Modulating Cytokines in Autoimmune disorders

Question 1

What is RA?

Answer 1

sterile joint inflammation of synvoial lining which over time damages the adjacent structures: cartilage and bone

Question 2

What happens to the synovium in RA?

Answer 2

becomes a proliferated mass of tissue (pannus) with neovascularisation, lymphangiogenesis and inflammatory cells

Question 3

What cells are normally found in the synovium?

Answer 3

macrophage-like and fibroblast like cells and type I collagen

Question 4

What are the driving cytokines in RA?

Answer 4

TNFa and IL-1

Question 5

What anti-inflammatory cytokines are lacking in RA?

Answer 5

soluble TNF receptor; IL-10; IL-1 receptor antagonist

Question 6

What is the dominant pro-inflammatory cytokine in rheuamtoid synovium?

Answer 6

TNFa

Question 7

Which cells mainly produce TNFa in RA?

Answer 7

macrophages in synovium

Question 8

What cytokines did inhibition of TNFa stop the production of?

Answer 8

IL-1; IL-6; GMCSF nad IL-8

Question 9

Why is TNFa described as pleotropic in RA?

Answer 9

affects osteoclasts; chondrocytes; synoviocytes

Question 10

Why are drugs such as anti-TNF described as biologics?

Answer 10

made in culture systems not synthesised

Question 11

Why were biologics needed?

Answer 11

lots of patients with RA were progressing despite DMARD therapy

Question 12

What was the problem with infliximab?

Answer 12

it was originally a human/mouse chimeric antibody so patients developed a human anti-chimeric response

Question 13

What is the name for the fully huamnised anti-TNF developed?

Answer 13

adalinumab

Question 14

What is the MOA of etanercept?

Answer 14

dimeric fusion protein: soluble TNF receptor which mops up TNF

Question 15

What is the name for the off patent versions of biologics?

Answer 15

biosimilar- not exactly the same as produced in a living system

Question 16

When can a patient be prescribed a biologic?

Answer 16

disease is severe with disease acitivty score (DAS28) >5.1; disease hasnt repsonded to a combo of DMARDs

Question 17

What are the biological therapies for SLE?

Answer 17

rituximab and belimumab

Question 18

What is rituximab?

Answer 18

chimeric anti-CD20 antibody used to deplete B cells

Question 19

What is belimumab?

Answer 19

monoclonal antibody against a B cell survival factor called BLYS

Question 20

Aside from biologics, what agents are currently available for SLE?

Answer 20

hydroxychloroquine; pred; azathioprine; mycophenolate

Question 21

What type of antibody is belimumab?

Answer 21

IgG1

Question 22

What other name is BLyS known as?

Answer 22

BAFF

Question 23

What does BAFF stand for?

Answer 23

B cell activating factor of the TNF family

Question 24

What is the effect of inhibiting BAFF?

Answer 24

impaired B cell survivial and reduced B cell numbers

Question 25

Why is BAFF inhibition particularly effective for autoimmune disorders?

Answer 25

autoimmune B cells are particularly relaint on BAFF

Question 26

How is belimumab used in SLe?

Answer 26

as an add-on therapy

Question 27

Which cells produce BLyS?

Answer 27

innate immune cells and activated T cells

Question 28

What does APRIL stand for?

Answer 28

a proliferation inducing ligand

Question 29

Why was BAFF antagonism thought to work in SLE?

Answer 29

BAFF and its soluble homolog APRIL are high in the serum of patients with SLE

Question 30

What demonstrates the difficulties in clinical trials for multi-system disorders such as SLE?

Answer 30

had to come up with a new SLE responder index to weight all the different manifestations of SLE

Question 31

What happened to B cell numbers in the phase II belimumab trials?

Answer 31

total B cell number decreased with no changes in T cell

Question 32

Which type of B cells were preferentially reduced with belimumab?

Answer 32

naive and transitional B cells- therefore BAFF is essentail for suvival of newly formed B cells that emerge fro mthe bone marrow

Question 33

What is the effect on markers of disease acitvity with belimumab?

Answer 33

big increase in C4 and big decrease in anti-dsdna- bigger than clinical data

Question 34

Who has access to belimumab?

Answer 34

sub-groups of patients with active SLE and is delivered through a managed access agreement

Question 35

What are the main SE with biologics?

Answer 35

increased infection risk

Question 36

What SE is TNFa inhibition assocaited with

Answer 36

increased susceptibility to TB

Question 37

What SE is B cell depletion therapy associated with?

Answer 37

hep B reactivation (esp. rituximab) and PML

Question 38

What type of virus is the JC virus?

Answer 38

polyomavirus