Immunosupression and Rheumatoid disease Flashcards
What is rheumatoid arthritis?
An autoimmune multi-system disease
Initially localized to synovium
Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
So there is an imbalance of more pro-inflammatory factors to anti-inflammatory factors
How do we diagnose RA?
It is diagnosed clinically but these are the major signs - Morning stiffness > 1 hour - Arthritis of > 3 joints - Arthritis of hand joints - Symmetrical arthritis - Serum rheumatoid factor And there are other signs, but if you see these it is far too late and should have been treated ages ago. - Rheumatoid nodules - X-ray changes
What are RA treatment goals?
Symptomatic relief
Prevention of joint destruction
What is the general RA treatment strategy?
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 SLE and vasculitis?
Both are multi-systemic, needs to be two or more systems involved(Heart and lungs are very connected so need more than these two alone)
Systemic Lupus Erythematosus -SLE
It is a systemic autoimmune disease
Vasculitis
Inflammation of blood vessels caused by an autoimmune response
What are the treatment goals in SLE and vasculitis?
Symptomatic relief e.g. arthralgia, Raynaud’s phenomenon in SLE
Reduction in mortality - induction of disease remission then maintenance
Prevention of organ damage e.g. renal failure in SLE
Reduction in long term morbidity caused by disease and by drugs
Name some immunosuppressants.
Corticosteroids Azathioprine Ciclosporin Tacrolimus Mycophenolate mofetil
Name some disease-modifying ant-rheumatic drugs (DMARDs)
Methotrexate (Most used) Sulphasalazine Anti-TNF agents Rituximab Cyclophosphamide (cytotoxic) (Can be dangerous)
What is the mechanism of action of corticosteroids?
Prevent interleukin (IL)-1 and IL-6 production by macrophages Inhibit all stages of T-cell activation
What are the key adverse effects of corticosteroids?
Weight gain Fat redistribution Striae Growth retardation Osteoporosis Avascular necrosis Glucose intolerance Adverse lipid profile Infection risk Cataract formation
What is azathioprine used for in practice?
SLE & vasculitis - as maintenance therapy
RA - weak evidence for efficacy
Inflammatory bowel disease
Bullous skin disease
Atopic dermatitis
Many other uses as ‘steroid sparing’ drug
What is azathioprine’s mechanism of action?
Cleaved to 6-mercaptopurine (6-MP)
Functions as an anti-metabolite to decrease DNA and RNA synthesis
What is the pharmacodynamic significance of azathioprine?
6-MP is metabolized by thiopurine methyltransferase
TPMT gene highly polymorphic
Individuals very markedly in TPMT activity
Those with low or absent TPMT levels are likely to develop myelosuppression (Bone marrow suppression)
Therefore test this before prescribing
What are the adverse effects of azathioprine?
Bone marrow suppression - Monitor FBC Increased risk of malignancy - Especially transplanted patients Increased risk of infection Hepatitis - Monitor LFT
Name 2 calcineurin inhibitors.
Ciclosporin and Tacrolimus
Name the mechanism of action of calcineurin inhibitors.
Active against helper T-cells, preventing the production of IL-2 via calcineurin inhibition
Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription
How are calcineurin inhibitors used in practice?
Widely used in transplant medicine
Also indicated for atopic dermatitis and psoriasis
Not commonly used in rheumatology
- Concerns about toxicity
Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow
(Monitor for toxicity - check BP and eGFR
What are some adverse effects of calcineurin inhibitors?
Nephrotoxicity
Hypertension
Hyperlipidemia
Nausea, vomiting, diarrhoea
Hypertrichosis (abnormal hair growth)
Gingival hyperplasia (Increased gum growth)
Hyperuricemia (High uric acid in the blood)
Multiple drug interactions are possible, primarily with agents affecting the cytochrome P450 system
What is the mechanism of action of Mycophenolate mofetil?
It is a prodrug
It inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis)
Impairs B and T cell proliferation
Spare other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)
What are some adverse effects of Mycophenolate acid?
Most common include nausea, vomiting, diarrhoea
Most serious is myelosuppression
What is Mycophenolate mofetil used for in practice?
Primarily in transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis
In transplantation medicine drug levels of the active metabolite, mycophenolic acid may be monitored
Toxicity may be precipitated by both renal and liver disease
Tell me about Cyclophosphamide.
Alkylating agent - Cross links DNA so that it cannot replicate Many immunological effects - Suppresses T cell and B cell activity Indication: - Lymphoma, leukaemia - Lupus nephritis - Wegener's granulomatosis - Polyarteritis nodosum
What sre the risks of using Cyclophosphamide?
Significant toxicity:
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility
- Monitor FBC
- Adjust dose in renal impairment
MMF may supersede cyc in lupus nephritis
Trial of MMF versus cyc for vasculitis is underway
What is Methotrexate used for in practice?
Gold standard treatment for RA Other indications: - Malignancy - Psoriasis - Crohn's disease
