Immunosuppression + disease modifying therapy Flashcards
Describe rheumatoid arthritis
How does it occur?
- autoimmune multi system disease
- autoantibodies attack synovium
- inflammatory change + proliferation of synovium (pannus) > dissolution of cartilage and bone
Clinical features of rheumatoid arthritis
- morning stiffness >1 hour
- arthritis of 3> joints
- arthritis of hand joints
- symmetrical arthritis
- rheumatoid nodules
Non clinical features of rheumatoid arthritis
- Serum rheumatoid factor/anti CCP antibodies
- X ray changes LESS
Aims of rheumatoid arthritis treatment
Symptomatic relief
Prevention of joint destruction
What pro inflammatory markers are involved in rheumatoid arthritis?
IL1
IL6
TNF-a
Treatment strategy of rheumatoid arthritis
- early use of disease modifying drugs to prevent progression
- aim to achieve good disease control
- use of adequate dosage + combination of drugs
- avoidance of long term corticosteroids
What type of drug is avoided in long term treatment of rheumatoid arthritis?
Corticosteroids
Treatment goals of systemic lupus erythematous + vasculitis
- symptomatic relief
- reduction in mortality
- prevention of organ damage
- reduction in long term morbidity
Examples of anti-proliferative drugs
Azathioprine
Mycophenolate mofetil
Cyclophosphamide
What class of drug is azathioprine?
Anti-proliferative immunosuppressant
What are the uses of azathioprine?
- systemic lupus erthymatous + vasculitis
- IBS
- rheumatoid arthritis (weakly)
- atopic dermatitis
- bullous skin disease
- steroid ‘sparing’ drug
What is the mechanism of action of azathioprine?
Inhibition of synthesis of purines needed for DNA + RNA transcription
What are adverse drug reactions of azathioprine?
Immunosuppression
- risk of malignancy
- hepatitis
- infection risk
- bone marrow suppression
Examples of calcineruin inhibitiors
Ciclosporin
Tacrolimus
What is the mechanism of action of calcineurin inhibitors?
Two examples + how they differ
- ciclosporin binds to cyclophilin protein
- tacrolimus binds to tacrolimus binding protein
- drug/protein complexes bind to calcineruin + cause inhibition
- reduces helper T cell activity
What are the uses of calcineurin inhibitors?
Transplantation
Atopic dermatitis
Psoriasis
What are adverse drug reactions of calcineruin inhibitors?
Renal toxicity
What are important drug drug interactions of calcineurin inhibitors?
- CYP inducers e.g. antivirals + antifungals
- CYP inhibitors e.g.omeprazole, carbamazepine
What is the mechanism of action of ciclosporin?
Calcineurin inhibitor
- Binds to cylophilin protein
- Drug/protein complex bind calcineurin + prevents it’s action > prevents production of IL-2 + T helper cell activity
What is the mechanism of action tacrolimus?
Calcineurin inhibitor
- binds to tacrolimus-binding protein
- drug/protein complex binds to calcineruin + inhibits its action > prevents production of IL-2 + T helper cell activity
What class of drug is mycophenolate mofetil?
Anti-proliferative immunosuppressant
What are the uses of mycophenolate mofetil?
Transplantation
Induction + maintenance therapy for lupus nephritis
Maintenance of vasculitis
What is the mechanism of action of mycophenolate mofetil?
- prodrug
- inhibitors inosine monophosphate dehydrogenase (needed for guanosine synthesis)
- impairs B+T cell proliferation
Why does mycophenolate mofetil impair B+T cell proliferation but spare other rapidly dividing cells?
Other cells have guanosine salvage pathways
What are adverse drug reactions of mycophenolate mofetil?
N+V
diarrhoea
Myelosuppresion (bone marrow)
What class of drug is cyclophosphamide?
Anti-proliferative immunosuppressant
What are the uses of cyclophosphamide?
- Lymphoma, leukaemia, solid cancers
- lupus nephritis
- Wegener’s granulomatosis
What is the mechanism of action of cyclophosphamide?
- Prodrug: converted in liver to active form by CYP450
- inhibtis B+T cell proliferation
What are adverse drug reactions of cyclophosphamide?
- increased risk of bladder cancer, lymphoma + leukaemia
- infertility
- monitor RBC
Examples of DMARDs (disease modifying anti rheumatic drugs)
Methotrexate
Sulfasalazine
Mesalazine
Hydroxychloroquine
Rituximab
What should be monitored whilst a patient is taking cyclophosphamide?
FBC
What class of drug is methotrexate?
Disease modifying anti-rheumatoid drug
DMARD
What are the uses of methotrexate?
RA
Malignancy
Psoriasis
Crohn’s disease
What is the mechanism of action of methotrexate in malignancy?
- Competitively + reversible inhibtis dihydrofolate reductase
- inhibtis dihydrofolate > tetrahydrofolate needed in purine + pyrimidine synthesis
- therefore, inhibits DNA, RNA + protein synthesis
What is the mechanism of action of methotrexate in non malignant disease e.g. RA?
- NOT via anti-folate action
- inhibition of accumulation of adenosine
- inhibits T cell activation
- suppression of intracellular adhesion molecule expression by T cells
What are adverse drug reactions of methotrexate?
- mucositis
- bone marrow suppression
- hepatitis + cirrhosis
- pneumonitis
- infection risk
- highly teratogenic
How can some of methotrexate ADRs be treated?
Bone marrow suppression + mucositis both respond to folic acid supplementation
What class of drug is sulfasalazine?
Disease modifying anti-rheumatic drug
DMARD
What are the uses of sulfasalazine?
RA
IBD
What is the mechanism of action of sulfasalazine?
5-aminosalicylic acid donor in RA > immunosuppression + anti inflammatory effec
What are the adverse drug reactions of sulfasalazine?
- myelosuppression
- hepatitis
- rash
- N+V
- abdominal pain
What DMARD should be avoided in pregnancy?
Methotrexate
What is the mechanism of action of ‘biologicals’/MAB?
- TNF-a inhibiton
- reduces inflammation, angiogenesis + joint destruction
What are adverse drug reactions of biologicals/MAB?
Risk of TB reactivation > screen for latent TB before anti-TNF treatment
What class of drug is rituximab?
‘Biologicals’
Monoclonal antibody
What is the mechanism of action of rituximab?
Binds to CD20 on specific B cells > B cell apoptosis
What are uses of rituximab?
RA
Examples of systemic corticosteroids
Hydrocortisone
Prednisolone
Betamethasone
Dexamethasone
What are uses of systemic corticosteroids?
Perioperative N+V
Chemotherapy
Palliation
What is the mechanism of action of systemic corticosteroids?
- prevents IL1+6 production by macrophages
- inhibits all stage of T cell activation
What are adverse drug reactions of corticosteroids?
Insomnia
Increased appetite
Increased blood sugar
What should be tested for before prescribing azathioprine and why?
- TPMT activity
- involved in metabolism of azathioprine
- TPMT gene is highly polymorphic
- low/absent TPMT level increases risk of myelosuprresion
Relationship between TPMT activity and myelosuppresion risk
Low/absent TPMT activity = risk of myelosuppresion
