L16 - Immuno pharmacology 2 COPY

Question 1

THERAPIES FOR RA - ANTI INFLAMMATORIES

i) what do these drugs provide?
ii) give an example of an NSAID? what do they inhibit?
iii) give an example of a steroidal anti inflam? what do they inhibit? why must a patient be started on low doses?

Answer 1

i) only provide symptomatic relief

ii) NSAID = naproxen and diclofenac
- inhibit COX

iii) steroidal anti inflam > prednisolone
- inhibit lipoxygenase 2
- start on low doses as there can be lots of side effects

Question 2

THERAPIES FOR RA - DMARDs

i) what do these drugs do?
ii) give an example of a synthetic DMARD
iii) give an example of a targeted synthetic DMARD
iv) which new class of drugs can be used? why are these good?

Answer 2

i) slow the clinical and radiographic progression of RA
ii) synthetic - methotraxate
iii) targeted synthetic > JAK inhibitors

iv) biologics eg TNF blockers
- good because they slow disease progression and also improve QOL

Question 3

SYNTHETIC DMARDs - METHOTREXATE

i) what does it inhibit? what does this make it good for?
ii) what does it increase levels of? what effect does this have? what does it reduce production of?
iii) what effect does it have on activated T cells?
iv) how does it affect inflammation? what effect does it have on CV disease?
v) which supplements should be taken alongside it?

Answer 3

i) inhibits cell proliferation > good for cancer treatment

ii) increases levels of adenosine therefore anti inflam
- reduces production of damaging polyamines (damage tiss)

iii) induces apoptosis of activated T cells

iv) reduces inflammation quickly and keeps it under tight control
- reduces risk of death from CVD in people with RA

v) take folic acid supplements to reduce side effects of folic acid depletion

Question 4

ADVERSE EFFECTS OF SYNTHETIC DMARDS

i) how long is treatment usually required to achieve symptomatic improvement?
ii) what % of patients on methotrexate experience side effects?
iii) name five general SEs of DMARDs
iv) what specific SE can hydroxychloroquinine cause? what can leflunomide cause?

Answer 4

i) 8-12 wks to get symptomatic improvement
ii) 30% of MTX patients get SEs
iii) general SEs > nausea, loss appetite, diarrhoea, rash, headache, hair loss, hep/neph toxicity
iv) hydroxychloroquinine > accum of drug in eye whoch results in retinal pigment epithelium atrophy

leflunomide > hypertension

Question 5

TARGETED SYNTHETIC DMARDS

i) which RA patients may these be given to?
ii) what does tofacitinib selectively inhibit? (2) give two other conditions it can be used in
iii) what does baricitinib selectively and reversibly inhibit? (2)
iv) give three adverse effects of each drug

Answer 5

i) given to mod to severe RA patients with inadequate response/intolerance to one or more DMARDs

ii) tofacitinib > inhibits JAK1 and JAK 3
- also used in psoriatic arthritis and UC

iii) baricitinib > inhibits JAK1 and JAK2
iv) tofa > anaemia, cough, diarrhoea, fatigue

bari > dyslipidaemia, herpes zoster, inc risk of infec, thrombocytosis

Question 6

BIOLOGICAL THERAPY - TNF A

i) which type of arthritis is TNF A a central player in?
ii) what effect on IL-1 does adding anti TNFa antibody to culture in RA and OA? what does this show?

Answer 6

i) TNFa is a central player in RA

ii) add anti TNFa to culture with RA cells > reduced IL-1
add to culture with OA cells > no effect on IL-1

Question 7

CENTRAL TOLE OF TNF IN INFLAM CASCADE OF RA

i) which cells produce it?
ii) what action does it have on synovial fibroblasts? which IL does this affect? what ultimately happens?
iii) name two other cell types TNF can affect?

Answer 7

i) produced by macrophages

ii) activates synovial fibroblasts
- production of IL-1 > activ T and B cell
- damage to cartilage

iii) can also affect monocytes and endothelial cells

Question 8

ANTI TNFa THERAPY

i) what were the results when 20 patients with RA were given a TNFa blocker? is it more effective than placebo?
ii) combining TNFa with which other drug has been shown to be more effective?
iii) name three other conditions TNFa blockers can be used in
iv) name three other parts of the pathway that can be targeted apart from TNF

Answer 8

i) nearly every RA patient had rapid reduction of pain
- it is more effective than placebo

ii) TNFa + methotrexate can make it more effective
iii) use in RA, crohns, ankylosing spondylitis and psoriasis
iv) also target IL-1 IL-6 and T/B cells

Question 9

BIOLOGICAL THERAPY CONT

i) how are these drug administered? what are they made of
ii) when is biol therapy recommended? (what have they failed to respond to?) which drug must be included in this
iii) which score is used to evaluate patient RA activity? name three things put into this score

Answer 9

i) protein drugs admin parenterally
ii) biol therapy when failed to respond to treatment with at least two standard DMARDs - one must be methotrexate

iii) use DAS 29
- put in CRP, ESR and joint tenderness

Question 10

CURRENTLY LICENSED BIOLOGICS

i) what group of drugs are infliximab, etanercept and adalimunmab?
ii) what type of drug is rituximab?
iii) what type of drug is abatacept?
iv) what type of drug is tocilizumab?
v) what type of drug is anakinra?

