Immunosupression

Question 1

what is Rheumatoid arthritis ?

Answer 1

An auto immune multi system disease , initially in synovium inflammatory and proliferation condition leading to dissolution of cartilage and bone

Question 2

what is the pathology of RA?

what cause erosion to joints ?

Answer 2

Hyperactivity and imbalance between pro (T-cells and macrophages) and anti (Anti-CCP) inflammatory
mettalloprotienases

Question 3

what is clinical criteria for RA?

Answer 3

Morning stiffness more than 1 hour , longer = more inflammation
Arthritis of more than 3 joints and hand joints
symmetrical arthritis
rheumatoid nodules - late stage

Question 4

what is non-clinical criteria for RA?

Answer 4

Serum rheumatoid factor / Anti CCP antibodies

X-Ray changes (6 months - 1yr), subluxations

Question 5

what are treatment goals for RA?

Answer 5

Symptom relief

Prevention of joint destruction

Question 6

what treatment principles do we use for RA?

Answer 6

Early use of DMARDs
adequate dosage
use combinations
avoid long term corticosteroids

Question 7

what symptoms of SLE?

Answer 7

Angry , mallor rash

affects all systems so variable

Question 8

what are features of Vasculitis ?

Answer 8

LFTs
leucokitic infiltrates
fibrinoid necrosis
Thrombosis

spotty rash
Consolidation in lungs

Question 9

what are treatment principles in SLE and vasculitis ?

Answer 9

symptomatic relief - arthralgia , Raynaud’s , etc
reduction in mortality
prevention of organ damage
reduction in long term morbidity caused by disease and drugs

Question 10

how do Corticosteroids work ?

Answer 10

prevent IL-1 and IL-6 production by macrophages

inhibit all stages of T Cell activations

Question 11

what are Non-biological DMARDs?

Answer 11

Hydroxychloroquine

Sulfasalazine

Question 12

what are biological DMARDs? why arent they used more ?

Answer 12

Rituximab

Infliximab, Adalimumab

Question 13

what is Azathioprine used for ?

Answer 13

SLE and vasculitis maintenance therapy
Inflammatory bowel disease
Atopic dermatitis

steroid sparing drug

Question 14

what can heavily affect pharmokinetics of Azathioprine ? what complications can it lead to so what must be done ?

Answer 14

TPMT enzyme polymorphicity (6-MP)

if low can lead to myelosupression(Low blood counts) so TPMT test is done before

Question 15

What is Azathioprine’s MOA?

Answer 15

Cleaved to 6-MP

this is Anti-Metabolite decreases DNA and RNA synthesis by reducing Purine synthesis and incorporating into DNA.

Question 16

what are Adverse effects of immunosuppressants ? how do you monitor them ?

Answer 16

Bone marrow - Monitor FBC
Increased risk of malignancy , infection
Hepatitis - LFTs

Question 17

what is Ciclosporin and tacrolimus used for ? what is major side efffect? what must you be aware of ?

Answer 17

after Transplantation
dermatitis and psoriasis

Renal toxicity, Gums swell
CYP3A4 inhibitors

Question 18

name some CYP3A4 inducers ?

Answer 18

Carbemazepine
phenytonin
Omeprazole
rifampicin

Question 19

what do IL 1,2,3,4 do ?

Answer 19

Hot T-Bone Steak
1= H= Fever
2= T= T cell activation 
3= B = Bone marrow 
4= S = IgE and IgA

Question 20

How do Ciclosporin and tacrolimus work ?

Answer 20

Calcineurin inhibitors - prevents IL-2 prod= stops T h cells
C= Cyclophilin protein
T= Tacrolimus protein
Drug/Protein complex inhibits Calcinurin

Question 21

what is Mycophenolate motfetil used for ?

Answer 21

transplantation
induction and maintenance of Lupus with nephritis
Vasculitis Maintence

Question 22

how does Mycophenolate motfetil work ?

Answer 22

Fungus inhibits inosine monophospahte dehydrogenase required for guanosine synthesis which impairs B and T cell proliferation whilst sparing other rapidly dividing cells

Question 23

what are Mycophenolate motfetil ADRs?

Answer 23

nausea , vomiting and diarrhoea

myelosuppression

Question 24

what are indications for Cyclophosphamide ? what is good about this drug?

Answer 24

Lymphoma , Leukaemia
Lupus nepritis

works in about 10 days (quick), only give for 6 months

Question 25

what is a major side effect of Cyclophosphamide ? Why and what can be given ?

Answer 25

Acrolein is made and us toxic to bladder = Hemorrhagic cystitis

give water and mesna

Question 26

what other side effects of cyclophosphamide exist ? what must you do therefore? what is a safer option ?

Answer 26

Increased irks of bladder cancer and other cancers
infertility - rises with dose and age

Mycophenolate mofetil- takes longer to work

Question 27

what is best treatment for RA? what other things is this drug good for ?

Answer 27

Methotrexate

malignancy
psoriasis
Crohn’s

Question 28

how does methotrexate work in RA route ?

Answer 28

not via anti-folate
stops adenosine production, stops T cell activation
via AICAR transformylase inhibtion

Question 29

what are the pharmokinetics of Methotrexate ? what Drug interactions are possible ?

Answer 29

Oral bioavilab = 33%
IM  bioavail = 76%
renal excretion 
long half life = Weekly dose
50% Protein bound so NSAIDs can displace

Question 30

what are advantages of Methotrexate ?

Answer 30

Well tolerated
can use for long time
can be used for combinations

Question 31

what are side effects of methotrexate ? what can counter act these ?

Answer 31

Mucositis
marrow surpresssion
Hepaitis ,
highly tetragenic

Folate supplements

Question 32

what is Sulfasalazine used for ?

Answer 32

relieve pain and stiffness and also fight infection

Question 33

what are immunological effects of Sulfasalazine ?

Answer 33

T-cell
– inhibition of proliferation
– possible T-cell apoptosis
– inhibition of IL-2 production
• Neutrophil
– reduced chemotaxis
– reduced degranulation

Question 34

where is main activity of sulfasalazine ?

Answer 34

within intestine - effective in IBD

Question 35

What are advantages of sulfasalazine ?

Answer 35

Effective and not much toxicity 
Long term blood monitoring not needed
few drug interactions
no carcinogenic potential 
safe in pregnancy

Question 36

what are the effects of blocking TNF- alpha ?

Answer 36

decrease Inflammation
Cytokine cascade
Recruitment of leukocytes to joint
decrease angiogenesis VEGF
decrease MMP 
development and maintenance of granulomata

Question 37

what is a risk on Anti-TNF therapy ? why ?

Answer 37

TB reactivation as TNF- Alpha

released by macrophages in response to M TB infection -screen for latent TB

Question 38

how does Rituximab work ?

Answer 38

binds specifically to a unique cell surface marker = CD20 on B cells but not on stem cells , etc.
B cells apoptosis

Question 39

what do B cells do ?

Answer 39

Present antigen to T cells

Produce cytokines and antibodies