Immunosuppressants Flashcards
(33 cards)
Lost the 3 main autoimmune diseases rheumatologist deal with
Inflammatory arthritis - rheumatoid arthritis
Systemic lupus erythematous
Systemic vasculitis
(Bones, joints, immune system)
What is rheumatoid arthritis?
1% UK
Autoimmune multisystem
Initially localised synovium
Inflammatory change and proliferation of synovium -> inflammatory pannus -> leading dissolution of cartilage and bone
Pathogenesis of rheumatoid arthritis
Dendritic cells present self antigens to autoreactive T cells -> cytokines* -> activate autoreactive B cells -> autoantibodies (rheumatoid factor/ anti-CCP antibodies) + immune complexes + immune cells (macrophages) deposition in joints
Metalloproteinases + other proteinases break down the extracellular matrix
- imbalance between pro-inflammatory (IL-1/IL-6/TNF-alpha) & anti-inflammatory (IL-4/ TGF- beta) cytokines
How do we diagnose RA?
Clinical criteria: Morning stiffness >_1hr Arthritis of _>3 joints Arthritis of hand joints Symmetrical arthritis Rheumatoid nodules
Non-clinical criteria:
Serum rheumatoid factor/ anti-CPP antibodies
X-ray changes (periarticular osteopenia, joint space narrowing, juxta-articular bony erosions, subluxation and gross deformity)
What’s the treatment strategy for rheumatoid arthritis?
Early use of disease modifying drugs
Aim to achieve good disease control
Use of adequate dosages
Use of combination of drugs
Avoidance of long term corticosteroids
Remission with drugs ideal
Systemic lupus erythematous effects
Systemic
Ulcers, seizures, psychosis, depression, pericarditis, endocarditis, myalgia, oedema, hypertension, renal failure, miscarriages, menstruated cycle irregularities, butterfly rash, vasculitis, anaemia, thrombocytopenia. Leukopenia, thrombosis, circulating autoantibodies/ immune complexes
90% women, develop between 15-45yrs
African
What is vasculitis?
Inflammation of blood vessels
Thickening/ weakening/ narrowing/ scarring can restrict blood flow -> organ/ tissue damage
Treatment goals in SLE and vasculitis
Symptomatic relief
Reduction in mortality
Prevention organ damage
Reduction long term morbidity caused disease and drugs
Give some examples of immunosuppressants
Corticosteroids
Methotrexate
Ciclosporin
Cyclophosphamide
How do corticosteroids work?
Binds to GRh receptor -> triggers intracellular cascade Prevent IL-1/ IL-6 production by macrophages
Inhibit all stages of T cell activation
Side effects of steroid use
Weight gain Thrush Immunosuppression Cataracts Bruising Glaucoma Osteoporosis Decreased muscle girth
‘Accelerated old age’
When are corticosteroids prescribed for autoimmune conditions?
RA: severe/ flare ups
Lupus: reduce swelling/ tenderness/ pain, once reduced lower dose slowly
Vasculitis: control inflammation, if needed for maintenance therapy lowest dose possible
Why is it important to slowly withdraw from corticosteroid therapy?
Causes: Adrenal cortex -> cortisol
Long term use: side effects + reduced feedback HPAA on adrenal gland (adrenal insufficiency) -> reduced appetite, fatigue, weight loss, nausea, V&D, abdo pain, life threatening
Need time for adrenal glands to return to normal secretion
List some disease modifying anti-rheumatic drugs (DMARDSs)
Non- biological:
Sulphasalazine
Hydroxychloroquine
Biologics:
Anti-TNF agents
Rituximab
IL-6 inhibitors, JAK inhibitors
Azathioprine mechanism of action and use
Anti-proliferation agent
Azathiprine cleaved to 6-MP (TPMT) -> 6-MeMP inactive + 6-TU inactive + TIMP (TPMT) -> 6-MeMPN (inhibits de novo purine synthesis) + 6-TGN (incorporation into DNA)
Overall stops DNA/ RNA synthesis & so immune cell synthesis
Slide 20
Use: SLE/ vasculitis - maintenance therapy RA - weak evidence IBD Bulbous skin disease Atopic dermatitis Steroid sparing drug
Why is it important to test TPMT activity before prescribing azathioprine?
Azathioprine cleaved to 6-MP which is metabolised by TPMT
TPMT is highly polymorphic - individuals have varying amounts of the enzyme
Low/ absent levels = risk of myelosupression
Adverse effects of azathioprine
Bone marrow suppression (monitor FBC)
Increased risk of malignancy (esp transplant patients) - same as all immunosuppressants
Increased risk infection
Hepatitis (monitor LFTs)
Mycophenolate use and mechanism of action
- primarily transplantation
- good efficacy as induction and maintenance therapy for lupus nephritis/ vasculitis maintenance
MOA:
Prodrug derived from fungus penicillium stolomiferum
Inhibits inosine monophosphate dehydrogenase (needed for guanosine synthesis)
Impairs B and T cell proliferation
Spares other rapidly dividing cells (guanosine salvage alternative pathway in other cells)
Mycophenolate mofetil adverse effects
Nausea Vomiting Diarrhoea Myelosuppression Increased risk cancer (esp skin)
Less immunosuppression than azathiprine
Uses of calcineurin inhibitors, examples, adverse effects
Widely used in transplantation
Atopic dermatitis
Psoriasis
Not often used in rheumatology - renal toxicity, check BP and eGFR regularly
Ciclosporin - gums to swell
and tacrolimus
Multiple drug reactions as metabolised by cytochrome P-450 e.g. inducers (decrease levels) rifampicin, omeprazole and inhibitors (increase) antifungals, HIV antivirals
Calcinuerin inhibitors mechanism of action
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 -> exerts phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription
Cyclophosphamide mechanism of action, uses
Cytotoxic agent - alkylation gets agent - cross links DNA so it can’t replicate
Suppresses T/ B cell activity
Uses:
Lymphoma, leukaemia, solid cancers, lupus nephritis, wegner’s granulomatosis (ANCA- vasculitis)
Cyclophosphamide adverse effects
Excreted by the kidney, acrolein another metabolite is toxic to the bladder epithelium -> haemorrhage cystitis (bleed form bladder)
Prevented through aggressive hydration &/or mesna
Increased risk: bladder cancer, lymphoma, leukaemia
Infertility
Monitor FBC
Adjust dose in renal impairment
Methotrexate uses
Gold standard treatment for RA Malignancy Psoriasis Crohn’s disease Ectopic pregnancies (obliterates folic acid) Vasculitis Steroid sparing agent asthma
