Modulating Cytokines in Autoimmune disorders Flashcards
What is RA?
sterile joint inflammation of synvoial lining which over time damages the adjacent structures: cartilage and bone
What happens to the synovium in RA?
becomes a proliferated mass of tissue (pannus) with neovascularisation, lymphangiogenesis and inflammatory cells
What cells are normally found in the synovium?
macrophage-like and fibroblast like cells and type I collagen
What are the driving cytokines in RA?
TNFa and IL-1
What anti-inflammatory cytokines are lacking in RA?
soluble TNF receptor; IL-10; IL-1 receptor antagonist
What is the dominant pro-inflammatory cytokine in rheuamtoid synovium?
TNFa
Which cells mainly produce TNFa in RA?
macrophages in synovium
What cytokines did inhibition of TNFa stop the production of?
IL-1; IL-6; GMCSF nad IL-8
Why is TNFa described as pleotropic in RA?
affects osteoclasts; chondrocytes; synoviocytes
Why are drugs such as anti-TNF described as biologics?
made in culture systems not synthesised
Why were biologics needed?
lots of patients with RA were progressing despite DMARD therapy
What was the problem with infliximab?
it was originally a human/mouse chimeric antibody so patients developed a human anti-chimeric response
What is the name for the fully huamnised anti-TNF developed?
adalinumab
What is the MOA of etanercept?
dimeric fusion protein: soluble TNF receptor which mops up TNF
What is the name for the off patent versions of biologics?
biosimilar- not exactly the same as produced in a living system
When can a patient be prescribed a biologic?
disease is severe with disease acitivty score (DAS28) >5.1; disease hasnt repsonded to a combo of DMARDs
What are the biological therapies for SLE?
rituximab and belimumab
What is rituximab?
chimeric anti-CD20 antibody used to deplete B cells
What is belimumab?
monoclonal antibody against a B cell survival factor called BLYS
Aside from biologics, what agents are currently available for SLE?
hydroxychloroquine; pred; azathioprine; mycophenolate
What type of antibody is belimumab?
IgG1
What other name is BLyS known as?
BAFF
What does BAFF stand for?
B cell activating factor of the TNF family
What is the effect of inhibiting BAFF?
impaired B cell survivial and reduced B cell numbers
Why is BAFF inhibition particularly effective for autoimmune disorders?
autoimmune B cells are particularly relaint on BAFF
How is belimumab used in SLe?
as an add-on therapy
Which cells produce BLyS?
innate immune cells and activated T cells
What does APRIL stand for?
a proliferation inducing ligand
Why was BAFF antagonism thought to work in SLE?
BAFF and its soluble homolog APRIL are high in the serum of patients with SLE
What demonstrates the difficulties in clinical trials for multi-system disorders such as SLE?
had to come up with a new SLE responder index to weight all the different manifestations of SLE
What happened to B cell numbers in the phase II belimumab trials?
total B cell number decreased with no changes in T cell
Which type of B cells were preferentially reduced with belimumab?
naive and transitional B cells- therefore BAFF is essentail for suvival of newly formed B cells that emerge fro mthe bone marrow
What is the effect on markers of disease acitvity with belimumab?
big increase in C4 and big decrease in anti-dsdna- bigger than clinical data
Who has access to belimumab?
sub-groups of patients with active SLE and is delivered through a managed access agreement
What are the main SE with biologics?
increased infection risk
What SE is TNFa inhibition assocaited with
increased susceptibility to TB
What SE is B cell depletion therapy associated with?
hep B reactivation (esp. rituximab) and PML
What type of virus is the JC virus?
polyomavirus
