SM_227a: Biologics and Therapeutics

Question 1

Describe the clinical course of RA

Answer 1

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

Question 2

Describe the therapeutic aim in RA

Answer 2

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

Question 3

Primary target in treating RA is state of ____

Answer 3

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)

Question 4

Describe non-biologic DMARDs in RA

Answer 4

Question 5

Describe the benefits and considerations of hydroxychloroquinone in RA

Answer 5

Hydroxychloroquinone

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

Question 6

Describe the benefits and considerations of sulfasalazine in RA

Answer 6

Sulfasalazine in RA

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

Question 7

Describe the benefits and considerations of methotrexate in RA

Answer 7

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

Question 8

Describe benefits and considerations of leflunomide inRA

Answer 8

Leflunomide in RA

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

Question 9

Describe the pathogenesis of RA

Answer 9

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)

Question 10

Describe the immune cascade in RA

Answer 10

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

Cytokine inhibitors function to ______

Answer 13

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

Question 14

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

Answer 14

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

Question 15

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

Answer 15

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

Question 16

Describe how TNF activates receptors on target cells

Answer 16

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

Question 17

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

Answer 17

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

Question 18

Monoclonal antibodies inhibit TNF by _____, preventing them from _____

Answer 18

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

Question 19

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

Answer 19

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

Question 20

Disability in RA is driven by _____ and _____

Answer 20

Disability in RA is driven by inflammation and damage

(inflammation is constant but joint damage is progressive)

Question 21

In RA, _____ is constant while _____ is progressive

Answer 21

In RA, inflammation is constant while damage is progressive

Question 22

Adalimumab contains unique ______, allowing ______

Answer 22

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

Question 23

Etanercept ______, preventing ______

Answer 23

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

(prevents activiation of cell surface receptors)

Question 24

Tocilizumab blocks cellular activation by inhibiting ______

Answer 24

Tocilizumab blocks cellular activation by inhibiting IL-6

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

Question 25

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

Answer 25

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)

Question 26

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

Answer 26

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)

Question 27

Describe T cell activation

Answer 27

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)

Question 28

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

Answer 28

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

Question 29

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

Answer 29

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

Question 30

Describe activation of signaling pathways via cytokine receptors

Answer 30

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

Question 31

Tofacitinib \_\_\_\_, modulating ____ important in pathogenesis of RA

Answer 31

Tofacitinib inhibits JAKs, modulating cytokines important in pathogenesis of RA

Question 32

\_\_\_\_, \_\_\_\_, \_\_\_\_, and ____ are involved in the JAK signaling pathway

Answer 32

JAK1, JAK2, JAK3, and TYK2 are involved in the JAK signaling pathway

Question 33

Cytokines signal through ____ of JAKs

Answer 33

Cytokines signal through pairs of JAKs (different combinations - JAK3 is expressed only in hematopoietic cells and pairs only with JAK1, JAK1/JAK2/TYK2 are ubiquitously expressed)