Immunosuppressants

Question 1

Steroids (e.g. prednisolone) are excellent immunosuppressants but are limited by intolerable side effects, especially at high dose. What are these side effects? [7]

Answer 1

1. Weight gain and fluid retention
2. Glaucoma
3. Osteoporosis
4. Infection
5. Hypertension and hypokalaemia
6. Peptic ulceration and GI bleed
7. Psychological/psychiatric symptoms

Question 2

List the non-steroid immunosuppressant drugs under the following headings:

1. inhibitors of DNA synthesis? [3]
2. lymphocyte signalling inhibitors? [4]

Answer 2

1. Inhibitors of DNA Synthesis
   
   • Methotrexate
   • Azathioprine
   • Mycophenolate
2. Lymphocyte Signalling Inhibitors
   
   • Cyclosporin
   • Tacrolimus
   • Sirolimus
   • Leflunomide

Question 3

Describe the mechanism of action of methotrexate [3]

Answer 3

1. inhibits dihydrofolate reductase, which converts dietary folic acid to tetrahydrofolate (FH4)
2. FH4 is required for DNA and protein synthesis, so lack of FH4 prevents cellular replication
3. the anti-inflammatory and immunosuppressive effects are mediated by inhibition of inflammatory mediators such as:
   
   • IL-6,
   • IL-8,
   • tumour necrosis factor (TNF)-α,

Question 4

What is methotrexate used to treat? [5]

Answer 4

1. Most commonly used for rheumatological disease (low dose → immunosuppression):
   
   • Rheumatoid arthritis
2. Psoriasis and psoriatic arthropathy
3. Steroid sparing agent in giant cell arteritis
4. High dose → cytotoxic chemotherapeutic agent

Question 5

What are the potential side effects of methotrexate? [8]

Answer 5

1. Gastrointestinal
   
   • Nausea,
   • Vomiting,
   • Diarrhoea
   • Hepatitis
   • Stomatitis
2. Haematological
   
   • Leukopenia
3. Others
   
   • Frequent infections
   • Pulmonary fibrosis

Question 6

Describe the mechanism of action of azathioprine [3]

Answer 6

1. inhibits purine synthesis
2. purines are needed to produce DNA and RNA
3. by inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression

Question 7

What is azathioprine used to treat? [4]

Answer 7

1. Most commonly used for inflammatory bowel diseases:
   
   • Ulcerative colitis
   • Crohn’s disease
2. Other severe autoimmune diseases:
   
   • Myaesthenia gravis
   • Eczema

Question 8

What are the potential side effects of azathioprine? [8]

Answer 8

1. Gastrointestinal:
   
   • Nausea,
   • Vomiting,
   • Diarrhoea
   • Hepatitis
   • Cholestasis
2. Haematological:
   
   • Leukopenia
   • Thrombocytopenia
3. Others:
   
   • Frequent infections

Question 9

Describe the mechanism of action of cyclosporin [3]

Answer 9

1. Small molecule inhibitor of calcineurin
2. Effect of inhibiting signal transduction from the activated TCR complex
3. Profound inhibition of T-cell activation

Question 10

What is cyclosporin used to treat? [2]

Answer 10

1. Usually given for organ transplantation:
   
   • Liver
   • Kidney
   • Heart/lung
2. Sometimes used for inflammatory conditions:
   
   • Can be used topically: i.e. to skin or eye

Question 11

What are the potential side effects of cyclosporin? [6]

Answer 11

1. Nephrotoxicity
2. Hypertension
3. Hepatotoxicity
4. Anorexia and lethargy
5. Hirsutism
6. Paresthesia

Question 12

What are the potential side effects of biologics? [4]

Answer 12

1. Hypersensitivity reactions
2. Infusion reactions
3. Mild gastrointestinal toxicity
4. Infections

Question 13

Name 4 commonly used biologic agents [4]

Answer 13

1. Anti-TNF therapy
2. Abatacept (anti-CD86)
3. Rituximab (anti-CD20)
4. Anti-IL-1 therapy

Question 14

What infections does anti-TNF therapy put you at increased risk of? [3]

Answer 14

1. TB, particularly disseminated TB
   
   • Need to screen for latent TB before prescribing.
2. Salmonella
3. Listeria

Question 15

What infections does abatacept (anti-CD86) put you at increased risk of? [3]

Answer 15

1. Pneumonia
2. Respiratory tract infection
3. TB (but less than TNF blockade)

Question 16

What infections does rituximab (anti-CD20) put you at increased risk of? [2]

Answer 16

1. Generalised increased risk of serious infection
2. Hepatitis B reactivation
   
   • Need to screen and prophylaxis if necessary

Question 17

What infections does anti-IL-1 therapy put you at increased risk of? [2]

Answer 17

1. Respiratory tract infection
2. Pneumonia