Immunosuppression in RA

Question 1

List some classes of drug used to treat RA and give an example of each

Answer 1

• Antiproliferative immunosuppressants, e.g. Azathioprine
• Calcineurin inhibitors - e.g. ciclosporin
• DMARDs - Methotrexate
• Corticosteroids
• Biopharmaceuticals - e.g. Infliximab

Question 2

Apart from RA, give some other uses for Azathioprine

Answer 2

SLE/vasculitis

IBD

Question 3

Outline the mechanism of action of Azathioprine

Answer 3

• Prodrug - cleaved to 6-MP and then to thioinosinic acid

- Inhibits purine metabolism - i.e. an antimetabolite

Question 4

What is important about Azathioprine metabolism?

Answer 4

Metabolised by a gene which is highly polymorphic - TMPT (thiopurine methyltransferase)
Therefore test TMPT levels before starting treatment

Question 5

List 4 important ADRs of Azathioprine

Answer 5

BM suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis - monitor LFTs

Question 6

Give some uses of cyclophosphamide apart from RA

Answer 6

Lymphoma/leukaemia

Wegener’s

Question 7

What is the broad mechanism of action of cyclophosphamide?

Answer 7

Cytotoxic alkylating agent

Question 8

Give 4 ADRs associated with cyclophosphamide

Answer 8

• Bladder cancer
• Lymphoma
• Infertility
• Teratogenesis

Question 9

What is the primary use for mycophenolate mofetil?

Answer 9

After transplantation

Question 10

What is the mechanism of action of Mycophenolate mofetil?

Answer 10

Inhibits enzyme inosine monophosphate dehydrogenase required for de novo synthesis of the purine guanosine

Question 11

Give 4 ADRs of mycophenolate mofetil

Answer 11

• N+V
• Leucopenia
• Myelosuppression
• Infection risk

Question 12

Name two calcineurin inhibitors and give some of their uses

Answer 12

• Ciclosporin, Tacrolimus

- Used post-transplant and in psoriasis

Question 13

What is the mechanism of action of the calcineurin inhibitors?

Answer 13

• Binds to intracellular immunophilin
• Drug/protein complex binds to calcineurin, inhibiting it
• Thus prevents phosphotase activity which would result in IL-2 transcription

Question 14

Give 4 ADRs of calcineurin inhibitors

Answer 14

Nephrotoxicity
Hypertension
Hyperlipidaemias
Hyperuricaemia

Question 15

Which drug is the gold-standard treatment for RA?

What else is it used for?

Answer 15

Methotrexate

Also used in malignancy, psoriasis, IBD

Question 16

What is its mechanism of action in non-malignant disease?

Answer 16

We’re not entirely sure - possibly increases adenosine, possibly inhibits T cell activation

Question 17

Give some important features of methotrexate administration

Answer 17

• Poor bioavailability - can be given IM instead of orally
• Highly plasma bound. Displaced by NSAIDs
• Weekly dosing NOT daily

Question 18

Give 4 ADRs of methotrexate

Answer 18

• Myelosuppression
• Mucositis
• Thinning hair
• Pneumonitis

Question 19

Which two compounds comprise Sulfasalazine?

Answer 19

• 5-aminosalicylate (5-ASA)

- Sulfapyridine

Question 20

Give some possible immunological effects of sulfasalazine

Answer 20

• Inhibition of T cell proliferation
• Possible T cell apoptosis
• Inhibition of IL-2 production

Question 21

Which part of Sulfasalazine treats IBD?

What about the other bit?

Answer 21

• 5-ASA stays in gut - IBD

- Sulfapyridine absorbed - systemic

Question 22

Give 3 ADRs of sulfasalazine

Which moeity produces these?

Answer 22

Produced by sulfapyridine as systemically absorbed

• Myelosuppression
• Hepatitis
• Rash

Question 23

Give 2 examples of anti-TNF drugs

Answer 23

• Infliximab

- Adalimumab

Question 24

Give some ADRs of anti-TNF agents

Answer 24

• Risk of serious infections
• TB reactivation
• Risk of malignancy if had prior malignancy

Question 25

What is the mechanism of action of Rituximab?

Answer 25

Binds specifically to CD20 on surface of some B cells - causes B cell depletion