SM_227a: Biologics and Therapeutics Flashcards Preview

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Flashcards in SM_227a: Biologics and Therapeutics Deck (33)
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1

Describe the clinical course of RA

Clinical course of RA

  • Chronic and progressive disease
  • 50% of patients have irreversible joint damage at 2 years: true cause of late disability
  • If not treated early and aggressively leads to increasing joint destruction and deformity, progressive physical disability, and reduced quality of life

2

Describe the therapeutic aim in RA

Therapeutic aim in RA

  • Signs and symptoms: improvement, remission
  • Joint damage: slowing, prevention, reversal
  • Disability: improvement, prevention, reversal

 

Requires a comprehensive approach: type of intervention, timing, follow-up management, assessment of comorbid conditions

3

Primary target in treating RA is state of ____

Primary target in treating RA is state of clinical remission

 

(low disease activity may be an alternative therapeutic goal, particularly in established long-standing disease)

4

Describe non-biologic DMARDs in RA

5

Describe the benefits and considerations of hydroxychloroquinone in RA

Hydroxychloroquinone

  • Effective for mild disease and in combo with methotrexate
  • Takes 3-6 months to become effective
  • No evidence of halting radiographic progression

6

Describe the benefits and considerations of sulfasalazine in RA

Sulfasalazine in RA

  • Effective for mild-moderate disease
  • May be used with other agents
  • Slows radiographic damage
  • Contraindicated in patients who have sulfa allergies

7

Describe the benefits and considerations of methotrexate in RA

Methotrexate in RA

  • Cornerstone for most treatment regimens
  • Well-tolerated once weekly medication
  • Slows radiographic damage
  • Contraindicated in potentially childbearing women
  • Usually administed with folic acid supplementation

8

Describe benefits and considerations of leflunomide inRA

Leflunomide in RA

  • For moderate-severe disease
  • Slows radiographic progression
  • Greater cost
  • Long half-life
  • Contraindicated in potentially childbearing women

9

Describe the pathogenesis of RA

Pathogenesis of RA

  1. Synoviocytes activated
  2. Angiogenesis
  3. T cells and other immune cells come into synovium
  4. Osteoclasts activated and break down bone
  5. Bone erodes

(synovium becomes hyperplastic, pannus eats away at interface between bone and cartilage)

10

Describe the immune cascade in RA

Immune cascade in RA

  1. APC/DC activates T cells
  2. T cells activate B cells, macrophages, fibroblast like synoviocytes (FLS)
  3. B cells turn into plasma cells -> RF autoantibodies
  4. FLS lead to inflammation and joint damage
  5. Macrophages secrete cytokines, MMPs, prostaglandins, and nitric oxide

11

_____ secreted by immune cells play a role in pathogenesis of RA

Cytokines secreted by immune cells play a role in pathogenesis of RA

12

_____ and _____ are pro-inflammatory cytokines, while _____, _____, and _____ are anti-inflammatory

TNF-alpha and IL-1 are pro-inflammatory cytokines, while sTNF-R, IL-10, and IL-Ra are anti-inflammatory

13

Cytokine inhibitors function to ______

Cytokine inhibitors function to restore balance between pro-inflammatory and anti-inflammatory cytokines

14

Biologic response modifiers are complex proteins that inhibit the inflammatory cascade by acting as _____, _____, and _____

Biologic response modifiers are complex proteins that inhibit the inflammatory cascade by acting as receptor antagonists, monoclonal antibodies, and soluble cytokine receptors

15

Inhibition of cytokines can be accomplished via _____, _____, and _____

Inhibition of cytokines can be accomplished via neutralization of cytokines, receptor blockade, and activation of anti-inflammatory pathways

16

Describe how TNF activates receptors on target cells

  1. Macrophages produce TNF
  2. TNF cleaved off cell surface by TACE
  3. TNF binds to 2 receptors on target cell surface simultaneously
  4. Activates cell

17

______, ______, ______, ______, and ______ are TNF-alpha inhibitors

Infliximab, Adalimumab, Golimumab, Etanercept, and Certolizumab are TNF-alpha inhibitors

18

Monoclonal antibodies inhibit TNF by _____, preventing them from _____

Monoclonal antibodies inhibit TNF by directly binding to TNF, preventing them from binding to receptors on the target cell

19

Success of infliximab therapy tended to ____ with successive cycles due to ____

Success of infliximab therapy tended to shorten with successive cycles to HACAs specific for the murine portion of cA2

20

Disability in RA is driven by _____ and _____

Disability in RA is driven by inflammation and damage

 

(inflammation is constant but joint damage is progressive)

21

In RA, _____ is constant while _____ is progressive

In RA, inflammation is constant while damage is progressive

22

Adalimumab contains unique ______, allowing ______

Adalimumab contains unique human CDR regions, allowing specific binding to TNF

23

Etanercept ______, preventing ______

Etanercept binds to and inhibits TNF, preventing TNF binding to receptors on the target cell

 

(prevents activiation of cell surface receptors)

24

Tocilizumab blocks cellular activation by inhibiting ______

Tocilizumab blocks cellular activation by inhibiting IL-6

 

 

(IL-6 is pro-inflammatory cytokine, tocilizumab particularly effective in anti-TNF failures)

25

Describe the different locations in the inflammatory cascade where medications can act to treat RA

Different locations in the inflammatory cascade where medications can act to treat RA

  • Abatacept blocks T cell activation
  • Rituximab blocks B cell activation
  • Cytokine inhibitors block cytokines (TNF-alpha, IL-1, IL-6)

26

Rituximab inhibits B cells by binding to ____ on the cell surface, transiently depleting ____ and ____

Rituximab inhibits B cells by binding to CD20 on the cell surface, transiently depleting pre-B and mature B cells

 

(progenitor and plasma cells not affected)

27

Describe T cell activation

T cell activation

  1. TCR receptor on T cell binds to antigen presented on MHC class II on dendritic cell and CD28 on T cell binds to CD80/86 on dendritic cell
  2. T cell activated

 

(if CTLA4 on T cell binds to CD80/86 on dendritic cell, T cells are downregulated)

28

Abatacept competes for binding of _____ to CD80/86 on dendritic cells, _____ T cell-mediated autoimmunity

Abatacept competes for binding of CD28 on T cells to CD80/86 on dendritic cells

29

Cytokine receptors lack _____ activity, relying on associated _____ such as _____ to transmit signals from the extracellular environment to the nucleus

Cytokine receptors lack intrinsic kinase activity, relying on associated tyrosine kinases such as JAKs to transmit signals from the extracellular environment to the nucleus

30

Describe activation of signaling pathways via cytokine receptors

Activation of signaling pathways via cytokine receptors

  1. Cytokine binding to its cell surface receptor to receptor polymerization and activation of associated JAKs
  2. Activated JAKs phosphorylate the receptors that dock STATs
  3. Activated JAKs phosphorylate STATs
  4. STATs dimerize and move into nucleus to activate new gene transcription

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