6.1 - Immunosuppression and Rheumatoid Arthritis

Question 1

Describe the pathogenesis of rheumatoid arthritis

Answer 1

• Inflammation of synovium of joints caused by T cells and macrophages.
• Macrophages release cytokines IL-1, IL-8, and TNF-alpha which results in inflammation and synovitis..
• Osteoblasts and fibroblasts activated to produce metalloproteinases
• Synovium thickens and joint effusions. Inflamed synovium becomes known as apannus.
• Pannus damages underlying cartilage, exposing bone.

Question 2

Describe the presentation of Rheumatoid arthritis

Answer 2

• Symmetrical
• Warm, tender joints with swelling
• fixed flexion (boutonniere) or fixed hyperextension (swan neck) deformities
• Pain and stiffness worse in mornings

Question 3

What type of drugs can be used to treat RA?

Answer 3

At first, DMARDs - Halt and reverse underlying processes

NSAIDs - reduce symptoms

Immunosuppressants

Question 4

Describe how methotrexate works in non malignant disease such as RA

Answer 4

• Methotrexate inhibits enzymes involved in purine metabolism, leading to increased adenosine in cell.
• Adenosine acts on GPCRs of inflammatory and immune cells leading to a reduced activity of T cells.

Question 5

How is methotrexate administered? How many times a day?

Answer 5

oral, Subcutaneous or intramuscular

Administered once a week!!

Question 6

What is the half life of methotrexate?

Answer 6

8-10 hours.

Question 7

How is methotrexate excreted?

Answer 7

renally

Question 8

Name 3 ADRs of methotrexate

Answer 8

myelosuppression, hepatitis, teratogenic, abortifactant.

Question 9

How is methotrexate monitored?

Answer 9

Baseline CXRs, FBCs (for myelosuppression), LFTs (hepatic damage), and U&Es and creatinine for renal function

Question 10

What is the mechanism of action of sulfasalazine in treating RA? What type of drug is it?

Answer 10

• Inhibits T-cell proliferation and IL-2 production
• DMARD

Question 11

What are the possible ADRs of sulfasalazine?

Answer 11

Nausea, fatigue, headaches

Myelosuppression, hepatitis

Question 12

Describe how azothioprine can be used to treat RA.

Answer 12

• Metabolised to 6-MP which inhibits purine synthesis
• Reduces therefore DNA and RNA synthesis.
• Acts on cells with high mitotic rates

Question 13

How does azothioprine treatment differ from patient to patient?

Answer 13

• TPMT enzyme eliminates 6-MP
• TPMT subject to genetic polymorphism, differing levels produced by different patients.

Question 14

What are the ADRs of azothiprine

Answer 14

myelosuppression, increased risk of infection, emergence of malignant cell lines.

Question 15

How do corticosteroids work?

Answer 15

Inhibitors of gene expression

Question 16

How does cyclophosphamide work?

Answer 16

• Forms DNA crosslinks between and within DNA strands, preventing replication.
• Acts on cells with higher mitotic rates

Question 17

What are the ADRs of cyclophosphamide?

Answer 17

Leukaemia, infertitlity, teratogenesis, bladder cancer

Question 18

How is cyclophospahmide excreted?

Answer 18

Renally

Question 19

How does mycophenolate mofetil work?

Answer 19

• Inhibits enzyme required for guanine synthesis
• Resulting in impaired B and T cell proliferation whilst sparing other rapidly dividing cells.

Question 20

What are the ADRs of mycophenolate mofetil?

Answer 20

myelosuppression, increased risk of infection, nausea, vomiting, diarrhoea.

Question 21

Name 2 calcineurin inhibitors.

Answer 21

Tacrolimus and ciclosporin

Question 22

How do calcineurin inhibitors work?

Answer 22

• Prevent IL-2 production by T helper cells by inhibiting calcineurin.
• Ciclosporin binds to cyclophilin. Tacrolimus binds to Tacrolimus-binding protein. These complexes then bind to calcineurin.

Question 23

Name the ADRs of calcineurin inhibitors

Answer 23

nephrotoxicity, hypertension, hyperlipidaemia, nausea, vomiting (hyperesis), diarrhoea, hyperuricemia.