Answer 10

i) inflix, etanerccept and adalim = TNF blockers
ii) rituximab is a monoclonal Ab against B cells
iii) abatacept is a T cell co-stim inhibitor
iv) toculizimab is a monoclonal Ab against IL-6R
v) anakinra is a IL-1R antagonist

Question 11

TNF BLOCKERS - INFLIXIMAB

i) what is it? what is it specific for?
ii) what does it do? (2)
iii) name two other conditions it can be used for?
iv) what drug must it be combined with to be NICE approved?

Answer 11

i) partially humanised mouse monoclonal TNFa antibody
- specific for TNFa

ii) neutralises free, membrane bound and receptor bound TNFa > antibod dep cell mediated cytotox
iii) crohns disease, ankylosing spon, psoriasis, UC
iv) must be combined with methotrexate

Question 12

TNF BLOCKERS - ETANERCEPT

i) what is it? what does it bind? what does this result in?
ii) give two conditions it can also be used in?
iii) is it human or mouse derived?

Answer 12

i) soluble TNF R dimer > binds TNFa and TNFb
- results in a reduction in accessible TNF > ADCC

ii) ankylosing spon, plaque psoriasis, juvenile idiopathic arthritis
iii) human derived

Question 13

CERTOLIZUMAB PEGOL

i) what two parts does it consist of? does it have an Fc portion?
ii) what is the purpose of attaching polyethylene glycol to drugs?
iii) name another condition it can be used for?

Answer 13

i) Fab fragment cov attached to polyethelene glycol
ii) PG cov attach to drugs reduces immunogenicity and prolongs circulatory time of the drugs
iii) can also be used in crohns disease

Question 14

what are drugs labelled A, B, C? what class do they belong to?

Answer 14

A - etanercept

B - infliximab

C - certolizumab pegol

• all TNF blockers

Question 15

ANTI TNF THERAPY - CONSIDERATIONS AND SEs

i) name four things patients will be screened for before commencing therapy?
ii) why may a CXR be done? (2)
iii) what type of vaccines should be avoided on this therapy?
iv) how long can anti TNF therapy by administered for?
v) what % of patients with RA may fail to respond to a TNF inhibitor + MTX?

Answer 15

i) screen for TB, MS, recurrent infection, leg ulcers, cancer
ii) do CXR to exclude signs of previous TB and heart failure as TNF blockers are strong immunosuppressors
iii) avoid live vaccines eg yellow fever/polio
iv) can give anti tnf therapy for as long as 10 years - as long as the patient continues to respond
v) 30% RA patients may not respond

Question 16

RITUXIMAB

i) what cell does this target? what is it made from?
ii) which four mechanisms mediate killing after rituximab opsonisation?
iii) what can it also be used for?

Answer 16

i) targets B cells > made from partially humanised anti CD20 Ab

ii) rituximab binds CD20 on B cells and opsonises
- complement mediated cytotoxicity
- antibody dep cell mediated cytotox
- FcR or complement R mediated phago by MPs
- apoptosis

iii) can also be used in SLE

Question 17

ABATACEPT

i) what does it inhibit? what is it made from?
ii) what does this inhibition lead to? (2) what does it increase the threshold of?
iii) what cells does it supress the proliferation of?
iv) how does it affect inflammatory mediator levels?

Answer 17

i) inhibits T cell co-stimulation
- made from CTLA-4/IgG1 soluble receptor fusion protein

ii) competitive inhibtior of CD28 on surface of T cells leads to inhibition of co-stim signal and therefore inhibits action of T cells
- increases threhold for T cell activation

iii) supresses proliferation of synovial recirculating T cells
iv) reduced level of inflam mediators

Question 18

TOCILIZUMAB AND SARILUMAB

i) what do they inhibit? what type of molecule are they?
ii) name another condition they are used in?
iii) which one is a fully humanised monoclonal Ab?
iv) what is a side effect of these drugs?

Answer 18

i) inhibit IL-6 R
- humanised anti IL-6 receptor monoclonal Ab

ii) also used in systemic juvenile idiopathic arthritis/COVID
iii) fully humanised = sarilumab
iv) SEs - immunosuppression

Question 19

ANAKINRA

i) what does it block?
ii) how does it differ from the native human molecule?
iii) name three effects it has in patients with RA?
iv) is it licensed in the UK for RA?

Answer 19

i) recombinant IL-1 R antagonist > binds IL01 R and prevents its activation by IL-1b
ii) has an additional methionine residue in its amino acid terminus
iii) In RA - reduces bone erosion, decreases osteoclast production and blocks IL-1 induced MMP release from synovial cells
iv) not used in the UK to treat RA

Question 20

ADVERSE EFFECTS OF BIOL THERAPIES

i) name three infections they can increase the risk of? why?
ii) which vaccines should a person receive before starting biol therapy? (2) which vaccines should they avoid?
iii) give four general side effects
iv) when are they contra indicated?

Answer 20

i) inc risk of URTIs, pneumonia and UTIs

ii) should have influenza and pneucmococcus vaccines
- avoid live vaccines when on treatment

iii) nausea, headache, hypertension, allergy
iv) contra indicated in pregnancy and while breastfeeding

Question 21

label the biological therapies A-D

Answer 21

A - anakinra

B - toculizimab/sarilumab

C - abatacept

D - rituximab