Immunosuppression + disease modifying therapy

Question 1

Describe rheumatoid arthritis
How does it occur?

Answer 1

• autoimmune multi system disease
• autoantibodies attack synovium
• inflammatory change + proliferation of synovium (pannus) > dissolution of cartilage and bone

Question 2

Clinical features of rheumatoid arthritis

Answer 2

• morning stiffness >1 hour
• arthritis of 3> joints
• arthritis of hand joints
• symmetrical arthritis
• rheumatoid nodules

Question 3

Non clinical features of rheumatoid arthritis

Answer 3

• Serum rheumatoid factor/anti CCP antibodies
• X ray changes LESS

Question 4

Aims of rheumatoid arthritis treatment

Answer 4

Symptomatic relief
Prevention of joint destruction

Question 5

What pro inflammatory markers are involved in rheumatoid arthritis?

Answer 5

IL1
IL6
TNF-a

Question 6

Treatment strategy of rheumatoid arthritis

Answer 6

• early use of disease modifying drugs to prevent progression
• aim to achieve good disease control
• use of adequate dosage + combination of drugs
• avoidance of long term corticosteroids

Question 7

What type of drug is avoided in long term treatment of rheumatoid arthritis?

Answer 7

Corticosteroids

Question 8

Treatment goals of systemic lupus erythematous + vasculitis

Answer 8

• symptomatic relief
• reduction in mortality
• prevention of organ damage
• reduction in long term morbidity

Question 9

Examples of anti-proliferative drugs

Answer 9

Azathioprine
Mycophenolate mofetil
Cyclophosphamide

Question 10

What class of drug is azathioprine?

Answer 10

Anti-proliferative immunosuppressant

Question 11

What are the uses of azathioprine?

Answer 11

• systemic lupus erthymatous + vasculitis
• IBS
• rheumatoid arthritis (weakly)
• atopic dermatitis
• bullous skin disease
• steroid ‘sparing’ drug

Question 12

What is the mechanism of action of azathioprine?

Answer 12

Inhibition of synthesis of purines needed for DNA + RNA transcription

Question 13

What are adverse drug reactions of azathioprine?

Answer 13

Immunosuppression
- risk of malignancy
- hepatitis
- infection risk
- bone marrow suppression

Question 14

Examples of calcineruin inhibitiors

Answer 14

Ciclosporin
Tacrolimus

Question 15

What is the mechanism of action of calcineurin inhibitors?
Two examples + how they differ

Answer 15

• ciclosporin binds to cyclophilin protein
• tacrolimus binds to tacrolimus binding protein
• drug/protein complexes bind to calcineruin + cause inhibition
• reduces helper T cell activity

Question 16

What are the uses of calcineurin inhibitors?

Answer 16

Transplantation
Atopic dermatitis
Psoriasis

Question 17

What are adverse drug reactions of calcineruin inhibitors?

Answer 17

Renal toxicity

Question 18

What are important drug drug interactions of calcineurin inhibitors?

Answer 18

• CYP inducers e.g. antivirals + antifungals
• CYP inhibitors e.g.omeprazole, carbamazepine

Question 19

What is the mechanism of action of ciclosporin?

Answer 19

Calcineurin inhibitor
- Binds to cylophilin protein
- Drug/protein complex bind calcineurin + prevents it’s action > prevents production of IL-2 + T helper cell activity

Question 20

What is the mechanism of action tacrolimus?

Answer 20

Calcineurin inhibitor
- binds to tacrolimus-binding protein
- drug/protein complex binds to calcineruin + inhibits its action > prevents production of IL-2 + T helper cell activity

Question 21

What class of drug is mycophenolate mofetil?

Answer 21

Anti-proliferative immunosuppressant

Question 22

What are the uses of mycophenolate mofetil?

Answer 22

Transplantation
Induction + maintenance therapy for lupus nephritis
Maintenance of vasculitis

Question 23

What is the mechanism of action of mycophenolate mofetil?

Answer 23

• prodrug
• inhibitors inosine monophosphate dehydrogenase (needed for guanosine synthesis)
• impairs B+T cell proliferation

Question 24

Why does mycophenolate mofetil impair B+T cell proliferation but spare other rapidly dividing cells?

Answer 24

Other cells have guanosine salvage pathways

Question 25

What are adverse drug reactions of mycophenolate mofetil?

