Immunosuppressants

Question 1

Corticosteroids

Answer 1

Indication: immunosuppressant
- temporal arteritis and PMR
- dexamethasone: meningitis, croup, palliative care
- methylprednisolone: pulse therapy (v. High dose), rapid influence on inflammatory arthritis, SLE, vasculitis, used for Intra-articular and IV injections

Route:
- prednisolone oral
- methylprednisolone iv/im/oral
- hydrocortisone IV
- dexamethasone IV/oral

Action:
- Prevent IL-1 and IL-6 production by macrophages
- inhibit all stages of T cell activation

Side effects:
Cushing’s syndrome
Osteoporosis
Retardation of growth
Thin skin
Immunosuppression
Cataracts and glaucoma
Oedema
Suppression of hypothalamic pituitary axis
Tetatogenic
Emotional disturbance
Raised BP and heart failure
Obesity
Increased body hair
Diabetes
Striae and stomach ulcers

Question 2

Azathioprine

Answer 2

Indication: immunosuppresant

• MAINTENANCE therapy for SLE and vasculitis
• IBS
• atopic dermatitis, bullous skin disease
• steroid sparing drug - enhances steroid effect - lower dose of steroid

Action:

• cleaved to 6-MP
• metabolised by TPMT to TIMP
• anti-metabolite decreases DNA and RNA synthesis (purine)

Adverse effects:

• bone marrow supression - monitor FBC
• increased risk of malignancy - especially transplanted patients
• increased risk of infection
• hepatitis - monitor LFT

Interaction: allopurinol

Other: TPMT gene highly polymoprhic so test activity before prescribing (low/absent levels = risk of myelosupression)

Question 3

Ciclosporin/tacrolimus

Answer 3

Indication: immunosupressant

• transplantation
• atopic dermatitis and psoriasis
• not often rheumatology - renal toxicity - check BP and eGFR

Class: calcineurin inhibitor

Action:

• ciclosprin binds to cyclophilin protein
• tacrolimus binds to tacrolimus-binding protein
• drug/protein complexes bind to calcineurin
• inhibit calcineurin, prevent production of IL-2 from T helper cells

Adverse effects:
- bone marrow supression - monitor FBC
- increased risk of malignancy - especially transplanted patients
- increased risk of infection
- hepatitis - monitor LFT
- hyperlipidaemia

Other: inhibit CYP 450 - multiple drug intercations possible

Question 4

Mycophenolate mofetil

Answer 4

Indication: immunosupressant
- transplants
- INDUCTION and MAINTENANCE in lupus nephritis
- MAINTENANCE in vascultitis

Class: antimetabolite

Action:
- prodrug derived from fungus penicllium stoloniferum
- inhibits inosine monophosphate dehydrogenase (guanosine synthesis)
- impairs B and T cell proliferation
- spares other rapidly diving cells - guanosine salvage pathways

Adverse effects:
- GI - nausea, vomiting, diarrhea
- myelosupression
- increased risk of malignancy
- increased risk of infections - hypoimmungolbinaemia
- hepatitis

Question 5

Cyclophosphamide

Answer 5

Indication: immunosupression

• lymphoma, leuakemia, solid cancers
• lupus nephritis
• wegener’s granulomatosis

Actions:

• prodrug - active metabolites are 4-hydroxycylcophosphamide and its tautomer aldophosphamide
• alkylating agents - cross link DNA so that it cannot replicate and supress B and T cell activity
• aldophosphamide converted to carboxyphosphamide (inactive), phosphoramide mustard (good metabolite), acrolein (toxic metabolite to the bladder leading to hemorrhagic cystitis - prevented by aggressive hydration and mesna)

Adverse effects: toxicity

• increased risk of badder cancer, lymphoma and leukaemia
• infertility (risk relates to cumulative dose and pateint age)
• monitor FBC and adjust dose in renal impairment

Other:
- mycophenolate mofetil safer and as effective in lupus nephritis

Question 6

Methotrexate

Answer 6

Indication: immunosuppressant

• gold standard for RA
• malignancy
• psoriasis
• crohn’s
• abortions

Action:

1. Malignant disease:
   - competitively and reversibly inhibits dihydrofolate reductase
   - inhibits conversion of dihydrofolate to active tetrahydrofolate (key in purine and thymidine synthesis)
   - inhibits synthesis of DNA, RNA and proteins - cytotoxic effect during S phase therefore more effective on rapdily dividing cells
2. Non malignant disease:
   - unclear
   - NOT via anti-folate action
   - possibly inhibition of accumulationof adenosine

Route: oral, IM or SC (if only partial response or nausea)

Dosing:
WEEKLY - long half life
Monday methotrexate
Friday folic acid

Adverse effects:
- mucositis (responds to folic acid supplementation)
- marrow supression (responds to folic acid supplementation)
- hepatitis/cirrhosis
- pneumontis
- infection
- highly tetratoegnic and abortifacient - need contraception

Other:
- 50% protein bound - NSAIDS displace
- RENAL EXCRETION
- no excessive alcohol
- NEVER give trimethoprim - also antifolate

Monitoring:
LFTs - hepatic metabolism - risk of hepatitis/cirrhosis,
U&Es - poor renal function will get methotrexate toxicity (may have to be stopped in AKI)

Question 7

Sulfasalazine

Answer 7

Indication: immunosupressant

• IBD (poorly absorbed - main activity in the intestine)
• RA

Action:

• 5-ASA anti-inflamatory, sulfapyridine antibiotic
• T cell inhibtion of proliferation and IL-2 production, apoptosis
• neutrophil - reduce chemotaxis and degranulation

Adverse effects:

• myelosuppression
• hepatitis
• rash
• nausea, vomiting, abdo pain
• temporary azospermia in young men

Other:

• safe in pregnancy
• few drug interactions
• effective and favourable toxicity
• do not prescribe if allergic to aspirin - ASA core

Question 8

Adalimumab, infliximab

Answer 8

Indication: immunosupressant

• RA
• IBD
• psoriasis
• psoriatic arthritis
• ankylosing spondilitis

Class: monoclonal antibody

Action: blocks/binds TNFa
- decrease inflamation - cytokine cascade, leukocutes to joint
- decrease angiogenesis - VEGF levels
- decrease joint destruction - MMps, bone reorption/erosion, cartilage breakdown

Adverse effects: TB reactivation - TNFa released by macrophages in response to TB infection and is essential for development and maintenenace of granulomata (screen for latent TB before anti-TNF treatement)

Other:
- increased risk of infection with intra-cellular pathogens e.g HIV, hepatitis, TB
- needs a DAS assesment
- all brands paraenteral

Question 9

Rituximab

Answer 9

Indication: immunosupressant
- RA
- lymphoma

Class: monoclonal antibody

Action:
- binds to CD20 found on a specific subset of B cells (not stem or plasma cells)
- causes B cell apoptosis (loss of antigen presentation to T cells, cytokines, antibodies)

Other: follow up infusions are not needed many months