06: Rheumatoid Arthritis Treatment

Question 1

Targets of TNF-a

Answer 1

• Macrophages: pro-inflammatory cytokines, chemokines –> ↑inflammation
• Endothelium: adhesion molecules –> ↑cell infiltrates; VEGF –> ↑angiogenesis
• Hepatocytes: APR –> ↑CRP
• Synoviocytes: metalloproteinase synthesis –> articular cartilage degradation
• Osteoclast progenitors: RANKL expression –> bone erosion

Question 2

etanercept

1. MOA
2. Efficacy
3. Side effects
4. Other

Answer 2

1. soluble TNF-receptor coupled to Fc portion of human IgG1 (binds circulating TNF)
2. As efficacious as MTX (but much more expensive; used as alternative); reduces pain and inflammation, improves labs (ESR, CRP), delays radiographic progression (erosions, joint space narrowing); best if used in combo w/ MTX
3. Injection site or infusion reactions, opportunistic infx (TB), demyelinating dz, CHF, malignancy (lymphoma, melanoma)?
4. Discontinuation results in rapid recurrence of inflammation; does not address underlying cause of RA

NB: **infliximab **similar, except is Ab against TNF-a

Question 3

Targets of IL-1

Answer 3

• Activated monocytes/macrophages –> inflammation
• Induced fibroblast proliferation –> synovial pannus formation
• Activated chondrocytes –> cartilage breakdown
• Activated osteoclasts –> bone resorption

NB: TNF (not IL-1) drives inflammatory pathways in RA

Question 4

What diseases respond well to IL-1 inhibition?

Answer 4

• Systemic onset JIA
• Gout

–> IL-1 plays a key role in pathogenesis of these disorders

Question 5

What are the downsides of TNF inhibition?

Answer 5

• Suppresses apoptotic function in infection and malignancy
• Enhances risk for reactivation of latent TB (more common w/ anti-TNF Abs than soluble TNF receptor)
  
  • Presents rapidly
  • Disseminated > pulmonary
  • Mechanism:
    
    • Anti-TNF therapy suppresses endothelial activation (normally allows influx of monocytes to granulomas)
    • Granulomas rapidly dissolve –> released organisms into lungs, circulation

Question 6

What does this image show?

Answer 6

dissolution of TB granulomas (may occur in pts treated w/ anti-TNF therapy)

Question 7

Role of interleukin-6

Answer 7

• Systemic manifestations of inflammation:
  
  • APR
  • Anemia
  • Hypergammaglobulinemia (“protein gap”)
  • Hypoalbuminemia
• Produced by:
  
  • Monocytes/macrophages
  • Endothelial cells
  • Mesenchymal cells, fibroblasts/synoviocytes

Question 8

tocilizumab

1. MOA
2. Efficacy
3. Side effects

Answer 8

1. Binds mIL-6R and sIL-6R, preventing binding of IL-6, thus inhibiting signal transduction
2. improves signs/sx of RA at all dz stages
3. Serious infx, neutropenia, GI perforations, LFT abnl, ↑lipids

Question 9

abatacept

1. MOA
2. Efficacy
3. Side effects

Answer 9

1. CTLA4-Ig; binds **CD80/86 **(APC) and prevents binding with **CD28 **(naive T cell) –> inhibition of T cell activation
2. RA monotherapy; in MTX failures; in anti-TNF failures
3. No major side effects (TB reactivation risk low; no suppressed response to immunizations)

Question 10

rituximab

1. ​MOA
2. Efficacy
3. Side effects

Answer 10

1. anti-CD20 mAb –> destroys B cells
2. poor efficacy as monotherapy; efficacious in combo w/ MTX in MTX failure and anti-TNF failure
3. Decline in Ig levels –> infx risk; rare CNS infx (PML)

Question 11

tofacitinib

1. MOA
2. Efficacy

Answer 11

1. JAK inhibition (mainly targets JAK-3); prevents signaling through common gamma chain of several cytokine receptors
2. Comparable to other Rx

Question 12

What is the method of therapy with RA?

Answer 12

Begin with MTX and decide from there (add drugs; do NOT stop current)

Question 13

RA treatment limitations

Answer 13

• Not curative
• No one tx highly effective in > 50% of pts
• Cannot predict who will respond to which drug