Rheumatoid arthritis - pathophysiology Flashcards
Aetiopathogenesis -Environmental factors -Genetic factors = susceptibility genes -Autoimmunity and synovial inflammation =Adaptive immune pathways =Activation of the innate immunity =Cytokines =Synovial fibroblasts
- Structural damage = mechanisms
- Systemic complications
Principles of pharmacological treatments
.
Functions of the synovium (synovial membrane)
Produce essential components of synovial fluid - lubricant, hyaluronic acid
Maintain intact tissue surface
Lubricate cartilage
Provide nutrition to chondrocytes within joints
Rheumatoid arthritis primary affects what joints
small joints of hands and feet
Rheumatoid synovitis is charactered by what processes
inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis
In RA, synovial fluid contains what WBC
neutrophils
What is pannus in terms of RA
Abnormal fibrovascular tissue that invades the space in between a joint’s bones, covering the bones and their protective layer of articular cartilage
–> bone + cartilage destruction
Formation of pannus
- Before the onset of RA, a smooth synovial membrane is just a few cells thick and produces synovial fluid, which lubricates and nourishes a joint.
- Rheumatoid arthritis can causes white blood cells to attack healthy synovium.
- The white blood cells release cytokines (proteins) that prompt the synovial membrane’s blood vessels to multiply (neoangiogenesis)
- The increased blood flow leads to excess tissue growth. The synovial cells reproduce at an abnormally fast rate, causing the synovium to thicken.
- The synovial membrane develops microscopic projections called villi on its surface. This makes the tissue rough and uneven.
- The thickening tissue requires space, and it invades the small space between the joint’s bones. This invasion causes the pannus to cover the surface the bones and their articular cartilage.
How does pannus contribute to joint pain + damage (3)
Excess fluid production.
- inflamed pannus produces excess fluid that contributes to joint pain and swelling. In addition, this fluid contains damaging proteins that degrade joint tissue.
Cartilage destruction.
- the pannus releases lysosomes that contain and release enzymes (proteins). These enzymes, called matrix metalloproteinases (MMPs), degrade cartilage.
Bone destruction.
- pannus contains high concentrations of osteoclasts that secrete acids and proteins that damage bone. These acids and proteins are part of the body’s normal cycle of bone cell destruction and replacement, but in RA this process can spin out of control, and bone cell loss can occur in concentrated areas at a rate too fast to be replaced.
Aetiological factors of RA
Genetics - genes susceptible to RA
Environmental - smoking, infection
Autoimmunity
Seropositive v seronegative RA
+ which more favourable prognosis
Seropositive
- involves rheumatoid factor
- involves anti-CCP
- involve citrullinated self proteins, e.g. keratin, fibrinogen
- LESS FAVOURABLE PROGNOSIS IF ANTI-CCP +VE
Seronegative
-don’t involve antibodies
What is rheumatoid factor
An antibody to normal antibodies, hence autoantibody
Specifically to the Fc portion of IgG –> forming an immune complex that contributes to disease process
Infection is an environmental factor of RA
- what infectious agents have been associated with triggering RA
Viruses (EBV, CMV)
E. coli
Mycoplasma
Periodontal disease (Porphyromonas gingivalis)
During inflammation in RA, a process called citrullination (deamination) occurs
- what is this
- what does it result in in relation to the immune system
Conversion of the amino acid arginine in a protein into the amino acid citrulline
If their shapes are significantly altered, the proteins may be seen as foreign antigens by the immune system
Leads to LOSS OF TOLERANCE + IMMUNITY
Inflammation of what is CENTRAL to the pathogenesis of RA
+ describe the pathogenesis of RA
Synovium (i.e. synovitis)
- synovium shows increased angiogenesis, cellular hyperplasia, influx of inflammatory cells, changes in the expression of cell surface adhesion molecules, and many cytokines
- the synovial lining becomes HYPERPLASTIC with infiltration of the sublining with T-cells, B cells, macrophages, and plasma cells
- NEOANGIOGENESIS is induced by hypoxia + cytokines
Anti T cell therapies (e.g. abatacept) are a subtype of biologics used to try and target T cells involved in the pathogenesis of RA
However what’s the issue with these
Limited efficacy because there’s relatively low levels of T cell cytokines present in the RA synovium
