Describe the pathogenesis of rheumatoid arthritis
- Inflammation of synovium of joints caused by T cells and macrophages.
- Macrophages release cytokines IL-1, IL-8, and TNF-alpha which results in inflammation and synovitis..
- Osteoblasts and fibroblasts activated to produce metalloproteinases
- Synovium thickens and joint effusions. Inflamed synovium becomes known as apannus.
- Pannus damages underlying cartilage, exposing bone.
Describe the presentation of Rheumatoid arthritis
- Warm, tender joints with swelling
- fixed flexion (boutonniere) or fixed hyperextension (swan neck) deformities
- Pain and stiffness worse in mornings
What type of drugs can be used to treat RA?
At first, DMARDs - Halt and reverse underlying processes
NSAIDs - reduce symptoms
Describe how methotrexate works in non malignant disease such as RA
- Methotrexate inhibits enzymes involved in purine metabolism, leading to increased adenosine in cell.
- Adenosine acts on GPCRs of inflammatory and immune cells leading to a reduced activity of T cells.
How is methotrexate administered? How many times a day?
oral, Subcutaneous or intramuscular
Administered once a week!!
What is the half life of methotrexate?
How is methotrexate excreted?
Name 3 ADRs of methotrexate
myelosuppression, hepatitis, teratogenic, abortifactant.
How is methotrexate monitored?
Baseline CXRs, FBCs (for myelosuppression), LFTs (hepatic damage), and U&Es and creatinine for renal function
What is the mechanism of action of sulfasalazine in treating RA? What type of drug is it?
- Inhibits T-cell proliferation and IL-2 production
What are the possible ADRs of sulfasalazine?
Nausea, fatigue, headaches
Describe how azothioprine can be used to treat RA.
- Metabolised to 6-MP which inhibits purine synthesis
- Reduces therefore DNA and RNA synthesis.
- Acts on cells with high mitotic rates
How does azothioprine treatment differ from patient to patient?
- TPMT enzyme eliminates 6-MP
- TPMT subject to genetic polymorphism, differing levels produced by different patients.
What are the ADRs of azothiprine
myelosuppression, increased risk of infection, emergence of malignant cell lines.
How do corticosteroids work?
Inhibitors of gene expression
How does cyclophosphamide work?
- Forms DNA crosslinks between and within DNA strands, preventing replication.
- Acts on cells with higher mitotic rates
What are the ADRs of cyclophosphamide?
Leukaemia, infertitlity, teratogenesis, bladder cancer
How is cyclophospahmide excreted?
How does mycophenolate mofetil work?
- Inhibits enzyme required for guanine synthesis
- Resulting in impaired B and T cell proliferation whilst sparing other rapidly dividing cells.
What are the ADRs of mycophenolate mofetil?
myelosuppression, increased risk of infection, nausea, vomiting, diarrhoea.
Name 2 calcineurin inhibitors.
Tacrolimus and ciclosporin
How do calcineurin inhibitors work?
- Prevent IL-2 production by T helper cells by inhibiting calcineurin.
- Ciclosporin binds to cyclophilin. Tacrolimus binds to Tacrolimus-binding protein. These complexes then bind to calcineurin.
Name the ADRs of calcineurin inhibitors
nephrotoxicity, hypertension, hyperlipidaemia, nausea, vomiting (hyperesis), diarrhoea, hyperuricemia.