S8) Rheumatology and Immunosuppressants Flashcards
Identify some diseases rheumatologists treat
- Rheumatoid arthritis (RA)
- Psoriatic Arthritis (PsA)
- Systemic lupus erythematosus (SLE)
- Systemic vasculitis
- Autoimmune myositis
- Spondyloarthropathy
Briefly illustrate the pathogenesis of rheumatoid arthritis
There is an imbalance between pro-inflammatory chemical mediators and anti-inflammatory chemical mediators
State 7 different possible ways of diagnosing RA
- Morning stiffness ≥ 1 hour
- Arthritis of ≥ 3 joints
- Arthritis of hand joints
- Symmetrical arthritis
- Rheumatoid nodules
- Serum rheumatoid factor
- X-ray changes
What are the treatment goals for RA?
- Symptomatic relief
- Prevention of joint destruction
Outline the treatment strategy for RA
- Early use of disease-modifying drugs
- Aim to achieve good disease control
- Use of adequate dosages
- Use of combinations of drugs
- Avoidance of long-term corticosteroids
What are the treatment goals in SLE & vasculitis?
- Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
- Reduction in mortality
- Prevention of organ damage
- Reduction in long term morbidity caused by disease and by drugs
Identify five immunosuppressant drugs
- Corticosteroids
- Azathioprine
- Ciclosporin
- Tacrolimus
- Mycophenolate mofetil
Identify five other disease-modifying anti-rheumatic drugs (DMARDs)
- Methotrexate
- Sulphasalazine
- Anti-TNF agents
- Rituximab
- Cyclophosphamide
Describe the mechanism of action of corticosteroids
- Prevent interleukin (IL)-1 and IL-6 production by macrophages
- Inhibit all stages of T-cell activation
Methotrexate is the gold standard treatment for Rheumatoid Arthritis.
What are its other indications?
- Malignancy
- Psoriasis/Psoriatic arthritis
- Crohn’s disease
In three steps, describe the mechanism of action for methotrexate on malignant cells, myeloid cells, GI & oral mucosa
⇒ Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
⇒ This prevents the conversion of dihydrofolate to active tetrahydrofolate in purine and thymidine synthesis
⇒ Thus, inhibits the synthesis of DNA, RNA and proteins (cytotoxic in S phase)
The mechanism of action of methotrexate in non-malignant disease e.g. RA, psoriasis is not clear. The mechanism is not via anti-folate action.
Suggest three possible mechanisms
- Inhibition of T cell activation
- Suppression of intercellular adhesion molecule expression by T cells
- Inhibition of enzymes involved in purine metabolism → accumulation of adenosine
What is adenosine and what does it do?
- Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress
- It interacts with specific GPCRs on inflammatory and immune cells to regulate their function
How is methotrexate administered?
- Oral
- Intramuscular
- Subcutaneous
How does the oral/intramuscular bioavailability change for methotrexate?
- Mean oral bioavailability = 33% (13-76%)
- Mean intramuscular bioavailability = 76%
When are doses given for methotrexate?
Weekly, not daily dosing – metabolised to polyglutamates with long half lives