10. Immunosuppression Flashcards
What are the diagnostic signs of rheumatoid arthritis?
Morning stiffness for over an hour, arthritis of 3+ joints, arthritis of hand joints, symmetrical arthritis, rheumatoid nodules, serum rheumatoid factor, X-ray changes.
What are the goals of rheumatoid arthritis treatment?
Symptomatic relief, prevention of joint destruction.
What is the treatment strategy for rheumatoid arthritis?
Early use of disease-modifying drugs, aim to achieve good disease control, use of adequate dosages, use of combinations of drugs, avoidance of long-term corticosteroids.
What are the treatment goals in systemic lupus erythematosus and vasculitis?
Symptomatic relief, reduced mortality, prevent organ damage, reduce long term morbidity from disease and drugs.
What are the main five immunosuppressant drugs?
Corticosteroids, azathioprine, ciclosporin, tacrolimus, mycophenolate mofetil.
What is the mechanism of action of corticosteroids?
Prevent interleukin 1 and 6 production by macrophages, inhibit all stages of T-cell activation.
What are the disease-modifying anti-rheumatic drugs (DMARDs)?
Methotrexate, sulphasalazine, anti-TNF agents, rituximab, cyclophosphamide.
What is azathioprine used for in practice?
SLE and vasculitis as maintenance therapy, weak evidence for RA, inflammatory bowel disease, as a steroid sparing drug.
What are the pharmacodynamics of azathioprine?
6-MP is metabolised by thiopurine methyltransferase.
Why does azathioprine have different risks of ADRs in different people?
6-MP is metabolised by TPMT which is highly polymorphic and levels vary in individuals. Low/absent TPMT - risk of myelosuppression.
What should be tested before prescribing azathioprine and why?
TPMT levels, if low/absent, risk of myelosuppression.
What is the mechanism of action of azathioprine?
Cleaved to 6-MP - antimetabolite decreases RNA and DNA synthesis.
What are the adverse drug reactions of azathioprine?
Bone marrow suppression, increased risk of malignancy, increased risk of infection, hepatitis.
Name two calcineurin inhibitors.
Ciclosporin and tacrolimus.
What are the uses of calcineurin inhibitors?
Transplantation, atopic dermatitis and psoriasis.
What should be checked regularly with calcineurin inhibitor use?
BP and eGFR as risk of hypertension and hyperkalaemia.
What are the DDI with calcineurin?
CYP 450 inducers - rifampicin, carbemazepine, phenytoin, omeprazole.
CYP 450 inhibitors - ciprofloxacin, antifungals, fluoxetine, paroxetine, HIV antivirals.
What is the mechanism of action of ciclosporin and tacrolimus (calcineurin inhibitors)?
Active against T helper cells, prevents IL-2 production via calcineurin inhibition. Ciclosporin binds cyclophilinprotein, tacrolimus binds tacrolimus-binding protein. The drug/protein complexes bind calcineurin to stop action.
What is the normal action of calcineurin?
Phosphatase activity on nuclear factor of activated T cells, factors migrates to nucleus to start IL-2 transciption.
When is mycophenolate mofetil used?
In transplantation, induction and maintenance therapy for lupus nephritis, transplantation medicine.
What are the ADRs of mycophenolate mofetil?
Nausea, vomiting, diarrhoea. Seriously - myelosuppression.
What is the mechanism of action for mycophenolate mofetil?
Inhibits inosine monophosphate dehydrogenase which impairs B and T cell proliferation but spares other rapidly dividing cells.
What are the indications for cyclophosphamide use?
Lymphoma, leukaemia, solid cancers, lupus nephritis, Wegener’s granulomatosis.
What is the overall action of cyclophosphamide?
Cytotoxic, immunological effects - suppressed T and B cell activity.
What is the mechanism of action of cyclophosphamide?
Alkylating agent - cross links DNA so it can’t replicate.
Why does cyclophosphamide need conversion in the liver by CP450?
It is a prodrug, so needs to be converted to active metabolite for action.
Where is cyclophosphamide excreted?
By the kidney.
How can cyclophosphamide lead to haemorrhagic cystitis?
Acrolien, another metabolite, is toxic to the bladder epithelium.
How can haemorrhagic cystitis be prevented with cyclophosphamide use?
Aggressive hydration and/or mesna (drug).
What are the significant toxicity risks of cyclophosphamide?
Increased risk of bladder cancer, lymphoma, and leukaemia; infertility.
What is a safer alternative for lupus nephritis treatment for cyclophosphamide?
Mycophenolate mofetil.
What are the indications for use of methotrexate?
Acute lymphophatic leukaemia, RA, malignancy, psoriasis, Crohn’s disease.
What is the mechanism of action of methotrexate considering treatment for ALL?
Competitively and reversibly inhibits dihydrofolate reductase and therefore inhibits synthesis of DNA, RNA and proteins. It is cytotoxic during the S-phase of the cell cycle so kills rapidly dividing cells.
What is the mechanism of action of methotrexate in non-malignant disease?
Not clear. Possibly inhibition of enzymes for purine metabolism -> accumulation of adenosine - regulatory autocoid that regulates immune cell function; inhibition of T cell activation; suppression of intercellular adhesion molecule expression by T cells.
What is the route of administration of methotrexate?
PO, IM, or SC.
What is an important about administration of methotrexate?
Weekly not daily dosing - THIS IS A NEVER-EVENT.
What are the oral and intramuscular bioavailabilities of methotrexate?
Oral 33%, intramuscular 76%.
What are the ADRs of methotrexate?
Mucositis, marrow suppression, hepatitis, cirrhosis, pneumonitis, infection risk. TERATOGENIC and abortifacient.
How can mucositis and marrow suppression be prevented with methotrexate use?
Folic acid supplementation.
What are the goals of treatment with sulfasalazine?
Relieve pain and stiffness, and to fight infection.
What are the immunological effects of sulfasalazine?
T cell - inhibits proliferation, may cause apoptosis, inhibition of IL-2 production.
Neutrophil - reduced chemotaxis and degranulation.
What are the ADRs of sulfasalazine?
Myelosuppression, hepatitis, rash, nausea, abdominal pain/vomiting.
What are the effects of blocking TNF-a?
Decreased inflammation, angiogenesis and joint destruction.
What is a risk of anti-TNF therapy?
TB reactivation.
Why can anti-TNF therapy result in TB reactivation?
TNFa is needed for development and maintenance of a granulomata so TB trapped in granulomas will stop being a contained infection.
What is the mechanism of action of rituximab?
Binds to CD20 surface marker on B cells so less presentation of antigens to T cells, fewer cytokines and fewer antibodies and B cell apoptosis.
What is rituximab used for?
RA.
