immunosurpressants Flashcards
RA cause
RA is a multi-system autoimmune disease, initially localised to the synovium, where inflammatory change and proliferation of synovium (pannus) leads to dissolution of bone and cartilage. The core of the pathogenesis is that pro-inflammatory cytokines (eg. IL-1, IL-6, TNF-α) outweigh the anti-inflammatory cytokines (eg. IL-4, TNF-β)
RA diagnostic criteria
clinical criteria (morning stiffness ≥1 hr, arthritis of ≥3 joints, arthritis of hand joints, symmetrical arthritis, rheumatoid nodules) and non-clinical criteria (serum rheumatoid factor/anti-CCP antibodies, x-ray changes)
RA treatment
early use of disease-modifying drugs to prevent joint destruction and provide symptomatic relief (avoid long-term corticosteroids cos side effects)
Name 6 immunosupressants
azathioprine calcineurin inhibitor cyclophosphamide methotrexate sulfasalazine rituximab
Azathioprine features
Immunosuppressant, inhibits de novo purine synthesis
Used as maintenance therapy for SLE and vasculitis, very weak evidence for RA, also might be used for IBDs, atopic dermatitis and bullous skin disease
Need to test for TPMT activity before prescribing (enzyme that metabolises 6-MP (active metabolite of azathioprine), without it the high 6-MP levels can cause myelosuppression)
azathioprine adverse effects
- Bone marrow suppression (monitor FBC)
- Increased risk of malignancy (esp. in transplanted patients - non Hodgkin’s lymphoma)
- Increased risk of infection
- Hepatitis (monitor LFT)
Name 2 calcineurin inhibitors
Ciclosporin, Tacrolimus
calcineurin inhibitor features
Immunosuppressants, active against helper T-cells, preventing production of IL-2 via calcineurin inhibition; CYP P450 inhibitor
Ciclosporin binds to cyclophilin protein, tacrolimus binds to tacrolimus-binding protein; drug/protein complexes bind to calcineurin
Used in transplantation, atopic dermatitis and psoriasis
Not often used in rheumatology due to renal toxicity (check BP and eGFR regularly)
calcineurin inhibitor adverse effects
- Bone marrow suppression (monitor FBC)
- Increased risk of malignancy (esp. in transplanted patients - non Hodgkin’s lymphoma)
- Increased risk of infection
- Hepatitis (monitor LFT)
cyclophosphamide features
Alkylating agent that cross-links DNA so it can’t replicate; suppresses B and T cell activity
Used for lymphomas, leukaemia, solid cancers, lupus nephritis, Wegener’s granulomatosis (ANCA-vasculitis)
Prodrug, gets metabolised by liver (cytochrome P450) to active metabolites, gets excreted by kidney
Mycophenolate mofetil safer and as effective in lupus nephritis
cyclophosphamide adverse effects
- Haemorrhagic cystitis (one of the active metabolites is toxic to bladder epithelium, prevented using aggressive hydration and/or mesna)
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility (risk relates to cumulative dose and patient age)
Methotrexate features
Used for RA, malignancy, psoriasis and Crohn’s
Malignancy: competitively and reversibly inhibits dihydrofolate reductase (catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis); basically it inhibits DNA, RNA and protein synthesis
RA: inhibits enzymes involved in purine synthesis causing accumulation of adenosine (has anti-inflammatory effects)
Methotrexate adverse effects
- Mucositis, marrow suppression (both respond to folic acid supplementation)
- Hepatitis, cirrhosis
- Pneumonitis
- Infection risk
- Highly teratogenic, abortifacient (stop 3 months prior to conception)
Sulfasalazine features
Inhibits T cell proliferation and IL-2 production, reduced chemotaxis and granulation of neutrophils
Used for RA and IBD
No carcinogenic potential, safe for pregnancy
sulfasalazine adverse effects
- Myelosuppression
- Hepatitis
- Rash
- Nausea, abdominal pain/vomiting
