Immunosuppression Flashcards by Elaine Brazier

What % of the population does RA affect?

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What is the pathogenesis of RA?

Proinflammatory agents outweigh antiinflammatory agents.

IL-1 + IL-6 + TNF alpha > IL-4 + TGF beta

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How do we treat RA?

Target against proinflammatory agents

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What are the aims of treatment of RA?

Symptomatic relief and prevention of joint destruction

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What are the treatment goals in SLE and vasculitis?

Symptomatic relief, reduce mortality, prevent organ damage, and decrease long term morbidity caused by disease and by drugs.

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What immunosuppressants can we use?

Corticosteroids
Azathioprine
Ciclosporin
Tacrolimus
Mycophenolate mofetil

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What DMARDs can we use?

Methotrexate
Sulphasalazine
ANti-TNF agents
Rituximab
Cyclophosphomide

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How do corticosteroids work? (MoA)

Prevent IL-1 and IL-6 production by macrophages.

Inhibits all stages of T cell activation across all systems.

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What are the side effects of steroids?

H&N - aggravate epilepsy, schizophrenia, exopthalmos, facial erythema, glaucoma, insomnia, corneal thinning, headaches,
Cardioresp - congestive HF, hiccups
GI - abdo distension, acute pancreatitis, dyspepsia
Systemic - bruising, hirsutism, hypercholesterolaemia, hyperhidrosis, hyperlipidaemia, impaired healing, thin skin, bruise easily.
Other - amenorrhoea, candidiasis, cushings syndrome

And others.

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What is azothioprine used for?

Maintenacnce therapy for SLE and vasculitis, and for difficult to treat IBD.

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How is azothioprine metabolised?

To 6MP by TPMT

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What is important to note about TPMT?

TPMT gene is highly polymorphic so everyone has different levels of activity. If those levels are low, high risk of myelosuppression.

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What should we test before starting azothioprine?

TPMT activity level

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What is 6MP?

6-mercaptopurine = antimetabolite that decreases DNA and RNA synthesis by inhibiting purine metabolism.

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What are the ADRs for azothioprine?

Bone marrow suppression
Increased risk of malignancy esp. in transplant pts
Increased risk of infection
Hepatitis

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What should be monitored with azothioprine?

FBC (myelosuppression)

LFTs (hepatitis)

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What class of drug are ciclosporin and tacrolimus?

Calcineurin Inhibitors

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What is calcineurin and why does it need inhibiting?

Enzyme with phosphatase activity which usually produces IL-2 with helper T cells. Drug/protein complexes bind to calcineurin to inactivate it.

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What monitoring do pts on ciclosporin/tacrolimus need and why?

BP and eGFR - nephrotoxic!

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What is mycophenolate mofetil used for?

Immunosuppression in transplantation, and in lupus nephritis.

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What are the ADRs associated with mycophenolate mofetil?

Nausea
V&D
GI ulceration
Myelosuppression

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How does mycophenolate mofetil work?

Inhibits monophosphate dehydrogenase to prevent guanine synthesis. This impairs B and T cell proliferation.

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What is the gold standard treatment for RA?

Methotrexate!

When else, apart from RA, can methotrexate be used?

Malignancy
Severe psoriasis
Crohn’s Disease

What is methotrexate similar to in structure?

Folic acid

What is the MoA of methotrexate?

In malignancy, it inhibits dihydrofolate reductase. | Not clear how it works in RA etc but it isn't via folate inhibition.

Tell me about the pharmacokinetics of methotrexate.

Administer PO, IM or S/C WEEKLY as its active metabolite has a long half life. Best bioavailability via IM route = 76%.

What % of methotrexate is protein bound?

50%

What can displace methorexate from protein binding?

NSAIDs

How is methotrexate excreted?

Renally

Is methotrexate well tolerated?

Yes, over 50% of pts continue the drug for over 5 years.

Can methotrexate be used with other drugs?

Yes alongside other DMARDs as an anchor drugs

What are the ADRs associated with methotrexate?

Mucositis (less so at RA doses) Marrow suppression Hepatitis, cirrhosis, pneumonitis, increased infection risk.

What should we do when methotrexate is prescribed in women of child bearing age?

Prescribe contraception as highly teratogenic and abortificient

What is sulphasalazine made up of?

Salicylate (5 ASA) and sulphapyridine molecules

What do the elements of sulphasalazine do?

5 ASA - relieve pain and stiffness. | Sulphapyridine - fights infection.

What is the MoA of sulphasalazine?

Inhibits T cell proliferation, and maybe induces T cell apoptosis. Inhibits IL-2 production.

Tell me about the pharmacokiinetics of sulphasalazine.

Poor GI absorption so acts mainly in GI tract (effective in IBD). Few drug interactions, low toxicity, not carcinogenic, safe in pregnancy.

What are the ADRs of sulphasalazine?

Myelosuppression Hepatitis Rash N&V/abdo pain Usually only present in the first few weeks.

What category do anti-TNF agents come into?

Biopharmaceuticals

Which biopharmaceuticals bind to TNF alpha?

Adalimumab Infliximab Golimumab Etanercept

How does rituximab work?

Depletes B cells by causing apoptosis so they can't act as ntigen presenting ells, or produce cytokines or antibodies.

What happens when TNF alpha is blocked?

- Reduced inflammation - Reduced angiogenesis - Reduced joint destruction

By what mechanism do TNF alpha blockers reduce inflammation?

Cytokine cascade and leukocyte recruitment to joint is reduced.

By what mechanism do TNF alpha blockers reduce angiogenesis?

Decrease VEGF levels

By what mechanism do TNF alpha blockers reduce joint destruction?

Decrease bone resorption and erosion, cartilage breakdown and MMPs/enzyme activity.

What is the biggest risk with Anti-TNF agents? Why?

Reactivation of TB as TNF alpha is essential for the formation and maintenance of granulomas.

How effective is cyclophosphamide?

Very, and it works much quicker than other agents (10 days rather than 4-6 weeks)

How does cyclophosphamide work?

As an alkylating agent - cross links DNA so it can't divide for replication. Suppresses T and B cell activity.

What are the indications for cyclophosphamide?

Lymphoma, leukaemia, and solid cancers Lupus nephritis Wegner's granulomatosis

Tell me abou the pharmacokinetics of cyclophosphamide .

Prodrug that is converted to active form in the liver by CYP450. Excreted by kidneys.

What is the main active metabolite of cyclophosphamide?

4-hydroxycyclophosphamide

What ADRs does cyclophosphamide have?

Hameorrhagic cystitis Infertility Lymphoma and leukaemia risk increases

How does cyclophosphamide cause haemorrhagic cystitis?

Acrolein = another metabolite of cyclophosphamide is toxic to bladder epithelium.

What are JAK inhibitors?

Small molecule agents already used in RA and oncology. Inhibit Janus kinases which are enzymes important in cell signalling.