10.2 Immunosupression Flashcards
What are the clinical and non clinical criteria for diagnosing rheumatoid arthritis?
Clinical
- morning stiffness >1 hr
- arthritis of >3 joints
- arthritis of hand joints
- symmetrical arthritis
- rheumatoid nodules
Non clinical
- x ray changes
- serum rheumatoid factor/anti CCP antibodies
What are the treatment goals for rheumatoid arthritis?
Symptomatic relief
Prevent joint destruction
EARLY USE of disease modifying drugs
What is a mallor rash?
A rash across the cheeks
Often seen in lupus
What impacts can lupus have on the body?
- seizures, headaches, psychosis in head
- ulcers in eyes and mucous membranes
- nausea and vomiting
- endocarditis, pericarditis in heart
- miscarriages and menstrual cycle irregularities
- anaemia
- fatigue and myalgia
What are the treatment goals in SLE and vasculitis?
Symptom relief
Reduce mortality
Prevent organ damage
What is systemic vasculitis?
Inflammation of blood vessels .
What is the mechanism of action of corticosteroids?
Prevent interleukin I-IL-1 and IL-6 production by macrophages
Inhibit all stages of T cell activation
Therefore have an immunosuppressant action
What are DMARDs?
Disease modifying anti rheumatoid drugs
They are anti inflammatories so have an immunosuppressive function
Non biological
- sulphasalazine
- hydroxychloroquine
Biological
- Anti TNF agents
- Rituximab
- IL-6 inhibitors, JAK inhibitors
What is azathioprine and when is it used?
IBD
RA if unresponsive to other treatments
It’s is cleaved to 6 MP, an anti metabolism that decreases DNA and RNA synthesis = less inflammation
Why should you be careful with Azathioprine prescription?
Azathioprine is metabolised to 6 MP, which is then metabolised by thiopurine methyltransferase (TPMT)
TPMT levels vary in individuals
Low TPMT levels = risk of myelosupression (low bone marrow activity = low blood count)
Therefore need to do a TPMT activity test before prescribing
What are the ADR of Azathioprine?
- bone marrow suppression (monitor FBC)
- increased risk of malignancy esp transplant patients
- increased infection risk
- hepatitis
When are ciclosporin and tacrolimus used?
In transplants, atopic dermatitis and psoriasis
Not used in rheumatology due to renal toxicity
What drugs are CYP 450 inducers?
Rifampicin
Carbamazepine
Phenytoin
Omeprazole
What are CYP 450 inhibitors?
Ciprofloxacjn Antifungals HIV antivirals Fluoxetine Paroxetine
What are the roles of IL 1-5?
IL1 = HOT (fever) IL2 = T (cell stimulator) IL3 = BONE (marrow stimulate) IL4+5 = STEAK (IgE+IgA)
What’s the mechanism of action of ciclosporin and tacrolimus?
Active against T helper cells, preventing IL2 production via calcineurin inhibition = no T cell stimulation
ciclosporin binds to cyclophilin protein
tacrolimus binds to tacrolimus protein
when is mycophenolate mofetil used in practise?
primarily in transplantation
good efficacy as induction and maintanance therapy for lupud/vasculitis
NB: induction therapy is to induce remission
maintenance therapy is to maintain remission
what is the mechanism of action of mycophenolate mofetil?
Is a prodrug
impairs B and T cell proliferation but spares other rapidly dividing cells
what are the adverse effects of mycophenolate mofetil?
nausea
vomiting
diarrhoea
most serious = myelosuppression
what is the action of cyclophosphamide and what are its indications?
a pro drug (converted by cytochrome P450 for active form)
excreted by the liver
works within 6 days
an alkylating agent
cross links DNA so that it cant replicate
many immunological effects
- suppresses T cell activity
- suppresses B cell activity
indications
- lupus
- lymphoma
how can cyclophosphamide damage the bladder?
acrolein, a metabolite, is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
this can be prevented through the use of aggressive hydration and/or mesna
what are the risks of use of cyclophosphamide?
significant toxicity
- infertility (under 25, negligible, 25-30, risk jumps to 12%, and 30+ = 25%)
- increased risk of bladder cancer, lymphoma and leukaemia
- adjust dose in renal impairment
mycophenolate mofetil is safer and as effective in lupus nephritis, HOWEVER takes 6 weeks to start to work unlike the 10 days of cyclophosphamide
what are the indications and roles of methotrexate?
indications
- RA
- Malignancy
- psoriasis
- crohns disease
unlicensed roles
- inflammatory myopathies
- vasculitis
- steroid sparing agent in asthma
what is the mechanism of action of methotrexate?
IN MALIGNANT DISEASES
it competitively and reversibly inhibits dihydrofolate reductase (high affinity for it, higher than folate)
dihydrofolate reductase catalyses a key stage in purine and thymidine synthesis
methotrexate, therefore, inhibits DNA, RNA and protein synthesis in the S phase of the cell cycle
MECHANISM IN NON MECHANISM DISEASES E.G RA, PSORIASIS IS NOT CLEAR
what are the pharmacokinetics of methotrexate?
- oral biovaliability is lower than IM
- administered POM IM or S/C
if nausea occours with PO, swap to S/C
WEEKLY, not daily doses due to long half life
50% protein bound. NSAIDs displace however.
renally excreted
what are the adverse effects of methotrexate?
- mucositis
- marrow supression
- hepatitis and cirrhosis
- pneumonitis
- infection risk
- HIGHLY teratogenic, abortifacient
what are the indications of sulfasalazine?
for
- RA
- relieve pain and stiffness (an anti inflammatory - 5-aminosalicyclic acid component )
- fight infection (sulfapyridine molecule component)
safe in pregnancy though and very few DDI!!!
what are the immunological effects of sulfasalazine?
T cell
- inhibition of proliferation
- possible T cell apoptosis
- inhibition of IL-2 production
Neutrophil
- reduced chemotaxis
- reduced degranulation
what are the ADR of sulfasalazine?
- myelosuppression
- hepatitis
- Rash
- nausea
- abdo pain/vomitting
what are the effects of blocking TNFa?
- reduced inflammation
- reduced angiogenesis
- reduced joint distruction
