RA, OA, Gout Flashcards
Causes of RA?
Genetic factors
Environmental factors
other factors
Combination of antibody and cell mediated immunity.
B cells involved
Rheumatoid factors (antibodies to Fc of IgG)
Symptoms of RA?
pain swelling stiffness progressive loss of function fatigue and general malaise eventually destroys joints in left untreated symmetrical generally
What cell types contribute RA?
Dendritic cells- APCs B cells T cells Fibroblasts Macrophages
All release ptoinflammatory cytokines- TNFa ILs PGs
Recruits more inflammatory cells
Uncontrolled leads to bone erosion and structural damage to joints
What does TNFa do?
1Pro inflammatory cytokine which acts on TNF a receipts to activate NF-KB, a transcription regulator. Activation of NF-KB occurs when TNFa signals a degradation of IKB by IKB kinases.
This removes the suppression of NF-KB, and allows it to produce inflammatory proteins such as ILs, more TNFa and other cytokines
What are 5 treatments for RA?
- DMARDs
- Corticosteriods
- Biological agents
- NSAIDs and paracetamol
- Natural products
How does methotrexate work in RA? (3 possible mechanism)
Inhibits dihydrofolate reductase which inhibits the synthesis of folic acid to FH4. Targets actively proliferating cells.
- Decreases the proliferation of cells responsible for inflammation of the synovial fluid in RA via DHFR inhibition
- Decreases the synthesis of potential toxic compounds that accumulate in chronic inflammation via DHFR inhibition
- Increase in adenosine released from cells and tissues is seen. This regulates anti-inflammatory effects
What are some adverse effects with methotrexate?
GI effects: nausea, stomatitis
Hepatoxicity- elevation of live enzymes
Decrease in blood cells
Folic acid to help with GI effects and hepatoxicity
Regular FBC
What is the MOA of leflunomide?
Inhibits pyrimidine synthesis in leucocytes and other rapidly dividing cells by inhibiting activity of dihydro-orotate dehydrogenase.
Effects on T cells, it can address several levels of the inflammatory cascade and has anti proliferative, anti inflammatory and anti destructive effects.
12 weeks for seen improvements
Counselling points for leflunomide?
Contraindicated in pregnancy
Abdominal pain and diarrhoea common
Need to monitor BP, FBC, renal and liver function at the start of tx, every 2-4 weeks for the first 3 months and every 3 months thereafter
How does Azathioprine work?
Interferes with purine synthesis
Which inhibits DNA synthesis
Depresses immune reaction as it inhibits clonal proliferation of T and B cells
Major A/E- Bone marrow toxicity (decrease WBC)
How does Sulfasalazine reduce inflammation?
Prodrug breaks down via colonic bacteria into 5-ASA and sulfapyridine
5-ASA: O2 scavenger COX inhibitor Decrease IL-1 IL-6 TNFa IKB breakdown inhibitor
How does cyclosporin work?
Decreases IL-2 gene activation in T cells
Hence decreases T cell proliferation and T cell dependent B cell responses
What anti inflammatory properties is exerted by Hydroxychloroquine?
Inhibits: lymphocyte proliferation Release of lysosomal enzymes toxic O2 metabolites IL-1
(Gold compounds have this MOA as well as TNFa)
What drug inhibits IL-1 production and reduces levels of circulating RF?
Penicillamine
What gene expression does corticosteriods modulate?
Decreases COX 2
Increase IKB and annexin 1
