Immunosuppressants

Question 1

What are the indications for immunosuppressants?

Answer 1

• abnormal inflammation (inflammatory arthropathies, UC/Crohn’s, psoriasis)
• unwanted normal inflammation (solid organ transplants, bone marrow grafts - prevent rejection)

Question 2

What are the advantages and adverse effects of steroid sparing agents?

Answer 2

Advantages: rapid onset, easy to administer, able to treat variety of inflammatory conditions

Adverse effects: weight gain and fluid retention, glaucoma, osteoporosis, infection, hypertension, hypokalaemia, peptic ulceration and GI bleed, psychological/psychiatric symptoms

Question 3

Describe the mechanism of action of corticosteroids

Answer 3

• glucocorticoid meets receptor and moves into nucleus of cell
• influences DNA transcription to down regulate inflammatory proteins and increase transcription of anti-inflammatory proteins

Question 4

List the non-steroid immunosuppressant drugs

Answer 4

• DNA synthesis inhibitors: methotrexate, azathioprine, mycophenolate
• lymphocyte signalling inhibitors: cyclosporin, tacrolimus, sirolimus, leflunomide

Question 5

Describe the mechanism of action of methotrexate

Answer 5

• interferes with dihydrofolate reductase in folic acid metabolism and thymidylate synthetase
• results in the reduction of thymidine availability and decreased DNA synthesis
• proliferation of cell arrested (S-phase arrest)

Question 6

List the adverse effects of methotrexate

Answer 6

• GI: nausea, vomiting, diarrhoea, hepatitis, stomatitis
• haematological: leukopenia
• other: frequent infection, pulmonary infection
• can be reduced with administration of folic acid 4 days after methotrexate

Question 7

Describe the clinical use of methotrexate

Answer 7

• given once a week with folic acid
• given orally (or s/c if not tolerated)
• takes weeks for effect
• regular blood monitoring of patient needed

Question 8

Describe the mechanism of azathioprine

Answer 8

• purine analogue which is converted within cells into a nucleoside analog which is incorporated into DNA and RNA chains
• results in premature termination of nucleic acid chains
• halts cell growth and metabolism
• favours lymphocytes (other cells have purine salvage pathway)

Question 9

What are the other actions of azathioprine?

Answer 9

• prevent immune responses through cytotoxic effect
• inhibits T cell co-stimulation through interference with CD28

Question 10

List the adverse effects of azathioprine

Answer 10

• GI: nausea, vomiting, diarrhoea, hepatitis and cholestasis
• haematological: leukopenia, thrombocytopenia
• other: frequent infection, hair loss

Question 11

Describe azathioprine metabolism and the importance of screening prior to treatment

Answer 11

• TMPT enzyme vital in reducing active drug levels in cells
• without it can result in accumulation of active metabolites and development of severe toxicity
• importance in checking TMPT activity in patients prior to therapy

Question 12

What are the indications for azathioprine in clinical practice?

Answer 12

• UC and Crohn’s (IBD)
• myasthenia gravis and eczema (inflammatory conditions)

Question 13

Describe the clinical use of azathioprine

Answer 13

• given orally on daily basis
• takes weeks for effect
• bloods need monitoring on monthly basis

Question 14

Describe the mechanism of action of cyclosporin

Answer 14

• small molecule inhibitor of calcineurin
• prevents activation of nuclear factors from activated TCR complex altering the transcription of activating cytokines (IL2)
• inhibition of T cell activation

Question 15

List the adverse effects of cyclosporin

Answer 15

• nephrotoxicity
• hypertension
• hepatotoxicity
• anorexia and lethargy
• hirsutism
• parenthesis

Question 16

Describe the mechanism of action of tacrolimus

Answer 16

• different class to cyclosporin but similar mode of action
• more potent than cyclosporin and better tolerated
• combines with other factors to inhibit calcineurin

Question 17

What are the indications for cyclosporin/tacrolimus?

Answer 17

• solid organ transplant (liver, kidney, heart, lung)
• inflammatory conditions (sometimes)
• topical treatment (skin/eye)

Question 18

Describe the clinical use of cyclosporin/tacrolimus

Answer 18

• given orally on daily basis
• dose established through therapeutic drug monitoring
• be aware of many drug interactions through cytochrome P450 enzymes
• bloods need regular monitoring

Question 19

What are the disadvantages of immunosuppressants?

Answer 19

• often insufficient in controlling inflammatory disease with subsequent progression and has a slow rate of onset so not good for acute severe disease
• highly toxic even in low doses (bone marrow suppression, frequent infections)

Question 20

List the features of biologic therapies

Answer 20

• able to target specifically designated components of the immune system with minimal off-target effects (lower toxicity)
• usually parenteral route with better side effect profile

Question 21

What are the side effects of biologic therapies?

Answer 21

• hypersensitivity
• infusion reactions
• GI toxicity
• risk of infection (but less of a problem compared to other therapy)

Question 22

Risk of infection associated with anti-TNF therapy

Answer 22

• increased risk of TB (disseminated)
• screening for latent disease before treatment (IGRA) and treat if required before treatment
• salmonella and listeria

Question 23

Risk of infection associated with rituxmab therapy

Answer 23

• increased risk of hep B reactivation
• screen and prophylaxis if necessary

Question 24

Risk of infection associated with abatacept therapy

Answer 24

• increased risk of pneumonia and RTI
• TB

Question 25

Risk of infection associated with anti-IL-1 therapy

Answer 25

• increased risk of RTI and pneumonia