LOCO Rheumatoid Arthritis Flashcards
Rheumatoid Arthritis cause
Interaction between genetics and environment
a. HLDA-DR1/DR4 with smoking or a pathogen.
Rheumatoid Arthritis Initial Onset
- Interaction between genetics and environment
- Cause leads to modification of antigens (such as IgG antibodies, Type II collagen and vimentin)
- Type II collagen and vimentin can be modified by citrullination.
a. Arginine –> citruline - Immune cell confused by these changes and produces anti-citrullinated antibodies.
a. Formed in the specific HLA alleles.
b. Can stimulate osteoclast differentiation.
i. And therefore lead to bone erosion - Antigens (Col. II, vimentin) picked up by APCs –> T-helper cells –> B-cells.
a. Produce specific autoantibodies
Rheumatoid Arthritis Initial Joint Impact
- T-cells and autoantibodies enter circulation and reach joints
- There T-cells secrete INF gamma and IL-17. This orchestrates synovitis and damage
a. Causes activation of dendritic cells: further secretion of pro-inflammatory cytokines.
b. Causes activation of B- cells
i. Further autoantibody secretion.
ii. Present antigen to T-cells to form complex with APC and T-cells.
iii. Stimulates synovial fibroblasts (through secretion of lymphotoxin beta and TNF).
1. These cause joint damage –> through secretion of MMPs and cathepsins (protease) - Proteases that break down cartilage –> Secrete RANK-L
c. Recruitment of macrophages
i. Production of further cytokines
1. IL-1, IL-6, TNF alpha.
ii. Stimulates synovial fibroblasts
d. Stimulation of osteoclasts
i. IL-1, IL-6, IL-17 from macrophages/T-cells
ii. RANK-L from fibroblasts
Pannus Formation
Result from inflammation and proliferation of synovium.
o Consists of fibroblasts, inflammatory cells.
o Acts like a tumour: grows over cartilage and bone
Causes joint erosion at joint margin.
Why are Synovial joints susceptible to inflammatory injury
Rich network of fenestrated capillaries
Limited ways it can respond.
Systemic Condition and inflammation
IL-1, IL-6, TNFa: from T-cells, B-cells and macrophages leak out into blood stream
o Result into systemic inflammation.
Methotrexate
Folate Acid Antagonist (DMARD)
MoA:
Prevents proliferation during cell mitosis by inhibiting dihydrofolate reductase (purine metabolism) and prevents DNA/RNA metabolism by inhibiting thymidylate synthase
Prevents binding of IL1b to surface of cells
Side Effects:
• Can cause liver problems
• Can affect blood count.
Dosage/Administration :
- Oral
- Subcutaneous/intramuscular
Loading dose: 50mg a week
Maintenance dose: 2.5mg tablet.
(!) 3-12 weeks before benefit seen.
Sulfasalazine
Old sulfur antibiotic (DMARD)
MoA:
Converted to 5-ASA
Treats Ulcerative Colitis and relieves arthritis symptoms
modulates distant sites of cytokine travel
Dosage/Administration:
Start 500mg daily, then gradually increase over 4 weeks to 1g twice a day.
(!) 12 weeks before benefit seen.
Hydrochloroquine
Anti-Malarial (DMARD)
MoA:
• Accumulates in lysosomes: increases pH, which decreases protein modification.
• Block TLR9: recognises DNA containing immune complexes –> decreases activation of dendritic cells
Side Effects:
Rash
Dosage/Administration:
Start 400mg daily
Reduced to 2-3 times a week.
Leflunomide
(DMARD)
MoA:
• Inhibits DNA and RNA synthesis though a different pathways vs methotrexate.
• Inhibits pyrimidine synthesis
Dosage/Administration:
10-20mg a day (1st 3 days higher dose than 100mg a day).
Gold Salts
(DMARD)
MoA:
Not well understood
Dosage/Administration:
Intramuscular injections
10-20mg a day.
Etanercept
(TNF Alpha Blocker)
Fusion protein between TNF receptor 2 and FC human IgG1
MoA:
• Extracellular receptor stuck to human FC.
• Finds free TNFa alpha in the system.
Dosage/Administration:
Subcutaneous injection
50mg once per week.
(!) 1-4 week for effect.
Progressive improvement over 3-6m.
Infliximab
(TNF Alpha Blocker)
Monoclonal antibody vs TNF alpha
MoA:
• Design against mouse binding site of TNFa. .
• Remains 75% human IgG.
Adalimumab
(TNF Alpha Blocker)
Human TNF alpha monoclonal antibody
MoA:
• Binds to TNFa both soluble and bound
Dosage/Administration:
Subcutaneous injection
100mg once a week
(!) 2-4 weeks for effect.
Anankinra
(IL-1 Blocker)
Human recombinant IL-1 receptor antagonist
MoA:
• Different from normal IL-1 by addition of methionine to the N-terminal.
