Rheumatology & Immunosuppression Flashcards
What is rheumatoid arthritis?
An autoimmune, multisystems disease which is initially localised to the synovium
Involves destruction of cartilage and bone
What key features do we look for when diagnosing RA?
Morning stiffness >1 hour Arthritis of >3 joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules Serum rheumatoid factor X-ray changes (LOSS)
What are the treatment goals for RA?
Symptomatic relief
+
Prevention of joint destruction
Give some examples of immunosuppressant drugs
Corticosteroids Azathrioprine Ciclosporin Tacrolimus Mycophenolate mofetil
What is the mechanism of action of corticosteroids?
Prevent IL-1 and IL-6 production by macrophages which inhibits all stages of T cell activation
What is the gold standard treatment for RA?
Methotrexate
Apart from for RA, what might Methotrexate be used to treat?
Malignancy
Psoriasis
Crohn’s disease
Methotrexate has a very similar chemical structure to what?
Folic acid
What is the mechanism of action of Methotrexate?
Competitive, reversible inhibition of dihydrofolate reductase (DHFR)
Inhibits the synthesis of DNA, RNA and proteins
How does Methotrexate target rapidly dividing cells specifically (i.e. cancer cells)?
It is cytotoxic during S-phase of the cell cycle
How does Methotrexate aid in the treatment of RA?
Mechanism is not clear
Possibly inhibits T cell activation
How can Methotrexate be administered?
Orally, Intramuscularly, Subcut
What is the dosing of Methotrexate?
WEEKLY dosing
Has a very long half life
Name some adverse effects of Methotrexate
How can these be avoided?
Mucositis
Marrow suppression
Highly teratogenic and may cause abortion
Folic acid supplementation
Avoid in pregnancy
What are the immunological effects of Sulfasalazine?
T cell inhibition, possible apoptosis, inhibition of IL-2
Neutrophil reduced chemotaxis and degranulation
Sulfasalazine is useful in the treatment of what condition?
Why?
IBD
It is poorly absorbed and has its main activity within the intestine
Name some adverse effects of sulfasalazine
Myelosupression Hepatitis Rash Nausea Vomiting Abdo pain
What conditions might Azathioprine be useful to treat?
Maintenance of SLE and vasculitis
What should be tested before prescribing Azathioprine?
TPMT activity- it is responsible for the cleavage of Azathioprine into its active form and is highly polymorphic
What is the mechanism of action of Azathioprine?
It is a pro drug that is cleaved by TPMT into 6-MP which decreases DNA and RNA synthesis
List some adverse effects of Azathioprine
Bone marrow suppression:
Increased risk of malignancy
Increased risk of infection
Hepatitis
What is Mycophenolic (mofetil) acid used for in practice?
To avoid transplant rejection
For lupus nephritis
What are the most common side effects of Mycophenolic (mofetil) acid?
Nausea
Vomiting
Diarrhoea
Myelosuppression
What is Mycophenolic acids mode of action?
Impairs B and T cell proliferation whilst sparing other rapidly dividing cells
Name a cyclotoxic agent that is a prodrug with indications in lymphoma, leukaemia and solid cancers as well as lupus nephritis
Cyclophosphamide
List some important considerations when using cyclophosphamide and how these can be overcome in practice
Bladder malignancy- +++++ hydration +/or Mensa
Infertility- care when giving to young patients
Dose should be adjusted in patients with renal impairment
Which drug is safer as just as effective as cyclophosphamide in the treatment of lupus nephritis?
Mycopenolate mofetil
List some monoclonal antibodies that may be used in the treatment of rheumatoid conditions such as RA, Crohn’s and psoriasis
Rituximab - RA, SLE, vasculitis
Adalimumab - RA, AS, psoriasis, Crohn’s
Golimumab - RA, AS, UC
How do monoclonal antibodies that block TNFalpha work work?
They reduce inflammation by blocking the cytokine cascade
They reduce angiogenesis
They reduce joint destruction
What must you screen for before stating a patient on Anti-TNFalpha therapy?
+ How?
Latent TB
Quantiferon gold
How does Rituximab work to reduce autoimmune responses in patients with rheumatological conditions?
It binds to CD20 on a specific B cell subset and causes apoptosis
What do you need to keep a close eye on in patients that are taking calcineurin inhibitors?
BP and eGFR
Due to renal toxicity
What is the mode of action of calcineurin inhibitors?
Give some examples
Activity against T cells, preventing production of IL-2
Ciclosporin and tacrolimus
