Exam 2: RA drugs

Question 1

Rheumatoid Arthritis

Pathophysiology

Answer 1

Autoimmune destruction of synovial membranes.

• Interaction between APC, T-cells, and B-cells
• T_H cells ⇒ TNF-α + other cytokines
  
  • Activates Mφ
• Mφ
  
  • Secrete TNF-α, IL-1, IL-6
• B-cells
  
  • Stimulated by T_H and Mφ to make autoAb
• TNF-α with central role in inflammation process

Question 2

Initial Treatment

Answer 2

Goal to reduce inflammation.

Does not slow disease process.

• NSAIDS
• Glucocorticoids
  
  • Low dose reduces joint destruction
  • Long term use with adverse effects
    
    • Weight gain
    • DM
    • Cataracts
    • Osteoporosis

Question 3

Disease Modifying Antirheumatic Drugs

(DMARDS)

Answer 3

Slows disease progression.

• Non-biologics ⇒ older agents
  
  • Methotrexate
  • Hydroxychloroquine
  • Sulfasalazine
• Ab or recombinant proteins ⇒ newer agents
  
  • Recombinant proteins called Biological Response Modifiers
• Most have high MW ⇒ must be given IV

Question 4

TNF-α Inhibitors

Answer 4

• Actions:
  
  • ↓ expression of adhesion molecules
    
    • ↓ leukocyte migration
  • ↓ [cytokines]
  • ↓ [metalloproteinases]
• Causes immunocompromise ⇒ ↑ risk of serious infections
• Used alone or with methotrexate
  
  • More effective than methotrexate alone
• Examples:
  
  • Etanercept
  • Infliximab
  • Adalimumab

Question 5

Anakinra

Answer 5

IL-1 Inhibitor

• Recombinant human IL-1 receptor antagonist
• IL-1
  
  • Causes cartilage degradation
    
    • Induces loss of proteoglycans
  • Stimulates bone resorption

Question 6

Tocilizumab

Answer 6

IL-6 Inhibitor

• Human Ab against soluble and membrane bound IL-6 receptors
• Inhibits IL-6 signaling
• IL-6
  
  • Produced locally by synovial cells
    
    • In response to inflammatory processes

Question 7

Leflunomide

Answer 7

Lymphocyte Antagonist

• Activated lymphocytes requires ↑ DNA/RNA synthesis
  
  • Depends on de novo synthesis of nucleotides
• Drug inhibits dihydroorotate dehydrogenase
  
  • ↓ UMP
• Causes cells to be arrested in G1 phase
• Mostly ↓ B cells but also has significant effect of T-cells

Question 8

Abatacept

Answer 8

Inhibitor of Co-Stimulation

• Recombinant fusion protein
• Binds CD80 and CD86 on APCs
  
  • Prevents interaction with CD28 on T-cells
• Prevents co-stimulatory signal ⇒ ⊗ T-cell activation