8. DMARDs

Question 1

Which 3 main drug types are given to manage RA? Why?

Answer 1

1. DMARDs: slow disease progression
2. NSAIDs: reduce inflammation + pain management
3. Corticosteroids: short term inflammation reduction in flares

Question 2

Name 3 examples of corticosteroids.

Answer 2

1. prednisolone
2. hydrocortisone
3. dexamethasone

Question 3

Describe the MOA of corticosteroids.

Answer 3

i) Bind and activate intracellular cytoplasmic R… translocation to nucleus…
ii) Act as transcription factor to activate or inhibit gene transcription, e.g.
- inhibits macrophage pro-inflammatory cytokine production (IL-1, IL-6)
- inhibit T cell activation

Question 4

Why should corticosteroids only be prescribed short-term?

Answer 4

Many side effects, e.g.

1. increased infection risk
2. hypertension (mineralocorticoid effect… Na retention)
3. osteoporosis (e.g. osteoblast inhibition, enhanced bone resorption)
4. weight gain and fat redistribution (central obesity, moon face…)
5. insulin resistance and DM (increased glucose production and insulin action antagonist)
6. thinning and bruising of skin (increased protein breakdown)
7. mood changes, e.g. psychosis, depression

Question 5

Why should Ps taking steroids carry a card that states so?

Answer 5

Steroids should never be stopped abruptly as usual adrenal axis is suppressed in these Ps.

Ps might need higher dose of steroids in cases of acute illness.

Question 6

What is the 1st line DMARD used in RA management? What is its MOA?

Answer 6

METHOTREXATE - anti-metabolite used in:

1) Malignancy: inhibits dihydrofolate reductase… inhibits DNA, RNA and protein synthesis
2) Autoimmune inflammatory disease: MOA unclear (not via anti-folate action), may involve inhibition of T cell activation

Question 7

Describe the possible ADRs of methotrexate. Is it well tolerated?

Answer 7

Well tolerated (50% Ps continue drug >5yrs, longer than any other DMARD) but ADRs can inc.:

1- mucositis (responds to folic acid supplementation)
2- myelosuppression (responds to folic acid supplementation)
3- hepatitis and liver cirrhosis
4- infection risk
5- pneumonitis
6- highly teratogenic, abortifacient

Question 8

Name an anti-metabolite used in management of rheumatological diseases, e.g. SLE. What is its MOA?

Answer 8

AZATHIOPRINE:

i) cleaved to 6-MP anti-metabolite by TPMT enzyme*…
ii) incorporated into DNA/RNA…
iii) mutation and synthesis inhibition

• TPMT gene highly polymorphic - must test for activity before prescribing drug

Question 9

Which paramenter must be monitored when Ps are on methotrexate or azathioprine?

Answer 9

FBC as myelosuppression is important s/e of these drugs (inhibit DNA sythesis in rapidly dividing cells, e.g. of BM)

Question 10

Describe the MOA of infliximab and etanercept. How do they reduce RA progression?

Answer 10

mAb that bind TNFa (pro-inflammatory cytokine):

1. decreases inflammation
2. decreases angiogenesis (decreases VEGF levels)
3. decreases joint destruction (inhibits MMPs and other destructive enzymes, bone resorption and cartilage breakdown)

Question 11

Which P feature should be checked before prescription of TNFa inhibitors?

Answer 11

Screen for latent TB due to risk of TB reactivation (TNFa released by macrophages in response to Mtb infection is essential for dev. and maintenance or granulomas)

Question 12

Describe the MOA of rituximab.

Answer 12

mAb that binds specifically to CD20 (unique cell surface marker found on B cell subset)… B cell apoptosis - inhibits Ag presentation to T cells and cytokine/Ab production.

Very safe and effective in RA but expensive.

Question 13

Describe the MOA of tocilizumab.

Answer 13

mAb that binds IL-6 R.