoantibodies:
-> Anti-cyclic-citrullinated peptide (aCCP)
-> Rheumatoid factor IgM autoantibody. - T cells migrate to synovial joint and release: TNF-a, IL-6, IL-8.
- Attracts inflammatory cells, mainly neutrophils and macrophages.
- Immune complexes deposit within the joint -> activate inflammatory response via complement system.
Within the joint the following occurs:
(1) reduce hyaluronan
(2) increased matrix metalloproteinases
(3) Synovium hyperplasia
(4) Synovium angiogenesis
–> Non-suppurative inflammatory synovitis.
(5) Granulation tissue + Pannus formation which erodes through cartilage
(6) increased bone resorption through increased RANK-L release
What is the AA swap to result in citruillination?
Arginine -> citrulline
How does rheumatoid factor play a role in RA?
What percentage of people with RA are RF+ve ? Name 3 other conditions which can be RF+
It is an IgM autoantibody which targets the Fc portion of IgG antibodies and can therefore trigger the complement system/phagocytosis by opsonization.
80% are RF+
Other conditions:
-Sjorgens syndrome
-systemic lupus erythematosus
-endocarditis
-hepatitis B/C
list 3 tests for RA
what is the specificity of each
Serology:
Anti-citrullinated peptide antibodies - 88-98%
Rheumatoid factor 80%
ESR/CRP
How does methotrexate results in bone marrow suppression?
Methotrexate has anti-folate effects through inhibition of dihydrofolate reductase.
This prevents the formation of purines/pyrimidines which are required by the bone marrow in order to synthesize nucleic acids for new cells.
The cells in bone marrow are rapidly dividing cells, meaning they are susceptible to methotrexate’s effects
outline MOA of methotrexate and list 3 ADR’s
Enters cell and becomes polyglutamated
-> antifolate effects: inhibits dihydrofolate reductase
-> anti-inflammatory effects: inhibits AICAR transformylase
This results in increased extracellular adenosine -> activation of A2a receptor leading to the following anti-inflammatory effects:
(1) reduced neutrophil adhesion
(2) reduced macrophage function
(3) reduced cytokine production
ADRS
(1) bone marrow supression -> leucopenia, anemia, thrombocytopenia
(2) GI disturbance: nausea, vomitting, diarrhea
(3) Mucosal ulcers
(4) hepatotoxicity
What is the usual treatment regimen for RA with methorexate?
ONCE WEEKLY LOW DOSE methotrexate
Daily folic acid, except on day of MT.
Takes 6-12 weeks to work
List 3 reasons why Folic acid should be supplemented
Reduces GI side effects
Reduces mouth ulcer formation
Protective against hepatotoxicity
NOT protective against bone marrow suppression
Describe the 3 main components of a synovial joint
(1) Joint capsule
- outer layer: Dense fibrous connective tissue, connecting both bones, stability.
-inner layer: loose connective tissue, highly vascularised, synovial fluid production.
(2) Articular cartilage
- Hyaline cartilage on both articulating surfaces: Chondrocytes, type II collagen, GAG’s, proteoglycans, intracellular water.
- partly vascularised- nutrients via diffusion from synovial fluid.
- no perichondrial covering
(3) Fluid-filled synovial cavity
- lined by the synovial membrane made up of cuboidal synoviocytes (3 cell layer thick)
-Type A: hyaluronic acid
-Type B: hyaluronic acid + lysosomal enzymes
-Synovial membrane projects inwards as villi to increase surface area.
-It lacks a basement membrane allowing for rapid diffusion between blood and synovial fluid.
Synovial fluid derived from ultrafiltrate of plasma:
-Water
-Hyaluronic acid
-Glycoproteins
-Lubricin for lubrication
-Proteoglycans
-Phagocytic cells
-lacks clotting factors
Functions:
Lubrication
nutritional support
shock absorption
Ingestion of debris
Rheopectic properties means it becomes more viscous with increasing sheering force
outline 5 changes in synovial membrane in RA
(1) synovial membrane inflammation and hyperplasia -> non suppurative inflammatory synovitis
(2) hypertrophy with Giant cells and villi formation
(3) Pannus formation
(4) Cartilage and bone erosion -> periarticular osteopenia
(5) PMN infiltrate
(6) Subchondral cysts.
Define the term monoclonal antibody and outline how they are produced
A monoclonal antibody are immunoglobulins derived from a single cell lineage, with a defined specificity for a single antigen.
They are produced through a process called somatic-cell hybridisation:
- a mouse is injected with a specific antigen of interest.
- the B cells from the mouse spleen are harvested
-Hybridoma is produced through fusion of B cells with myeloma cells from human.
-monoclonal antibodies are then derived. a
List 4 groups of biological therapies used for RA
TNF-alpha inhibitors e.g. Infliximab/Adalimumab
IL-6 receptor antagonists e.g. Tocilizumab
T cell co-stimulation blockers e.g. Abatacept
B-cell depletion e.g. Rituximab
