Immunosuppresants

Question 1

How do corticosteroids work?

Answer 1

Prevent IL-1 and IL-6 production by macrophages and inhibit all stages of T cell activation.

Question 2

Anti-Rheumatics can be classified into two categories

Answer 2

Non-biologics

Biologics

Question 3

Give an example of each class of disease modifying anti-rheumatic drugs

Answer 3

Non-biologics:

• sulphasalazine
• hydroxychloroquine

Biologics:

• anti-TNF
• rituximab
• IL-6 inhibitors, JAK inhibitors

Question 4

Azathioprine is a drug used for what immune disorders?

Answer 4

SLE and vasculitis - maintenance therapy 
RA - weak evidence 
Inflammatory bowel disease 
Bullous skin disease 
Atopic dermatitis

Question 5

How does azathioprine work ?

Answer 5

It is cleaved to 6-mercaptopurine (6-MP); an antimetabolite which decreases DNA and RNA synthesis

Question 6

Why must individuals be tested for TPMT activity before prescribing azathioprine?

Answer 6

6- MP is metabolised by TPMT which is highly polymorphic and therefore people vary in activity. Low/absent levels increase the risk of myelosupression.

Question 7

What are the possible adverse effects of immunosuppressants and azathioprine ?

Answer 7

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

Question 8

Name a calcineurin inhibitor

Answer 8

Ciclosporin and tacrolimus

Question 9

When might calcineurin inhibitors be prescribed?

Answer 9

Transplantation
Atopic dermatitis
Psoriasis

Question 10

Calcineurin inhibitors require which tests to be conducted regularly?

Answer 10

Blood pressure

EGFR- renal toxicity

Question 11

Why are multiple drug interactions possible with calcineurin inhibitors?

Answer 11

Use CYP450 and therefore other drugs can alter activity of these enzymes

Question 12

Give examples of CYP450 inducers

Answer 12

Rifampicin
Carbamazepine
Phenytoin
Omeprazole

Question 13

Give examples of CYP450 inhibitors

Answer 13

Ciprofloxacin
Antifungals 
Fluoxetine 
Paroxetine 
HIV antivirals

Question 14

How does ciclosporin work?

Answer 14

Binds to cyclophilin protein and these complexes then bind calcineurin.
Calcineurin has phosphatase activity of activated T cells, then nuclear factor migration starts IL-2 transcription.
Essentially it prevents IL-2 production

Question 15

How does tacrolimus work?

Answer 15

Tacrolimus binds tracrolimus binding protein and this drug/protein complex binds calcineurin.
This prevents IL-2 production by activated T cells, through inhibiting the phosphatase activity induced by calcineurin.

Question 16

What is mycophenolate mofetil used for?

Answer 16

Transplantation

Induction and maintenance for lupus nephritis and vasculitis

Question 17

What are the adverse effects of mycophenolate mofetil?

Answer 17

Nausea, vomiting and diarrhoea
Myelosupresssion
Mucositis
Skin cancer

Question 18

What is the mechanism of action for mycophenolate mofetil?

Answer 18

Prodrug
Inhibit inosine monophosphate dehydrogenase (guanosine synthesis requires it)
Impairs B and T cell proliferation
Spares other rapidly dividing cells as there are guanosine salvage pathways in other cells.

Question 19

What is cyclophosphamide used for?

Answer 19

Lymphoma, leukaemia and solid cancers
Lupus nephritis
ANCA vasculitis

Question 20

What is the mechanism of action for cyclophosphamide?

Answer 20

Alkylating agent- cross links DNA

Suppresses T and B cell activity

Question 21

What is the pharmacodynamics of cyclophosphamide ?

Answer 21

Prodrug
converted in the liver to the main active metabolite 4-hydroxycyclophosphamide.
4-hydroxycyclophosphamide exits in equilibrium with its tautomer aldophosphamide.

Most aldophosphamide is oxidise to carboxyphosphamide, with only a small amount of aldophosphamide being converted to phosphoramide mustard.

Question 22

Why can patients on cyclophosphamide experience haemorrhagic cystitis?

Answer 22

Acrolein (another metabolite) is toxic to bladder epithelium.
Can prevent this cystitis by using aggressive hydration and/or Mesna.

Question 23

What are the important considerations regarding cyclophosphamides toxicity?

Answer 23

Increased risk of bladder cancer, lymphoma and leukaemia

Infertility

Question 24

Methotrexate is used in which diseases?

Answer 24

Rheumatoid arthritis - gold
Malignancy
Psoriasis
Crohn’s disease

Question 25

What is the mechanism of action of methotrexate in malignancy?

Answer 25

Competitive and irreversible inhibition of dihydrofolate reductase (DHFR) of 1000 times affinity compared to folate. Therefore it inhibits purine and thymidine synthesis - inhibiting DNA, RNA and proteins. It is cytotoxic in the S-phase. Greatest effect in rapidly dividing cells.

Question 26

What is the proposed mechanism of action of methotrexate for non-malignant conditions?

Answer 26

Inhibition of accumulation of adenosine Inhibition of T cell activation Suppression of intercellular adhesion molecule expression by T cells.

Question 27

Why is methotrexate given weekly?

Answer 27

Methotrexate itself has a shorter half life, but its metabolites - polyglutamates- have long half lives.

Question 28

What must you be aware of when giving methotrexate ?

Answer 28

Use of NSAIDs - NSAIDs displace and 50% is protein bound.

Question 29

Which adverse effects of methotrexate respond to folic acid?

Answer 29

It prevents adverse effects of mucositis and marrow suppression.

Question 30

What are the main adverse effects of methotrexate?

Answer 30

Hepatitis, cirrhosis Pneumonitis Infection risk Teratogenic and abortifacient

Question 31

Why must sulfasalazine be avoided in those with an aspirin allergy?

Answer 31

Similar structure

Question 32

What are the immunological effects of sulfasalazine?

Answer 32

Inhibits proliferation, IL-2 production and induces apoptosis of T cells. Reduces chemotaxis and degranulation of neutrophils.

Question 33

Why is sulfasalazine so effective in the large bowel?

Answer 33

It is poorly absorbed and therefore the main activity is within the intestine, effective for IBD.

Question 34

What are the ADRs of sulfasalazine?

Answer 34

``` Myelosuppression Hepatitis Rash Nausea Abdominal pain Vomiting ```

Question 35

Why is sulfasalazine good in practice?

Answer 35

Effective with favourable toxicity Long term blood monitoring not requires and very few drug interactions No carcinogenic potential and safe in pregnancy.

Question 36

What are the effects of blocking TNF-alpha?

Answer 36

Decreased inflammation - through inhibition of the cytokine cascade Decreased angiogenesis Decreased joint destruction by MMP and other destructive enzymes

Question 37

What disease must be screened for before giving anti-TNF therapy and why?

Answer 37

Latent TB | It is a risk of reactivating Tb, as TNF-alpha is essential for development and maintenance of a granuloma.

Question 38

Biologic use is linked to cancer by what type of relationship?

Answer 38

Unmasking cancer rather than causation

Question 39

What is rituximab and by what mechanism does it work?

Answer 39

A monoclonal antibody which binds to CD20, inducing B cell apoptosis. Very effective in rheumatoid arthritis, with good safety data.

Question 40

What is RA and how is it diagnosed?

Answer 40

Autoimmune disease which is initially localised to synovium Inflammatory change and proliferation of synoviuum leading to dissolution of cartilage and bone ``` Morning stiffness >1 Arthritis > 3 joints HandA/feet/wrist joints Symmetrical arthritis Rheumatoid nodules Serum RF/ anti CCP ab X-ray changes ```