Immunosuppression

Question 1

Explain the pathophysiology of rheumatoid arthritis

Answer 1

• Rheumatoid arthritis initially localised to the synovial joints
• Inflammatory change and proliferation of synovial membrane leads to dissolution of cartilage and bone
  
  • T-cells secrete cytokines including IL-y, IL-17 which recruits macrophages
  • More cytokines are produced, including IL-1, IL-6, TNF-α
• Proliferation of synovial cells leads to pannus (thick swollen synovial membrane)
• Inflammatory cytokines recruit T cells which stimulate osteoclasts to break down bone
• Antibodies also recruited, including rheumatoid factor which form immune complexes leading to activation of complement system
  - Chronic joint inflammation and injury

Question 2

Describe the systems affected and presentation of rheumatoid arthritis

Answer 2

• Inflammatory cytokines affect multiple organ systems
  
  • Skeletal muscle - protein breakdown
  • Skin - rheumatoid nodules
  • Brain - IL-1, IL-6 pyogenes lead to fever
  • Blood vessel - vasculitis
• Affects multiple joints, symmetrical, flares, stiffness

Question 3

Describe the aims of rheumatoid arthritis treatment

Answer 3

• Diagnoses of rheumatoid arthritis involves looking at symmetry of arthritis, rheumatoid nodules, serum rheumatoid factor and x-ray changes
• Treatment includes disease modifying antirheumatic drugs (DMARDs) + corticosteroids
• Aim of rheumatoid arthritis treatment is for symptomatic relief and prevention of joint destruction
  
  • Early use of disease-modifying drugs
  • Use of combinations of drugs with adequate dosages to control the disease
    
    • Avoidance of long-term corticosteroids

Question 4

Describe the aim of lupus treatment

Answer 4

• Aim of lupus and vasculitis treatment is for symptomatic relief, reduction in mortality, prevention of organ damage, reduction in long term morbidity caused by disease and by drugs
• Drugs include NSAIDs, corticosteroids, antimalarials, immunosuppressants

Question 5

Describe the mechanism of corticosteroid action

Answer 5

• Prevent IL-1 and IL-6 production by macrophages by changing the transcription of mRNA responsible for its production
  
  • Reduces pro-inflammatory marker release from macrophages, thus acts as anti-inflammatory drug
• Inhibit all stages of T-cell activation

Question 6

State the common ADRs of systemic corticosteroids

Answer 6

• Osteoporosis
• Cataracts
• Hypertension
• Diabetes
• Weight gain

Question 7

Describe the mechanism of methotrexate

Answer 7

• Acts as chemotherapy agent and immunosuppressant
• Mechanism of action for malignant diseases
  
  • Competitively and reversibly inhibits DHFR
  • DHFR is responsible in catalysing the synthesis of DNA, RNA and proteins
  • Methotrexate acts specifically during DNA and RNA synthesis and thus has a greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
• Mechanism of action in non-malignant disease not clear
  
  • Possible mechanism includes inhibition of enzymes involved in purine metabolism, inhibition of T cell activation

Question 8

Describe the administration, dosing and plasma transport of methotrexate

Answer 8

• Administered orally, IM or subcutaneous
• Weekly dosing - long half lives mean only 1 dose a week
• 50% protein bound - NSAIDs displace methotrexate, leading to a greater response

Question 9

List the main ADRs of methotrexate

Answer 9

• MeTH IP
• Mucositis - can be resolved with folic acid supplements
• Marrow suppression - blood tests needed, can be resolved with folic acid supplements
• Highly teratogenic - must not be pregnant or thinking of near-future pregnancy
• Hepatitis, cirrhosis
• Infection risk
• Pneumonitis

Question 10

Describe the mechanism of action of sulphasalazine

Answer 10

• Acts as DMARD
• Mechanism of action
  
  • Inhibits T-cell proliferation and induces T cell apoptosis
  • Inhibits neutrophil by reducing chemotaxis and degranulation (release of cytotoxins)
  • Poorly absorbed - main activity is within intestine - effective in IBD

Question 11

State ADRs of sulphasalazine

Answer 11

• MR GH
• Myelosuppression - anaemia
• Hepatitis
• Rash
• GI symptoms - pain, vomiting

Question 12

Describe the clinical monitoring required in methotrexate and sulphasalazine

Answer 12

• Methotrexate required FBC, U&E, LFT every 2 weeks
• Sulphasalazine - no long term blood monitoring required
  
  • Very few drug interactions
  • No carcinogenic potential
    
    • Safe in pregnancy

Question 13

Describe the mechanism of azathioprine

Answer 13

• Acts as immunosuppressant
• Used in SLE and vasculitis as maintenance therapy and occasionally RA and IBD
• Mechanism of action
  
  • Cleaved to 6-MP, which acts as an anti-metabolite decreasing DNA and RNA synthesis

Question 14

Describe the monitoring of azathioprine

Answer 14

• TPMT test needed before prescribing - low TPMT levels = risk of myelosuppression
• Monitor FBC and LFT

Question 15

List the ADRs of azathioprine

Answer 15

• BIHI
• Bone marrow suppression - monitor FBC
• Increased risk of malignancy
• Increased risk of infection
• Hepatitis - monitor liver function

Question 16

Describe the mechanism of mycophenolate mofetil

Answer 16

• Immunosuppressant primarily used in transplantation and maintenance therapy for lupus
• Mechanism of action
  
  • Prodrug inhibiting DNA synthesis
    
    • Impairs B and T cell proliferation

Question 17

List the main ADRs of mycophenolate mofetil

Answer 17

• Nausea, vomiting, diarrhoea

- Myelosuppression

Question 18

Describe the mechanism of cyclophosphamide

Answer 18

• Acts as chemotherapy agent and immunosuppressant
• Used in lupus, lymphoma, leukaemia, solid cancers, ANCA vasculitis
• Mechanism of action
  
  • Cytotoxin
  • Alkylating agent - cross links DNA so that it cannot replicate
  • Suppresses T and B cell activity

Question 19

Describe the ADRs and clinical monitoring of cyclophosphamide

Answer 19

• ADRs
  
  • Significant toxicity
  • Increased risk of bladder cancer, lymphoma, leukaemia
  • Infertility
• Clinical monitoring
  
  • Monitor FBC for toxic effects
    
    • Adjust dose in renal impairment

Question 20

Explain the mechanism and monitoring of calcineurin inhibitors

Answer 20

• Mechanism of action
  
  • Active against T helper cells, preventing production of IL-2
• Monitor BP and eGFR regularly
• Multiple drug interactions are possible as metabolised by CYP450

Question 21

Describe the use of biological molecules as RA treatment

Answer 21

• Extracted from living systems - whole blood, stem cell therapy
• Recombinant DNA technology produces substances that are nearly identical to the body’s own key signaling proteins (growth hormone, EPO)
• Monoclonal antibodies made to block any given substance in the body or to target any specific cell type
• Receptor constructs (fusion proteins), usually based on a naturally occurring receptor, acting to block it

Question 22

Describe the mechanism of drugs that block TNFa

Answer 22

• Reduces inflammation by affecting cytokine cascade
  
  • Recruitment of leukocytes to joint to target foreign material
• Reduces angiogenesis
• Reduces joint destruction

Question 23

Describe how TNFa blockers increase risk of TB infection

Answer 23

• Risk of TB reactivation
• TNFα is released by macrophages in response to TB infection
• TNFα essential for development and maintenance of granulomas - reduction in TNFα leads to breakdown of granulomas and thus releasing the latent TB bacteria within it
• Screen for latent TB before anti-TNF treatment - Quantiferon-TB gold test (blood test)