Biologic Response Modifiers in Rheumatologic Disease Flashcards
What is the pathology of RA?
Initially, the synovium becomes grossly edematous, thickened, and hyperplastic. There is also a dense perivascular inflammatory infiltrate composed of lymphoid follicles (mostly CD4+ helper T cells), plasma cells, and macrophages filling the synovial stroma.
There is also increased vascularity that results from vasodilation, angiogenesis, and pannus formation.
What is the pannus in RA?
A pannus is a fibrocellular mass of synovium and synovial stroma, consisting of inflammatory cells, granulomatous tissue, and fibroblasts,
that causes erosion of underlying cartilage.
What are biologic response modifiers?
complex proteins designed to inhibit the inflammatory cascade in RA and other diseases
several approaches:
- receptor antagonists
- monoclonal antibodies
- soluble cytokine receptors
What are ways to inhibit cytokines?
monoclonal antibody to cytokine or receptor
soluble receptor
receptor antagonist
anti-inflammatory cytokine
What are the structures of TNF-alpha inhibitors in RA?
infliximab (chimeric monoclonal antibody)
adalimumab and golimumab (human recombinant antibodies)
etanercept (human recombinant receptor/Fc fusion protein)
certolizumab (humanized Fab’ fragment)
infliximab
monoclonal antibody directed against TNF (high affinity and specificity)
chimeric mouse/human
single dose shows large improvement, but multiple treatments when used along decrease in effetiveness (reduced time before recurrence of symptoms)
is able to reduce inflammation as well as structural damage
What is the benefit of using infliximab with methotrexate?
better response and long-term maintenance
What are the trends of inflammation and disability in RA?
in the beginning, the disability and inflammation model each other
later on in the disease, the disability goes up even if inflammation goes down
radiographs are better predictors of disability in the later stages
adalimumab
contains human frame-work sequences in the original germ-line encoded configuration
contains unique human CDR regions, allowing specific binding to TNF
etanercept
contains Fc region of human IgG1 and two extracellular domains of human p75 TNF receptor
can work alone without methotrexate, but may not be better than methotrexate so use when methotrexate fails
What is the role of interleukin-1 in RA?
pro-inflammatory cytokine
important mediator of joint damage:
- activates collagenase and stromelysin
inhibits synthesis of collagen and proteoglycan
stimulates bone resorption by activating osteoclasts through an intermediatry cytokine, osteoprotegrin ligand
tocilizumab
humanized monoclonal antibody
blockade of IL-6 signaling
IL-6 is effective pleiotropic cytokine whose overexpression is thought to contribute to RA pathogenesis
- IL-6 induces a chemotactic response by leukocytes2
- IL-6 is involved in the production of acute phase reactants2
- IL-6 helps promote T- and B-cell proliferation and differentiation2
rituximab
a chimeric anti-CD20 monoclonal antibody
transiently depletes pre-B and mature B cells only
progenitor and plasma cells not affected
abatacept
a human immunoglobulin receptor fusion protein
binds to CD80/86, which is a coactivation receptor on APCs that activate T-cells
binding of this drug blocks activation by preventing binding of CD28
What is the cascade of activation that results from the presence of cytokines?
cytokine binding to its cell surface receptor leads to receptor polymerization and activation of associated JAKs
activated JAKs phosphorylate the receptors that dock STATs
activated JAKs phosphorylate STATs, which dimerize and move to the nucleus to activate new gene transcription
