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