Immunosupression Flashcards
What happens in rheumatoid arthritis?
This is a chronic inflammatory autoimmune disease characterised by inflammation of the synovial joints. The immune system attacks the synovium where rheumatoid factor is forming immune complexes with IgG. This stimulates CD4 cells and macrophages which release pro inflammatory cytokines (TNF-a and IL-6) which activates synoviocytes leading to synovial hyperplasia, osteoclast and protease activity leading to bone and cartilage destruction. This is a type III hypersensitivity reaction.
What symptoms would you expect in somebody suffering from RA?
Symmetrical distal small joint synovitis - heat, redness, swelling, pain, stiffness (particularly in the morning or after inactivity)
Hand deformities
Distal interphalangeal is only affected in osteoarthritis
Describe the pathophysiology of systemic lupus erythematous
This is an autoimmune disorder where autoantibodies are produced and form immune complexes in microvasculature leading to complement activation and inflammation (malar rash). They can also deposit in the basement membrane of skin and kidneys
Describe the pathophysiology of systemic vasculitis
The immune system attacks the blood vessels (triggered by infection, medicine, other condition, idiopathic) leading to a pupuric rash (internal bleeding).
Corticosteroid profile
Indications - RE (others include asthma, transplantation, SLE, vasculitis)
Pharmacokinetics - taken orally (inhaler for asthma)
Mechanism - binds to glucocorticoid receptors and the complex enters the nucleus to down regulate translation of DNA (genes for inflammatory response) preventing IL-1 and IL-6 production and T cell activation
ADRs - hypercholesterolaemia, cataracts, weight gain, striae, osteoporosis, hypertension, increased susceptibility to infection, adrenal suppression (don’t suddenly stop)
Name 2 DMARD drugs
Methotrexate, sulfasalazine
Methotrexate DMARD profile
Indications - RA, IBD
Contraindications - infection, ascites, immunodeficiency, pleural effusion
Pharmacokinetics - oral, once weekly, half life of 8-10 hours but is metabolised to polyglutamates with long half life, 50% protein bound, renal elimination
Mechanism - inhibits purine metabolism which leads to increased adenosine which acts on GPCRs on inflammatory and immune cells to reduce their activity and reduce T cell activity.
ADRs - mucositis (supplement folic acid), myelosupression (supplement with folic acid), cirrhosis, increased risk of infection, TERATOGENIC, ABORTIFACIENT
DDIs - immunosuppressants, anti-cancer drugs, drugs affecting renal flow and elimination, NSAIDs (protein binding displaces)
Monitoring - baseline CXR, FBC (myelosupression), LFT (hepatic damage), U&Es and creatinine (renal function)
Sulfasalazine profile
Indications - RA, IBD
Contraindications - urinary or intestinal blockage
Pharmacokinetics - oral (RA), oral/rectal (IBD), made of 5-aminosalicylate (5-ASA) and sulfapyridine. It is poorly absorbed until it reaches the colon where bacteria breaks it down. 5-ASA is the active component but sulfapyridine is needed for it to reach the target area but also causes ADRs
Mechanism - inhibits T cell proliferation and IL-2 production (may cause T cell apoptosis) for IBD but the mechanism in RA is not understood.
ADRs - nausea, fatigue, headache, myelosupression, hepatitis, allergic rash
What are the main immunosuppressants?
Corticosteroids - e.g. Prednisolone
Azathioprine
Mycophenolate mofetil
Cyclophosphamide
Calcineurin inhibitors - ciclosporin, tacrolimus
Biological agents - rituximab, adalimumab, infliximab, etanercept
What are the mechanisms of the biological agents and their ADRs?
Rituximab
Mechanism - antibody that binds specially to CD20 found on B cells (not stem cells) and activates complement mediated B cell lysis
ADRs - increased risk of infection, hypersensitivity, blocked immune response
Etanercept (SC), adalimumab (SC), infliximab (IV)
Mechanism - these are anti-TNF agents that are antibodies which bind to TNF-a to block its interaction witH TNF receptors thus reducing the recruitment of further cytokines (IL-1 and IL-6)
ADRs - skin infection, soft tissue infection, TB reactivation, increased risk of cancer in those who have had it previously
Azathioprine profile
Indications - SLE, vasculitis, RA, IBD, transplants, leukaemia
Contraindications - absent TPMT activity
Pharmacokinetics - oral, prodrug converted to 6-MP and then to a purine analogue, eliminated by TPMT which is subject to polymorphism (can lead to under or over treatment)
Mechanism - acts selectively on cells with high mitotic rate (steroid sparing) by blocking purine synthesis (by the purine analogue) thus reducing DNA and RNA synthesis
ADRs - myelosupression, increased risk of infection, hepatitis, NHL
DDIs - ACE inhibitors and cotrimoxazole in renal transplant patients can lead to an exaggerated leukopenic response, allopurinol (gout) inhibits metabolism (increases effect)
Monitoring - TMPT levels, FBC (myelosupression), LFT (hepatitis)
Mycophenolate mofetil profile
Indications - transplants
Pharmacokinetics - oral, prodrug metabolised to mycophenolic acid, renal excretion
Mechanism - mycophenolic acid inhibits inosine monophosphate dehydrogenase required for guanine synthesis in B cells and T cells (other cells have a guanosine salvage pathway)
ADRs - myelosupression, increased risk of infection, leukopenia, nausea
Cyclophosphamide profile
Indications - cancer chemotherapy, RA
Contraindications - haemorrhagic cystitis
Pharmacokinetics - oral/IV (chemotherapy), IV (RA and others), prodrug activated by CYP450 to produce alkylating electrophilic cytotoxic metabolites (phosphoramide mustard)
Mechanism - the metabolites cross link DNA so cells can not replicate (selective to cells with high mitotic rate e.g. B and T cells
ADRs - haemorrhagic cystitis, bladder cancer, leukaemia, lymphoma
Monitoring - significant toxicity, monitor FBC, U&Es
Calcineurin inhibitors profile - ciclosporin and tacrolimus
Indications - severe RA, transplants
Contraindications - ocular infection, abnormal renal function, malignancy, hypertension, uncontrolled hypertension
Pharmacokinetics - oral, excreted in faeces
Mechanism - lipophilic polypeptide diffuses into T cell and binds to cyclophilin to form a complex that binds to calcineurin (unbound stimulates nuclear factor of activated T cells). The nuclear factor can not enter the nucleus to promote cytokines production
ADRs - nephrotoxic, hepatotoxic, increased risk of infection, hyperkalaemia
DDIs - CYP34A inducers/ inhibitors. G
Monitor - liver, kidney, FBC
How would you treat RA?
Pain relief - NSAIDs
DMARD x 2 (methotrexate + another) + short course of corticosteroids
If unresponsive try different DMARDs
If unresponsive consider biological agent + DMARD
Use corticosteroids in flares
