SM_227a: Biologics and Therapeutics Flashcards
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
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
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)
Describe non-biologic DMARDs in RA
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
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
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
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
Describe the pathogenesis of RA
Pathogenesis of RA
- Synoviocytes activated
- Angiogenesis
- T cells and other immune cells come into synovium
- Osteoclasts activated and break down bone
- Bone erodes
(synovium becomes hyperplastic, pannus eats away at interface between bone and cartilage)
Describe the immune cascade in RA
Immune cascade in RA
- APC/DC activates T cells
- T cells activate B cells, macrophages, fibroblast like synoviocytes (FLS)
- B cells turn into plasma cells -> RF autoantibodies
- FLS lead to inflammation and joint damage
- Macrophages secrete cytokines, MMPs, prostaglandins, and nitric oxide
_____ secreted by immune cells play a role in pathogenesis of RA
Cytokines secreted by immune cells play a role in pathogenesis of RA
_____ 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
Cytokine inhibitors function to ______
Cytokine inhibitors function to restore balance between pro-inflammatory and anti-inflammatory cytokines
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
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
Describe how TNF activates receptors on target cells
- Macrophages produce TNF
- TNF cleaved off cell surface by TACE
- TNF binds to 2 receptors on target cell surface simultaneously
- Activates cell
______, ______, ______, ______, and ______ are TNF-alpha inhibitors
Infliximab, Adalimumab, Golimumab, Etanercept, and Certolizumab are TNF-alpha inhibitors
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
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
Disability in RA is driven by _____ and _____
Disability in RA is driven by inflammation and damage
(inflammation is constant but joint damage is progressive)
In RA, _____ is constant while _____ is progressive
In RA, inflammation is constant while damage is progressive
Adalimumab contains unique ______, allowing ______
Adalimumab contains unique human CDR regions, allowing specific binding to TNF
Etanercept ______, preventing ______
Etanercept binds to and inhibits TNF, preventing TNF binding to receptors on the target cell
(prevents activiation of cell surface receptors)
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)
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)
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)
Describe T cell activation
T cell activation
- 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
- T cell activated
(if CTLA4 on T cell binds to CD80/86 on dendritic cell, T cells are downregulated)
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
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
Describe activation of signaling pathways via cytokine receptors
Activation of signaling pathways via cytokine receptors
- Cytokine binding to its cell surface receptor to receptor polymerization and activation of associated JAKs
- Activated JAKs phosphorylate the receptors that dock STATs
- Activated JAKs phosphorylate STATs
- STATs dimerize and move into nucleus to activate new gene transcription
Tofacitinib ____, modulating ____ important in pathogenesis of RA
Tofacitinib inhibits JAKs, modulating cytokines important in pathogenesis of RA
____, ____, ____, and ____ are involved in the JAK signaling pathway
JAK1, JAK2, JAK3, and TYK2 are involved in the JAK signaling pathway
Cytokines signal through ____ of JAKs
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)
