Immunosuppression and disease modifying therapy Flashcards
What is rheumatoid arthritis?
- An autoimmune multi-system disease
- Initially localised to synovium
- Inflammatory change and proliferation of synovium (pannus) causes dissolution of cartilage and bone
What is the pathogenesis of rheumatoid arthritis?
- Imbalance between pro-inflammatory mediators (IL-1, IL-6, TNF a) and anti-inflammatory mediators
What is the strategy for rheumatoid arthritis treatment?
- Early use of disease-modifying drugs
- Aim to achieve good disease control
- Use of adequate doses
- Use of combinations of drugs
- Avoidance of long-term corticosteroids
- Aim to achieve remission assisted by drugs
What are the treatment goals in SLE and vasculitis?
- Symptomatic relief
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and drugs
Give some examples of immunosuppressants
- Corticosteroids
- Azathioprine
- Mycophenolate mofetil
- Ciclosporin
- Tacrolimus
- Cyclophosphamide
- Methotrexate
- Sulfasalazine
What is the mechanism of action of corticosteroids?
- Prevent IL-1 and IL-6 production by macrophages
- Inhibit all stages of T cell activation
- Not very targeted in its approach
Which rheumatoid arthritis drugs are non-biologics?
- Sulfasalazine
- Methotrexate
- Azathioprine
Which rheumatoid arthritis drugs are biologics?
- Anti-TNF agents
- Rituximab
- IL-6 inhibitors, JAK inhibitors
What are the uses of azathioprine?
- Maintenance therapy in SLE and vasculitis
- Not especially useful in RA
- IBD
- Steroid sparing drug
What is the mechanism of action of azathioprine?
- Cleaved to 6-mercaptopurine (6-MP)
- Acts as an anti-metabolite
- Decreases DNA and RNA synthesis (purine synthesis)
- Inflammatory cells are inhibited
What are the adverse effects of azathioprine?
- Bone marrow suppression
- Monitor FBC
- Increased risk of malignancy
- Increased risk of infection e.g. Hepatitis
- Monitor LFTs
Give some examples of calcineurin inhibitors?
- Ciclosporin
- Tacrolimus
What are calcineurin inhibitors used to treat?
- Used in transplantation
- Atopic dermatitis
- Psoriasis
- Not often used in rheumatology - renal toxicity
- Check BP and eGFR regularly
- Multiple drug interactions are possible (CYP450)
What is the mechanism of action of calcineurin inhibitors?
- Active against helper T-cells
- Prevents production of IL-2 via calcineurin inhibition
- Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
- Drug/protein complexes bind calcineurin
What are the uses of mycophenolate mofetil in practice?
- Primarily in transplantation
- Good efficacy as induction and maintenance therapy for lupus nephritis
- Vasculitis maintenance
What is the mechanism of action of mycophenolate mofetil?
- Inhibits inosine monophosphate dehydrogenase
- Required for guanosine synthesis
- Impairs B and T cell proliferation
- Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells)
What are the adverse effects of mycophenolate mofetil?
- Most common include nausea, vomiting, diarrhoea
- Most serious is myelosuppression
What is the mechanism of action of cyclophosphamide?
- Alkylating agent - cross-links DNA so that it cannot replicate
- Many immunological effects - suppresses T cell activity and B cell activity
What are the indications of cyclophosphamide?
- Lymphoma, leukaemia, solid cancers
- Lupus nephritis
- Wegener’s granulomatosis
What are the pharmacodynamics of cyclophosphamide?
- prodrug
- Converted in the liver (cytochrome P450) to active forms
What are the pharmacokinetics of cyclophosphamide?
- Excreted by the kidney
- Can result in haemorrhagic cystitis
- Can be prevented through the use of aggressive hydration and/or Mesna
What are the important considerations of cyclophosphamide?
- Significant toxicity
- Increased risk of bladder cancer, lymphoma, and leukaemia
- Infertility (especially between ages 25-30)
- Monitor FBC
- Adjust dose in renal impairment
What are the indications for methotrexate?
- Gold standard for rheumatoid arthritis
- Malignancy
- Psoriasis
- Crohn’s disease
- Vasculitis
What is the mechanism of action of methotrexate?
- Competitively and reversibly inhibits dihydrofolate reductase (DHFR)
- DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate
- Tetrahydrofolate is key for purine and thymidine synthesis
- Methotrexate therefore inhibits synthesis of DNA, RNA and proteins
- Greater toxic effect on rapidly dividing cells which replicate their DNA more often
What is the mechanism of action of methotrexate in non-malignant disease?
- Mechanism of action is not clear
- Not via anti-folate action
How is methotrexate administered?
- Administered PO, IM, or SC
- Weekly not daily dosing
- Metabolised to polyglutamates with long half lives
What are the adverse effects of methotrexate?
- Mucositis and marrow suppression (both respond to folic acid supplementation)
- Hepatitis
- Cirrhosis
- Pneumonitis
- Infection risk
- Highly teratogenic
What are the benefits of methotrexate?
- Well-tolerated
- Improved QOL
- Retardation of joint damage
- Good adherence
What is the mechanism of action of sulfasalazine?
- T cell - inhibits proliferation and causes apoptosis
- Inhibits IL-2 production
- Reduced chemotaxis and degranulation of neutrophils
What are the adverse effects of sulfasalazine?
- Mainly due to sulfapyridine moiety - myelosuppression, hepatitis, rash
- Milder side effects include nausea and abdo pain/vomiting
What are the benefits of using sulfasalazine?
- Effective
- Favourable toxicity
- Long term blood monitoring not always needed
- Very few drug interactions
- No carcinogenic potential
- Safe in pregnancy
Give 3 examples of monoclonal antibodies used to treat RA?
- Adalimumab (Humira) - binds TNFa
- Infliximab (Remicade) - binds TNFa
- Rituximab (Mabthera) - depletes B cells
What are the effects of blocking TNFa?
- Decreases inflammation
- Decreased angiogenesis
- Decreased joint destruction
What are the risks of Anti-TNF therapy?
- TB reactivation
- TNFa is essential for development and maintenance of granulomata
- Screen for latent TB before anti-TNF treatment
