PHAR: Rheumatoid Arthritis

Question 1

What are the two therapeutic goals for rheumatoid arthritis treatment?

Answer 1

• Preserve function.

- Prevent pain.

Question 2

Immune cells associated with RA.

Answer 2

• Macrophages.
• T and B lymphocytes.
• Endothelial layer of blood vessels.
• Fibroblasts.

Question 3

What are the three DMARDs that inhibit T cell proliferation and function?

Answer 3

• Methotrexate (MTX)
• Leflunomide
• Glucocorticoids

Question 4

Name two drugs that have an unknown method of action.

Answer 4

• Sulfasalazine.

- Hydroxychloroquine.

Question 5

What immune cell produces TNFa?

Answer 5

Macrophages.

Question 6

What immune cell stimulates macrophages to produce TNFa?

Answer 6

T lymphocyte.

Question 7

• What are two examples of potent glucocorticoids?

- What molecule is modified to make these glucocorticoids?

Answer 7

• Prednisolone. (potent glucocorticoid).
• Dexamethasone. (very potent glucocorticoid).
• Hydrocortisone (cortisol)

Question 8

What are some adverse effects of MTX?

Answer 8

• Neutropenia.
• Thrombocytopenia.
• Mouth ulcers.
• GI upset.
• Teratogenicity risk.
• Hepatotoxicity.
• Pulmonary fibrosis.

Question 9

Which class of RA medication are TNF-alpha inhibitors?

Name 2 examples.

Answer 9

Biologicals

Infliximab and Adalimumab

Question 10

What are adverse effects of TNF-alpha inhibition?

Answer 10

• Immune suppression
• Increased infection rate
• Dorman tuberculosis reactivation
• Increased rate of some malignancies?

Question 11

How does MTX prevent T-cell proliferation?

Answer 11

Folate antagonist (has v similar structure). 
Folate delivers building blocks for DNA through conversion from tetrohydrofolate (FH4) to folate. 
DHFR is the enzyme which converts folate back to FH4. 

• Inhibits Dihydrofolate Reductase (DHFR) enzyme
• Prevents conversion folic acid to terahydrofolic acid
• Prevents nucleic acid synthesis
• Prevents T-cell proliferation.

Question 12

How is MTX excreted? (and hence, what function needs to be checked beforehand)

Answer 12

Really excreted, renal function

Question 13

How does leflunomide prevent T-cell proliferation?

Answer 13

• Blocks dihydroorotate deyhdrogenase

- Prevents pyrimidine synthesis

Question 14

How do non-steroidal anti-inflammatory drugs (NSAIDS) work?

Do they prevent disease progression?

Answer 14

• Inhibit prostaglandin production, suppressing signs of inflammation (inc. pain)
• Do not prevent disease progression.

Question 15

What are DMARDs?

Answer 15

Disease Modifying Anti-Rheumatoid Drugs

Question 16

What are the 3 main targets/mechanisms/classes of DMARDs?

Answer 16

1. Targeting T-cells
2. Targeting macrophages
3. Unknown mechanism

Question 17

Which drugs target macrophage action?

Answer 17

1. TNFa inhibitors
2. Anti-IL6
3. Glucocorticoids

Question 18

What is the mechanism of action of glucocorticoid?

Answer 18

1. Enter cytosol & bind to a receptor
2. translocate to nucleus
3. Bind to GRE (glucocorticoid responsive element) promoter gene, stimulating transcription of anti-inflammatory proteins.

Question 19

What is the effect of glucocorticoids on inflammatory cells?

Answer 19

T-cells: decrease recruitment & proliferation

B-cells: decrease antibody production

Macrophages: decrease cytokine production, including TNFa. Also decreases it’s other pro-inflammatory functions.

Question 20

What are the adverse effects of glucocorticoids?

How are these avoided?

Answer 20

• metabolic effects (changing metabolism, developing diabetes)
• mineralocorticoid effects (salt & water retention)

Avoided by giving locally (long acting joint injections for RA, asthma puffers, creams)

Question 21

Why should leflunomide be avoided in young women?

Answer 21

Even more teratogenic than MTX.

Very long half-life.

Question 22

Are glucocorticoids DMARDs?

Answer 22

No, while they blunt the immune reaction they are insufficient to slow progression of the disease

(some evidence they may have DMARD effects in early stages)

Question 23

What is the typical order/choice of drugs?

Answer 23

1. MTX
2. leflunomide
3. add sulfasalazine or hydroxychloroquine
4. add biologic (ie Infliximab or Adilimumab)
5. supplement with NSAIDs for pain relief
6. glucocorticoids low-dose systemic in early treatment or locally via injection for acute flare ups.