Describe pathophysiology of RA
Either decrease of anti inflammatory or increase in pro inflammatory molecules
Leading to dissolution of articular cartilage and bone. Formation of a pannus (inflammatory cell infiltrate into synovium so fibrovascular layer over joint surface)
Clinical features of RA
Early morning stiffness (>1 hour)
Symmetrical pain and swelling of small joints (at least 3)
Rheumatoid nodules
Hand deformities
Immunosuppressants used to treat autoimmune disorders
Corticosteroids
Calcineurin inhibitors (tacrolimus and ciclosporin)
Azathioprine
Mycophenolate mofetil
Examples of DMARDs
Methotrexate Sulphasalazine Anti-TNF Rituximab Cyclophosphamide
MoA of corticosteroids
Inhibit T cell activation
Inhibit IL1 and IL6 (proinflammatory)
Indications for azothioprine
SLE
IBD
Vasculitis
What needs to be done prior to starting azathioprine
Test TPMT activity (metabolises azathioprine)
If lower activity need lower dose
MoA of azathioprine
Steroid sparing drug
Cleaved to 6-MP which decreases DNA synthesis
Side effects of azathioprine and what needs to be monitored
Bone marrow suppression - need to monitor FBC
Malignancy and infection risk
Hepatitis - need to monitor LFTs
Indications for calcineurin inhibitors
Transplant
Atopic dermatitis
Psoriasis
MoA of calcineurin inhibitors
Ciclosporin binds to cyclophilin
Tacrolimus binds to tacrolimus binding protein
Complexes bind to calcineurin which prevents calcineurin from activating T cell to start IL2 transcription
Sided effects of calcineurin inhibitors and what needs monitoring
Nephrotoxic - monitor GFR and BP
Diarrhoea and vomiting
Hyperlipidaemia - monitor cholesterol
Indications for MM
Transplant
Lupus nephritis
MoA of MM
MPA (prodrug) inhibits inosine monophosphate dehydrogenase so prevents guanine synthesis
This impairs B and T cell proliferation
Indications for methotrexate
RA
Malignancy
Psoriasis
Crohn’s
Interactions of methotrexate
Highly protein bound so is displaced by NSAIDs
Dose regimen of methotrexate
Weekly
MoA of methotrexate in non-malignancy dose
Inhibits purine metabolism and increases adenosine which reduces T cell activation
Contraindications for methotrexate
Chronic liver disease
Pregnancy
MoA of methotrexate in malignancy dose
Inhibits DHFR so inhibits folate synthesis which is needed for DNA synthesis (S phase of cell cycle)
Has greater toxicity in rapidly dividing cells
What needs to be done before starting methotrexate
LFTs
CXR
Pregnancy test if applicable
Side effects of methotrexate
Mucositis in malignancy dose Bone marrow suppression Hepatitis Cirrhosis Pneumonitis Infection risk
Indications for sulphasalazine
RA
IBD
What is contained in sulphasalazine and why does this make it good for treating IBD
5-ASA (active part)
Sulfapyridine (poorly absorbed by gut so drug stays at site of action)
MoA of sulphasalazine
Inhibits T cell proliferation
Inhibits IL2 production
Reduces neutrophil degranulation
Side effects of sulphasalazine
Bone marrow suppression Hepatitis Rash Abdominal pain Nausea (Side effects usually last <8 weeks)
What needs to be done prior to starting anti-TNF therapy
Latent TB screen
MoA of anti-TNF
anti inflammatory
Decreases angiogenesis
Inhibits metalloproteinases so slows joint destruction
Indications for rituximab
RA mainly
SLE
Vasculitis
MoA of rituximab
Monoclonal antibody which binds to CD20 causing B cell apoptosis
Indications for cyclophosphamide
Leukaemia
Lymphomas
Lupus nephritis
ANCA vasculitis
MoA of cyclophosphamide
Prodrug cleaved to 4-HC
Cross links DNA and suppresses B and T cell activity
Side effects of cyclophosphamide
Bladder cancer
Lymphoma
Leukaemia
Infertility (proportional to dose and age)
What should be done before starting pre menopausal women on cyclophosphamide
Freeze eggs
Infertility counselling
How does cyclophosphamide affect the bladder and what can prevent this
Acrolein is a cyclophosphamide metabolite which is toxic to bladder epithelium and causes haemorrhagic cystitis
Prevent by high hydration and mesna (binds to acrolein)