11) Immunosuppression and Rheumatology Flashcards
Describe rheumatoid arthritis:
Autoimmune multi-system disease initially localised to synovium
What is the pathogenesis of rheumatoid arthritis due to?
Imbalance between pro and anti-inflammatory molecules
How is rheumatoid arthritis diagnosed?
Morning stiffness > 1 hour
Arthritis in 3 or more joints
Arthritis in hand joints
Symmetrical arthritis
What are the treatment goals in RA?
Symptomatic relief and prevention of joint destruction
What is SLE?
Autoimmune disease causing inflammation of various parts of the body
What is vasculitis?
Inflammation of blood vessels, can affect kidney, skin and lungs
What are the treatment goals in vasculitis?
Symptomatic relief
Reduction in morbidity and mortality
Prevention of organ damage
What is the mechanism of action of corticosteroids?
Bind to intracellular gluco-corticoid receptors and prevent IL-1 and IL-6 production by macrophages. Inhibit T cell activation
Give examples of immunosuppressants:
Corticosteroids Azathioprine Ciclosporin Tacrolimus Mycophenolate mofetil
Give examples of disease modifying anti-rheumatic drugs (DMARDs):
Methotrexate Sulfasalazine Anti-TNF alpha Rituximab Cyclophosphamide
When is azathioprine indicated?
SLE, vasculitis, IBD, transplantation, atopic dermatitis
What is the mechanism of action of azathioprine?
Inhibits purine metabolism (anti-metabolite)
What are the side effects of azathioprine?
Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis
When are calcineurin inhibtors (ciclosporin, tacrolimus) indicated?
Transplants, atopic dermatitis, psoriasis
What is the mechanism of action of calcineurin inhibitors?
Prevent production of IL-2 by T helper cells via calcineurin inhibition
Ciclosporin binds to cycophilin protein
Tacrolimus binds to tacrolimus binding protein
What are the side effects of calcineurin inhibitors?
Renal toxicity Drug interactions (CYP P450)
When is mycophenolate mofetil indicated?
Transplantation, induction and maintenance of lupus
What is the mechanism of action of mycophenolate mofetil?
Inhibits monophosphate dehydrogenase required for guanosine synthesis, impairing B and T cell proliferation
What are the side effects of mycophenolate mofetil?
Leucopenia and neutropenia Myelosuppression Nausea Diarrhoea GI ulcers
When is cyclophosphamide indicated?
Lymphoma, leukemia, lupus, ANCA vasculitis
What is the mechanism of action of cyclophosphamide?
Alkylating agents that cross links DNA so that it cannot replicate
What are the side effects of cyclophosphamide?
Metabolite (acrolein) is toxic to bladder epithelium - haemorrhage cystitis
Risk of bladder cancer, lymphoma and leukemia
Infertility
When is methotrexate indicated?
RA, malignancy, psoriasis, Crohn’s
What is the mechanism of action of methotrexate (malignant)?
Inhibits dihydrofolate reductase to stop conversion of dihydrofolate to tetrahydrofolate used in purine and thymidine synthesis
What is the mechanism of action of methotrexate (non-malignant)?
Inhibition of purine metabolism leading to accumulation of adenosine, inhibition of T cell activation
How is methotrexate administered and how often?
IM or SC
Weekly dosing
What are some side effects of methotrexate?
Mucositis Myelosuppression Hepatitis Cirrhosis Pneumonitis Teratogenic
How is cyclophosphamide excreted and therefore what needs to be given alongside?
Excreted by kidneys but metabolite toxic to bladder epithelium so give aggresive hydration +/- mesna
What drugs interact with methotrexate?
NSAIDs
Phenytoin
Tetracyclins
Penicillins
When is sulfasalazine indicated?
RA, IBD (Crohn’s)
What is the mechanism of action of sulfasalazine in RA?
Inhibits T cell proliferation, T cell apoptosis inducer and inhibits IL-2 production
What is the mechanism of action of sulfasalazine in IBD?
In colon broken down to 5-ASA and sulfapyridine
5-ASA is poorly absorbed and affects gut flora
What are some side effects of sulfasalazine?
Myelosuppression Hepatitis Rash Abdo pain N&V
What are the effects of anti-TNF alphas?
Decreased inflammation - down reg of cytokine cascade
Decreased angiogenesis
Decreased joint destruction
What must be screened for before giving anti-TNFs?
Latent TB
What is the mechanism of action of rituximab and when is it used?
Binds to CD20 on B cells, causes B cell apoptosis
RA, lupus, vasculitis