Answer 25

N+V diarrhoea Myelosuppresion (bone marrow)

Question 26

What class of drug is cyclophosphamide?

Answer 26

Anti-proliferative immunosuppressant

Question 27

What are the uses of cyclophosphamide?

Answer 27

- Lymphoma, leukaemia, solid cancers - lupus nephritis - Wegener’s granulomatosis

Question 28

What is the mechanism of action of cyclophosphamide?

Answer 28

- Prodrug: converted in liver to active form by CYP450 - inhibtis B+T cell proliferation

Question 29

What are adverse drug reactions of cyclophosphamide?

Answer 29

- increased risk of bladder cancer, lymphoma + leukaemia - infertility - monitor RBC

Question 30

Examples of DMARDs (disease modifying anti rheumatic drugs)

Answer 30

Methotrexate Sulfasalazine Mesalazine Hydroxychloroquine Rituximab

Question 31

What should be monitored whilst a patient is taking cyclophosphamide?

Answer 31

FBC

Question 32

What class of drug is methotrexate?

Answer 32

Disease modifying anti-rheumatoid drug DMARD

Question 33

What are the uses of methotrexate?

Answer 33

RA Malignancy Psoriasis Crohn’s disease

Question 34

What is the mechanism of action of methotrexate in malignancy?

Answer 34

- Competitively + reversible inhibtis dihydrofolate reductase - inhibtis dihydrofolate > tetrahydrofolate needed in purine + pyrimidine synthesis - therefore, inhibits DNA, RNA + protein synthesis

Question 35

What is the mechanism of action of methotrexate in non malignant disease *e.g. RA*?

Answer 35

- NOT via anti-folate action - inhibition of accumulation of adenosine - inhibits T cell activation - suppression of intracellular adhesion molecule expression by T cells

Question 36

What are adverse drug reactions of methotrexate?

Answer 36

- mucositis - bone marrow suppression - hepatitis + cirrhosis - pneumonitis - infection risk - highly teratogenic

Question 37

How can some of methotrexate ADRs be treated?

Answer 37

Bone marrow suppression + mucositis both respond to folic acid supplementation

Question 38

What class of drug is sulfasalazine?

Answer 38

Disease modifying anti-rheumatic drug DMARD

Question 39

What are the uses of sulfasalazine?

Answer 39

RA IBD

Question 40

What is the mechanism of action of sulfasalazine?

Answer 40

5-aminosalicylic acid donor in RA > immunosuppression + anti inflammatory effec

Question 41

What are the adverse drug reactions of sulfasalazine?

Answer 41

- myelosuppression - hepatitis - rash - N+V - abdominal pain

Question 42

What DMARD should be avoided in pregnancy?

Answer 42

Methotrexate

Question 43

What is the mechanism of action of ‘biologicals’/MAB?

Answer 43

- TNF-a inhibiton - reduces inflammation, angiogenesis + joint destruction

Question 44

What are adverse drug reactions of biologicals/MAB?

Answer 44

Risk of TB reactivation > screen for latent TB before anti-TNF treatment

Question 45

What class of drug is rituximab?

Answer 45

‘Biologicals’ Monoclonal antibody

Question 46

What is the mechanism of action of rituximab?

Answer 46

Binds to CD20 on specific B cells > B cell apoptosis

Question 47

What are uses of rituximab?

Answer 47

RA

Question 48

Examples of systemic corticosteroids

Answer 48

Hydrocortisone Prednisolone Betamethasone Dexamethasone

Question 49

What are uses of systemic corticosteroids?

Answer 49

Perioperative N+V Chemotherapy Palliation

Question 50

What is the mechanism of action of systemic corticosteroids?

Answer 50

- prevents IL1+6 production by macrophages - inhibits all stage of T cell activation

Question 51

What are adverse drug reactions of corticosteroids?

Answer 51

Insomnia Increased appetite Increased blood sugar

Question 52

What should be tested for before prescribing azathioprine and why?

Answer 52

- **TPMT activity** - involved in metabolism of azathioprine - TPMT gene is highly polymorphic - low/absent TPMT level increases risk of myelosuprresion

Question 53

Relationship between TPMT activity and myelosuppresion risk

Answer 53

Low/absent TPMT activity = risk of myelosuppresion