8.1 Immunosuppression Flashcards
What is rheumatoid arthritis?
Multi-system disease localised to the synovium
Antibodies attack the snyovial membrane which leads to:
- Inflammatory change and proliferation of the the synovium (pannus)
- Pannus formation
- Erosion of cartilage and bone
What is the pathogenesis of rheumatoid arthritis?
Imbalance between pro-inflammatory and anti-inflammatory mediators
Pro-inflammatory
IL-1
IL-6
TNF-alpha
T and B cells
Rheumatoid factor
Anti-CCP antibodies
Anti-inflammatory
IL-4
TGF-beta
What are the clinical features of rheumatoid arthritis?
Morning stiffness for more than an hour
Arthritis of more than 3 joints
Arthritis of MCPJ/PIPJ
Symmetrical arthritis
Rheumatoid nodules
What are the non-clinical features of rheumatoid arthritis?
- Serum rheumatoid factor/ Anti-CCP antibodies
- X-ray changes- SPADES
- Soft-tissue swelling
- Peri-articular osteoporosis
- Absent osteophytes
- Deformity
- Erosions (later feature)
- Subluxation (later feature)
What are the treatment goals of rheumatoid arthritis?
Symptomatic relief
Prevention of join destruction
What is the treatment strategy for rheumatoid arthritis?
- Early use of disease-modifying drugs
- Good disease control
- Adequate dosages
- Combinations of drugs
- Avoidance of long-term corticosteroids
What is systemic lupus erythematosus?
Auto-immune condition affecting the entire body
Systemic LUPUS Erythamotsus
Sleepy (extreme fatigue) and myalgia
Leukopenia, thrombocytopenia,anaemia
proteinUria, renal failure
Psychosis,seizures and cognitive dysfunction
Ulcers in eyes,nose, mouth
Skin rash over face and cheeks
Emesis, nausea and diarrhoea
What is vasculitis?
Inflammation of the vessels
Affects large, medium or small vessels
How does vasculitis present?
Purpura rash
Lung consolidation on X-ray due to blood
Glomerulonephritis- coke coloured urine
What are the treatment goals in SLE & vasculitis?
- Symptomatic relief e.g. arthralgia, Raynauds
- Reduction in mortality
- Prevent organ damage
- Reduction in long term morbidity caused by disease and drugs
What are some examples of immunosuppressants?
Corticosteroids
Methotrexate
Ciclosporin
Cyclophosphamide
How do corticosteroids work?
Prevent IL-1 and IL-6 production by macrophages
Inhibits all stages of T-cell activation
How are other disease-modifying anti-rheumatic drugs (DMARDs) classified?
Non-biologics
- Methotrexate, sulphasalazine
- Hydoxycholorquin, Leflunomide
- Azathioprine
Biologics
- Anti-TNF agents
- Rituximab
- IL-6 inhibitors, JAK inhibitors
What is Azathioprine used for?
SLE & Vasculitis
Rheumatoid arthritis
IBD
Atopic dermatitis
Bullous skin disease
Many other uses as ‘steroid sparing’ drug
What are the pharmacodynamics of azathioprine?
6-MP is metabolised by thiopurine methyltransferase (TPMT)
TPMT gene is highly polymorphic
Low/absent TPMT levels- risk of myelosuppression
Test TPMT activity before prescribing
What are the adverse of azathioprine?
Bone marrow suppression
-Monitor FBC
Increased risk of malignancy
-Especially in transplanted patients
Increased risk of infection
Hepatitis
-Monitor LFT
Give two examples of calcineurin inhibitors
Ciclosporin
Tacrolimus
Widely used in transplantation
What are calcineurin inhibitors used for?
Atopic dermatitis
Psoriasis
Transplantation
Many possible drug interactions due to CYP450
What are the adverse drug reactions of calcineurin inhibitors?
Renal toxicity
What important drug to drug interactions need to be considered for ciclosporin and tacrolimus?
CYP inducers
CYP inhibitors
Give some examples of CYP450 inducers and inhibitors
Inducers
Rifampicin
Carbemazepine
Phenytoin
Omeprazole
Inhibitors
Ciprofloxacin
Antifungals
HIV antivirals
How do ciclosporin and tacrolimus work?
Prevents production of IL-2 via calcineurin inhibition
Active against helper T-cells
What does ciclosporin bind to?
Cyclophilin protein
What does tacrolimus bind to?
Tacrolimus- binding protein
How do cyclophosphamides and mycophenolate mofetil work?
Prevent proliferation of B and T cells
What are adverse drug reactions can happen with cyclophosphamide and mycophenolate mofetil?
Toxic to bladder epithelium- can cause haemorrhagic cystitis/ cancer
Nausea, vomiting
Myelosuppression
Infertility
What are some important drug to drug interactions for cyclophosphamide and mycophenolate mofetil?
Many vaccinations
What is methotrexate the gold standard treatment of?
Rheumatoid arthritis
Also used in malignancy, psoriasis and Crohn’s
How does methotrexate work in malignancy?
Competitively and reversibly inhibits dihydrofolate reductase
Affinity of methotrexate for dihydrofolate reductase is 1000x that of folate
Dihydrofolate reductase catalyses conversion of dihydrofolate to active tetrahydrofolate, key carrier in purine and thymidine synthesis
Methotrexate therefore inhibits synthesis of DNA, RNA and proteins
What part of the cell cycle is methotrexate cytotoxic?
Acts during DNA and RNA synthesis therefore S-phase
Greater toxic effect on rapidly dividing cells which replicate DNA more frequently
What is the mechanism of action in non-malignant disease?
e.g. RA and psoriasis
Not clear
Mechanism is not via anti-folate action
Possibly by
- Inhibition of accumulation of adenosine
- Inhibition of T cell activation
What is the bioavailability of methotrexate via different methods?
Oral-13%
Intramuscular- 76%
Administered PO, IM or SC
Why do you need to be careful with taking NSAIDs with methotrexate?
50% of methotrexate is protein bound
NSAIDs displace
What are the adverse drug reactions of methotrexate?
Mucositis
Marrow suppression
Hepatitis, cirrhosis
Pneumonitis
Infection risk
Highly teratogenic
What is sulfasalazine used for?
Rheumatoid arthritis
What immunological effects does sulfasalazine have?
T cell
- Inhibition of proliferation
- Possible T-cell apoptosis
- Inhibition of IL-2 production
Neutrophil
- Reduced chemotaxis
- Reduced degranulation
What are the adverse drug reactions of sulfasalazine?
Myelosuppression
Hepatitis
Hypersensitivity
What are the important drug to drug reactions for sulfasalazine?
Very few
Caution with some PPIs
What are some examples of biological therapies?
Infliximab
Rituximab
How do biological disease modifying anti-rheumatic drugs work? (DMARDs)
Monoclonal antibodies inhibit TNF-alpha
What effect does blocking TNF alpha have?
Decreased inflammation as reduced cytokine cascade
Decreased angiogenesis
Decreased joint destruction
What are the ADRs for biological DMARDs?
Teste for latent TB may reactivate latent disease due to the inhibition of TNF alpha
What are some important drug to drug interactions for biological therapies?
Other immunosupressants
