CPT19 - Immunosuppressants

Question 1

4 features of calcineurin inhibitors as DMARDs

Examples x2
Mechanism
Usage x5
Side Effects x5

Answer 1

1. ) Examples - ciclosporin and tacrolimus
   - ciclosporin binds to cyclophilin protein
   - tacrolimus binds to tacrolimus binding protein
2. ) Mechanism - reduction in T helper cells
   - protein complexes inhibit calcineurin by binding to it
   - this ↓production of IL-2 –> less stimulation of Th cells
3. ) Usage
   - organ transplant, IBD, RA, psoriasis, dermatomyositis
4. ) Side Effects - ciclosporin only
   - damages kidney and liver (hepato/nephrotoxic)
   - eye discomfort, gingival hyperplasia
   - interaction with CYP inducers/inhibitors

Question 2

5 features of azathioprine as a DMARD

Mechanism x2
TPMT
Xanthine Oxidase
Usage x4
Side Effects x2

Answer 2

1. ) Mechanism - inhibits purine synthesis to ↓WBCs
   - active: 6-mercaptopurine (purine synthesis inhibitor)
   - ↓WBCs: ↑apoptosis and ↑myelosuppression
2. ) TPMT - enzyme inactivating 6-mercaptopurine
   - low TPMT levels –> risk of complete myelosuppression
   - TPMT gene is highly polymorphic so TPMT activity must be tested so that the correct dose is given
3. ) Xanthine Oxidase - inactivates 6-mercaptopurine
   - xanthine oxidase inhibitors (allopurinol and febuxostat) will increase levels of 6-mercaptopurine
4. ) Usage
   - organ transplantation, IBD, RA, SLE
   - safe to use during pregnancy
5. ) Side Effects - due to overactivity
   - bone marrow suppression, thrombocytopenia

Question 3

3 features of mycophenolate mofetil as a DMARD

Mechanism x3
Usage x3
Side Effects x4

Answer 3

1. ) Mechanism - prevents purine synthesis
   - inhibits inosine monophosphate dehydrogenase
   - selective for T/B cells since only pathway blocked
2. ) Usage
   - organ transplantation, IBD, SLE nephritis/vasculitis
3. ) Side Effects
   - nausea/vomiting, diarrhoea
   - myelosupression, ↑risk of skin malignancy
   - abortifacients (stop 3 months before conception)

Question 4

4 features of cyclophosphamide as a DMARD

Mechanism x2
Usage x5
Haemorrhagic Cystitis
Other Side Effects x3

Answer 4

1. ) Mechanism - triggers cell apoptosis
   - hepatic activation: 4-hydroxycyclophosphamide –> phosphoramide mustard + acrolein
   - phosphoramide mustard forms irreversible DNA cross-links which leads to cell apoptosis
2. ) Usage
   - SLE nephritis, systemic vasculitis (e.g. ANCA)
   - cancer: lymphoma, leukaemia
3. ) Haemorrhagic Cystitis - main side effect
   - acrolein is toxic to bladder epithelium
   - prevented using aggresive hydration and/or Mesna (IV infusion allowing easier excretion of acrolein)
4. ) Other Side Effects
   - ↑ risk of bladder cancer, lymphoma, leukaemia
   - teratogenic (stopped 3 months before conception)
   - infertility
   - hair loss

Question 5

5 features of methotrexate as a DMARD

Mechanism (cancer only)
Usage x4
Investigations 
Side Effects x3
Contraindications

Answer 5

1. ) Mechanism - ↓folic acid synthesis
   - reversibly inhibits dihydrofolate reductase (DHFR)
   - acts during S-phase so ↑toxicity on ↑dividing cells
   - has long half life (30hrs) so should be only given weekly
2. ) Usage - gold standard for RA
   - IBD, RA, psoriatic arthritis, cancer
   - ectopic pregnancy before rupture
3. ) Investigations
   - bloods: FBC (Hb, WCC), LFTs, U+Es,
   - chest X-ray: due to risk of pneumonitis
4. ) Side Effects - inflammation
   - pneumonitis, stomatitis, hepatitis, mucositis (painful ulcers)
   - bone marrow suppression
   - teratogenic and abortifacient
5. ) Contraindications
   - pregnancy (stopped >6 months before conception)
   - liver disease or excessive alcohol intake
   - severe renal impairment (GFR <30)

Question 6

3 features of sulphasalazine as a DMARD

Mechanism
Usage x3
Side Effects x4

Answer 6

1.) Mechanism - unknown

2. ) Usage
   - IBD, RA, ankylosing spondylitis
3. ) Side Effects
   - nausea/vomiting, dizziness
   - arthralgia (joint pain), leucopenia
   - related allergies to aspirin
   - safe in pregnancy

Question 7

3 groups of biological agents used as a DMARD

Anti-TNF x2
B-cell Depleting x1
IL-6 Inhibitors x1

Answer 7

1. ) Anti-TNF - infliximab, adalinumab
   - must screen for TB before (TNF needed to form a granuloma)
2. ) B-cell Depleting - rituximab
   - stop 1 year before conception

4.) IL-6 inhibitors - tocilizumab