Rheumatoid Arthritis Flashcards
What is the normal response to infection?
- Inflammation
- There will be acute or chronic response involving immune cells and you will eventually get resolution.
Why is an incorrect immune response significant?
-Incorrect immune response can lead to autoimmunity
What are some examples of autoimmune disease?
- Rheumatoid arthritis
- Graves Disease
- Diabetes
Why dont we all get autoimmune disease?
- Immune system has regulatory checks
- We have a level of tolerance (controlled unresponsiveness to self) maintained by numerous control mechanisms
What are the symptoms of rheumatoid arthritis?
- Widespread joint pain, stiffness and swelling leading to joint destruction
- Fatigue
- Weight loss
- Fevers
What are some risk facotrs of rheumatoid arthritis?
-Females
What is rheumatoid arthritis?
-Chronic inflammatory disorder of joints but can also affect the skin, lungs, blood vessels and more.
What are some commonly affected joints by RA?
- Smaller joints; MCP, PIP, MTP
- Larger; shoulder, elbow, knees, ankles
What are the diagnostic tests for RA?
- Blood tests; look out for increased rheumatoid factor and increased anti CCP antibody
- Imaging; in Xray look for soft tissue sweilling, narrowed joint space, decrease in bone density, bony erosions
What are possible treatments for RA?
- DMARDS
- Biologics
- NSAIDS
- Corticosteroids
What are some examples of DMARDS and what do they do?
- Methotrexate
- Hyroxychloroquine
- Sulfasazine
- They supress inflammation
What are some examples of biologics and what do they do?
- Abatacept; supress T cells
- Rituximab; supress B cells
- Infliximab; blocks chemokines such as TNF
- Anakinra; block IL1
- Tocilizumab; blocks IL6
Are single drugs better for RA treatment or combinations?
Combinations
What are biological agents?
-Drugs such as monoclonal antibodies, receptors or peptides, which have been developed rationally by targetting important processes in disease pathogenesis eg. cytokines, T-cells, B-cells
What needs to be considered when making therapeutics from immunological understanding?
- Define behaviour of molecular target
- Ask, does it participate in disease process
- Can it be effectively inhibited ex vivo or en vivo
Why is inhibiting TNF in RA significant?
- TNF seen as major conductor of pathology in RA
- Ability to block cytokine signalling via its receptor
What are biosimilars?
-Cheaper alternatives
What is the issue with biosimilars of biologic agents?
-Still some uncertainities surrounding use as they are more complex than any other medicine
What type of inhibition is more effective?
-Intracellular as it offers oppurtunity to inhibit multiple pathways
What are the future of inhibitors?
-JAK inhibitors
What is the genetic part of the pathophysiology of RA?
-There are certain susceptibility genes eg. HLA-DR1 and HLA-DR4
What is the environmental part of pathophysiology of RA?
- EG. cig smoke, pathogens
- This may lead to modifications to our own antigens eg. type II collagen, vimentin.
What changes occur as a result of environmental and genetic triggers of RA?
- Citrullination of arginine
- Due to susceptibility genes, these are no longer recognised as self antigens.
What happens as a result of our genes not being recognised as self in RA?
-Antigen picked up by antigen presenting cell and taken to lymph nodes to activate CD4 cells which stimulate B cells to produce autoantibodies against self antigens.
What happens after autoantibodies produced against self antigens?
-CD4 cells and autoantibodies enter circulation and go to joints.
They then secrete cytokines eg. interferon gamma and IL-17 to recruit macrophages.
What happens when macrophages produced in joints for RA?
- Produce more cytokines eg. TNF-alpha, IL-1, IL-6 which cause synovial cells to proliferate.
- This forms a pannus (made of fibroblasts, myofibroblasts and inflammatory cells)
What does the creation of the pannus lead to?
-Over time this can damage cartilage and other soft tissue.
Proteases may be secreted and destroy cartilage.
What other things may cytokines cause in RA?
-More RANK-L on T cells which recruit osteoclasts
What is an eg of an autoantibody produced in RA?
-Anti-CCP; targets citrullinated proteins to form immune complexes to activate complement system.
How does RA also effect organs around the body?
-The cytokines escape and cause problems all over eg. artheroscleratic plagues in blood vessels.
