Biologic Response Modifiers in Rheumatologic Disease Flashcards

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1
Q

What is the pathology of RA?

A

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.

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2
Q

What is the pannus in RA?

A

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.

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3
Q

What are biologic response modifiers?

A

complex proteins designed to inhibit the inflammatory cascade in RA and other diseases

several approaches:

  • receptor antagonists
  • monoclonal antibodies
  • soluble cytokine receptors
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4
Q

What are ways to inhibit cytokines?

A

monoclonal antibody to cytokine or receptor

soluble receptor

receptor antagonist

anti-inflammatory cytokine

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5
Q

What are the structures of TNF-alpha inhibitors in RA?

A

infliximab (chimeric monoclonal antibody)

adalimumab and golimumab (human recombinant antibodies)

etanercept (human recombinant receptor/Fc fusion protein)

certolizumab (humanized Fab’ fragment)

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6
Q

infliximab

A

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

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7
Q

What is the benefit of using infliximab with methotrexate?

A

better response and long-term maintenance

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8
Q

What are the trends of inflammation and disability in RA?

A

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

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9
Q

adalimumab

A

contains human frame-work sequences in the original germ-line encoded configuration

contains unique human CDR regions, allowing specific binding to TNF

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10
Q

etanercept

A

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

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11
Q

What is the role of interleukin-1 in RA?

A

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

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12
Q

tocilizumab

A

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
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13
Q

rituximab

A

a chimeric anti-CD20 monoclonal antibody

transiently depletes pre-B and mature B cells only

progenitor and plasma cells not affected

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14
Q

abatacept

A

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

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15
Q

What is the cascade of activation that results from the presence of cytokines?

A

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

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16
Q

tofacitinib

A

novel inhibitor of JAKs that modulates cytokines important in pathogenesis of RA

17
Q

anakinra

A

a soluble IL-1 receptor

not as effective as some of the other biologics

18
Q

What are some safety issues with biologic DMARDs?

A

serious infections

opportunistic infections

malignancies

demyleination

hematologic abnormalities

administration reactions

congestive heart failure

autoantibodies and lupus-like syndrome