Immunosuppresion & disease modifying therapy Flashcards
What is rheumatoid arthritis?
Autoimmune multi-system disease
Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone
How is RA diagnosed?
Critical criteria:
- Morning stiffness >1 hour
- Arthritis of >3 joints
- Arthritis of hand and wrist joints
- smmetrical arthritis
- Rhematoid nodules
Non clinical criteria:
- serum rheumatoid factor/Anti CCP antibodies
- X-ray changes
What are the treatment goals for treating RA?
- Symptomatic relief
- Prevention of join destruction
What are the treatment goals for SLE and vasculitis?
- Symptomatic relief e.g arhralgia and Raynaud’s phenomenom
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
How do corticosteroids work as a DMARD?
- Prevent interleukin IL-1 and IL-6 production by macrophages
- Inhibit all stages of T cell activation
What are some of the side effects of corticosteroids?
- weight gain
- thrush
- immunosuppresion
- glaucoma
- cateracts
- blood glucose changes
- accelerates aging
- mood changes
- bruising
What is azathioprine used to treat?
- Maintenance therapy in SLE and vasculitis
- weak evidence of benefit in RA
- used in inflammatory bowel disease
How can effects of azothioprine differ between individuals?
- 6-MP metabolised by TPMT (thiopurine methyltransferase)
- TPMT gene highly polymorphic
- Individuals with low/ absent TPMT levels have risk of myelosuppression
- TPMT test done before prescribing
What is the mechanism of azathioprine?
- Azathioprine cleaved to 6 mercaptopurine (6-MP)
- Anti-metabolite decreases DNA and RNA synthesis
- Immune cells can’t go on to cause inflammatory response
What are some of the adverse effects of azathioprine treatment?
- Bone marrow suppression (monitor FBC)
- Increased risk of malignancy (true of all immunosuppressants)
- increased risk of infection
- hepatitis (monitor LFTs)
When are calcineurine inhibitors used in practice?
- Atopic dermatitis and Psoriasis
Name 2 calcineurin inhibitors
- Ciclosporin
- Tacrolimus
What is the MoA of ciclosporin and tacrolimus?
- Active against helper T cells - prevents production of IL-2 via calcineurin inhibition
- Ciclosporin- binds to cyclophilin protein
- Tacrolimus binds to tacrolimus binding protein
When is mycophenolate mofetil used in practice?
- primarily in transplanation
- good efficacy as induction and maintenance therapy for SLE and Vasculitis maintenance
What is the mechanism of action of mycophenolate mofetil?
- Pro-drug derived from fungus penicillum stoloniferum
- Inhibits inosin monophosphate dehydrogenase (required for guanosin synthesis
- Impairs B and T cell proliferation
- Spares other rapidly dividing cells
What are some of the adverse effects of mycophenolate mofetil?
- Nausea + Vomiting
- Diarrhoea
- Myelosuppression (most serious)
- Mucocitis- ulceration and sores in mouth
How does cyclophosphamide work?
- Cytotoxic agent
- Alkylating agent- cross links DNA so that it can’t replicate
- Suppresses T and B cell activity
In what conditions is cyclophosphamide indicated?
- Lymphoma
- Leukaemia
- Solid cancers
- Lupus nephritis
- Wegener’s granulomatosis
What are the pharmacodynamics of cyclophosphamide?
- Prodrug needs activating by CYP450 in liver
- Active metabolite is 4-hydroxycyclophosphamide
- Exists in equilibrium with its tautomer aldophosphamide
How is cyclophosphamide excreted, why can this be problematic?
- Excreted by the kidney
- Acrolein (a metabolite) is toxic to bladder epithelium → haemorrhagic cystitis
- Can be prevented by aggressibe hydration and or Mesna
What important considerations must you make when prescribing cyclophosphamide?
Significant toxicity
- increased risk of bladder cancer, lymphoma and leukaemia
- Infertility
- Monitor FBC
- Adjust dose in renal impairment
What is the gold standard for treatment of rheumatoid arthritis?
Methotrexate
What conditions other than RA, is methotrexate used to treat?
- Malignancy
- Psoriasis
- Crohn’s disease
- Ectopic pregnancy
What is the mechanism of action of methotrexate?
- Competitive, reversible inhibitor of DHFR (dihydrofolate reductase)
- Affinity x1,000 more than folate for DHFR
- Inhibits synthesis of DNA, RNA and proteins
- Cytotoxic during the S-phase of the cycle
- Greater toxicity in rapidly dividing cells
Mechanism in non-malignant disease is unclear
How can you administer methotrexate?
- PO
- IM
- SC
How is methotrexate dosed?
Given weekly not daily
Given with folate supplement
Otherwise: can affect liver and kidney if given daily
What is the effect of giving methotrexate and NSAIDs together?
Methotrexate is 50% protein bound
NSAIDs can displace methotrexate
What are some of the side effects of methotrexate?
- Mucositis
- Marrow suppression
- Hepatitis
- Cirrhosis
- Pneumonitis
- Infection risk
- Highly teratogenic → used as an abortifacient
What is sulfasalazine?
A conjugate of salicylate designsed to relief pain and stiffness
What immunological effects does sulfasalazine have?
T cells:
- inhibits proliferation
- possible T cell apoptosis
- inhibits IL-2 production
Neutrophils
- reduces chemotaxis
- reduces degranulation
Why is sulfasalazine effective in treatment of IBD?
- poorly absorbed
- Mainly active within the intestine
What are some of the side effects of sulfasalazine?
Mild
- nausea
- adbo pain/ vomiting
Adverse
- myelosuppression
- hepatitis
- rash
What are biologicals?
Recombinant DNA technoligcal producing substances that are idnetical to the body’s own signalling proteins
What are some of the effects of blocking TNF alpha?
- Decrease inflammation
- Decreased angiogenesis
- lowers VEGF levels
- Decreased joint destruction
What is one of the main risks of anti-TNF therapy?
TB reactivation
TNFalpha is essential for development of maintenance of granulomas - inhibition will break down granuloma
Need screening for latent TB
How does rituximab work?
Monoclonal antibody- binds to CD20 found of a subset of B cells
B cells; present antigens to T cells, produce cytokines and antibodies → rituximab causes B cell apoptosis
