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
Identify five ADRs of methotrexate
- Mucositis
- Marrow suppression
- Hepatitis
- Cirrhosis
- Pneumonitis
How can mucositis and marrow suppression as a result of methotrexate be treated?
Folic acid supplementation
Why should a female patient on methotrexate not fall pregnant?
Methotrexate is highly teratogenic and abortifacient
Which conditions are treated by sulphasalazine?
Sulphasalazine is used to treat inflammatory arthritis:
- Rheumatoid arthritis
- Psoriatic Arthritis
- Spondyloarthritis
What are the immunological effects of sulphazine on T cells?
T cell:
- Inhibition of proliferation
- Apoptosis (possible)
- Inhibition of IL-2 production
What are the immunological effects of sulphazine on neutrophils?
Neutrophil:
- Reduced chemotaxis
- Reduced degranulation
Where is the site of release for sulphasalazine and what is the significance of this?
- Site of release is the colon (poorly absorbed)
- Effective in IBD
The adverse effects of sulphasalazine are mainly due to sulfapyridine moiety.
What are they?
- Myelosuppression
- Hepatitis
- Rash
Which clinical conditions are treated by azathioprine in practice?
- SLE
- Vasculitis
- Atopic dermatitis
- Bullous skin disease
Describe the mechanism of action of azathioprine
- Cleaved to 6-mercaptopurine (6-MP)
- Anti-metabolite decreases DNA and RNA synthesis
What are the adverse effects of azathioprine?
- Bone marrow suppression (monitor FBC)
- Increased risk of malignancy
- Increased risk of infection
- Hepatitis (onitor LFT)
When is mycophenolate mofetil used in practice?
- Transplantation (primariliy)
- Lupus nephritis (induction and maintenance therapy)
What are the adverse effects of mycophenolate mofetil?
- Nausea
- Vomiting
- Diarrhoea
- Myelosuppression
Describe the mechanism of action of mycophenolate mofetil
- Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis)
- Impairs B- and T-cell proliferation
- Spares other rapidly dividing cells
Cyclophosphamide is a cytotoxic alkylating agent which cross links DNA so that it cannot replicate.
What are its immunological effects?
- Suppresses T cell activity
- Suppresses B cell activity
What are the indications for cyclophosphamide?
- Lymphoma
- Leukaemia
- Solid cancers
- Lupus nephritis
- Wegener’s granulomatosis (ANCA vasculitis)
Cyclophosphamide has significant toxicity and thus, some important considerations should be made.
What are these?
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility
- Monitor FBC
- Adjust dose in renal impairment
What are biopharmaceuticals / “biologicals”?
- Biologicals are drugs made from substances extracted from living systems e.g. blood components, stem cell therapy
- It uses recombinant DNA technology to produce substances nearly identical to the body’s own key signalling proteins e.g. GH, EPO
What are the three effects of blocking TNF-α?
- ↓ Inflammation
- ↓ Angiogenesis
- ↓ Joint destruction
What are the risks of Anti-TNF therapy?
TB reactivation – TNFα is essential for development + maintenance of granulomata (released from macrophages in reponse to M TB infection)
The biological, rituximab is very effective in RA.
Explain why by describing its mechanism of action
- Binds specifically to a cell-surface marker CD20 found on a subset of B cells
- Causes B cell apoptosis
Identify two calcineurin inhibitors
- Ciclosporin
- Tacrolimus
Describe the three uses of ciclosporin and tacrolimus in clinical practice
- Transplantation
- Atopic dermatitis
- Psoriasis
Why are calcineurin inhibitors not used in rheumatology?
Renal toxicity
Describe the mechanism of action of calcineurin inhibitors
Active against helper T cells, preventing production of IL-2 via calcineurin inhibition:
- Ciclosporin binds to cyclophilin protein
- Tacrolimus binds to tacrolimus-binding protein
- Drug/protein complexes bind calcineurin
