11) Immunosuppression and Rheumatology

Question 1

Describe rheumatoid arthritis:

Answer 1

Autoimmune multi-system disease initially localised to synovium

Question 2

What is the pathogenesis of rheumatoid arthritis due to?

Answer 2

Imbalance between pro and anti-inflammatory molecules

Question 3

How is rheumatoid arthritis diagnosed?

Answer 3

Morning stiffness > 1 hour
Arthritis in 3 or more joints
Arthritis in hand joints
Symmetrical arthritis

Question 4

What are the treatment goals in RA?

Answer 4

Symptomatic relief and prevention of joint destruction

Question 5

What is SLE?

Answer 5

Autoimmune disease causing inflammation of various parts of the body

Question 6

What is vasculitis?

Answer 6

Inflammation of blood vessels, can affect kidney, skin and lungs

Question 7

What are the treatment goals in vasculitis?

Answer 7

Symptomatic relief
Reduction in morbidity and mortality
Prevention of organ damage

Question 8

What is the mechanism of action of corticosteroids?

Answer 8

Bind to intracellular gluco-corticoid receptors and prevent IL-1 and IL-6 production by macrophages. Inhibit T cell activation

Question 9

Give examples of immunosuppressants:

Answer 9

Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil

Question 10

Give examples of disease modifying anti-rheumatic drugs (DMARDs):

Answer 10

Methotrexate
Sulfasalazine
Anti-TNF alpha
Rituximab
Cyclophosphamide

Question 11

When is azathioprine indicated?

Answer 11

SLE, vasculitis, IBD, transplantation, atopic dermatitis

Question 12

What is the mechanism of action of azathioprine?

Answer 12

Inhibits purine metabolism (anti-metabolite)

Question 13

What are the side effects of azathioprine?

Answer 13

Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis

Question 14

When are calcineurin inhibtors (ciclosporin, tacrolimus) indicated?

Answer 14

Transplants, atopic dermatitis, psoriasis

Question 15

What is the mechanism of action of calcineurin inhibitors?

Answer 15

Prevent production of IL-2 by T helper cells via calcineurin inhibition
Ciclosporin binds to cycophilin protein
Tacrolimus binds to tacrolimus binding protein

Question 16

What are the side effects of calcineurin inhibitors?

Answer 16

Renal toxicity
Drug interactions (CYP P450)

Question 17

When is mycophenolate mofetil indicated?

Answer 17

Transplantation, induction and maintenance of lupus

Question 18

What is the mechanism of action of mycophenolate mofetil?

Answer 18

Inhibits monophosphate dehydrogenase required for guanosine synthesis, impairing B and T cell proliferation

Question 19

What are the side effects of mycophenolate mofetil?

Answer 19

Leucopenia and neutropenia
Myelosuppression
Nausea
Diarrhoea
GI ulcers

Question 20

When is cyclophosphamide indicated?

Answer 20

Lymphoma, leukemia, lupus, ANCA vasculitis

Question 21

What is the mechanism of action of cyclophosphamide?

Answer 21

Alkylating agents that cross links DNA so that it cannot replicate

Question 22

What are the side effects of cyclophosphamide?

Answer 22

Metabolite (acrolein) is toxic to bladder epithelium - haemorrhage cystitis
Risk of bladder cancer, lymphoma and leukemia
Infertility

Question 23

When is methotrexate indicated?

Answer 23

RA, malignancy, psoriasis, Crohn’s

Question 24

What is the mechanism of action of methotrexate (malignant)?

Answer 24

Inhibits dihydrofolate reductase to stop conversion of dihydrofolate to tetrahydrofolate used in purine and thymidine synthesis

Question 25

What is the mechanism of action of methotrexate (non-malignant)?

Answer 25

Inhibition of purine metabolism leading to accumulation of adenosine, inhibition of T cell activation

Question 26

How is methotrexate administered and how often?

Answer 26

IM or SC | Weekly dosing

Question 27

What are some side effects of methotrexate?

Answer 27

``` Mucositis Myelosuppression Hepatitis Cirrhosis Pneumonitis Teratogenic ```

Question 28

How is cyclophosphamide excreted and therefore what needs to be given alongside?

Answer 28

Excreted by kidneys but metabolite toxic to bladder epithelium so give aggresive hydration +/- mesna

Question 29

What drugs interact with methotrexate?

Answer 29

NSAIDs Phenytoin Tetracyclins Penicillins

Question 30

When is sulfasalazine indicated?

Answer 30

RA, IBD (Crohn's)

Question 31

What is the mechanism of action of sulfasalazine in RA?

Answer 31

Inhibits T cell proliferation, T cell apoptosis inducer and inhibits IL-2 production

Question 32

What is the mechanism of action of sulfasalazine in IBD?

Answer 32

In colon broken down to 5-ASA and sulfapyridine | 5-ASA is poorly absorbed and affects gut flora

Question 33

What are some side effects of sulfasalazine?

Answer 33

``` Myelosuppression Hepatitis Rash Abdo pain N&V ```

Question 34

What are the effects of anti-TNF alphas?

Answer 34

Decreased inflammation - down reg of cytokine cascade Decreased angiogenesis Decreased joint destruction

Question 35

What must be screened for before giving anti-TNFs?

Answer 35

Latent TB

Question 36

What is the mechanism of action of rituximab and when is it used?

Answer 36

Binds to CD20 on B cells, causes B cell apoptosis | RA, lupus, vasculitis