Loco PBL 4: Rheumatoid Arthritis Flashcards
What is the cause of flexion contractures in rheumatoid arthritis?
The long tendons of the forearm run in synovial tendon sheaths which re affected be rheumatoid arthritis; this causes the sheaths to damage and rupture and because the flexors tend to be stronger, they pull the fingers into a flexion deformity
What are occipital headaches (C2 neuralgia)?
Where the occipital nerves are inflamed or injured and pain is felt in the base of the skull
What are the risk factors for developing rheumatoid arthritis?
Genetics (HLA-DR1/DR4/PTPN22, TRAF5), infections (EBV, porophyromonas gingivitis, ruebella) and hormones (reduced RA in pregnancy)
What genetics are associated with rheumatoid arthritis?
HLA DR-1, HLA-DR4, PTPN22, TRAF5
How may imprinting be associated with rheumatoid arthritis?
Differential methylationof chromosomes by the parent of origin may play a role in explaining why RA is more common in women
How are infections associated with rheumatoid arthritis?
Mycoplasma, EBV, porphyromonas gingivalis (periodontal infection) and rubella virus
How are hormones thought to be associated with rheumatoid arthritis?
In pregnancy there seems to be a reduction in rheumatoid arthritis
What inflammatory cytokines are involved in rheumatoid arthritis?
IL-17, IL,-1, IL-6, TNF
Explain the pathophysiology of rheumatoid arthritis
> External trigger causes an autoimmune reaction, synovial cell hyperplasia and endothelial cell activation. > This excessive proliferation and inflammation of the synovium (pannus) destroys tissue (bone, ligament, tendon, blood vessels) is orchestrated by Th17 cells. > Th17 cells produce IL-17 which activates macrophages which then (alongside Th17) induce RANKL on type B synoviocytes to stimulate osteoclasts and produce MMPs (degrade cartilage and bone matrix), and activate type A synoviocytes to secrete IL-1/IL-6-TNF. In addition, B cells produce auto-antibodies (anti-citrullinated protein and rheumatoid factor) which may stimulate initial osteoclast activity)
Which cell mediates the inflammatory process of rheumatoid arthritis?
Th17 cells
How do type A synoviocytes contribute to the degradation of tissues rheumatoid arthritis?
Local inflammation instigated by Th17 cells leads to the activation of type A (macro-phage like) cells which then secrete IL-1, IL-6 and TNF which induce Dkk expression by type B synoviocytes which inhibits osteoblast differentiation directly and induces sclerostin expression by osteocytes to further inhibit osteoblasts
How do type B synoviocytes contribute to the degradation of tissues rheumatoid arthritis?
Th17 cells and macrophages induce RANKL production by type B cells (fibroblasts) which stimulates osteoclasts and the production of MMPs which degrade the cartilage and bone matrix
How do B cells contribute to the degradation of tissues rheumatoid arthritis?
B cells produce autoantibodies such as anti-citrullinated protein and rheumatoid factors which may stimulate the initial osteoclastic activity and initial bone loss
How is synovial fluid affected by rheumatoid arthritis?
Increased production and less viscous (due to shorter hyaluronic acid strands; because neutrophil accumulation causes respiratory burst producing superoxide anion radicals causing damage which shortens the strands)
Why are synovial joints most susceptible to inflammation?
They have a rich network of fenestrated capillaries and a limited number of ways in which they can respond.
How do type A synoviocytes affect sclerostin production in rheumatoid arthritis?
Induces sclerostin expression by osteocytes to further inhibit osteoblasts
Why is there an increased production of synovial fluid in rheumatoid arthritis?
Due to an increased leakiness/permeability of the blood vessels
What is pannus?
Growing and proliferating synovial membrane which grows into the articular cartilage and underlying bone causing damage
What causes the pain of rheumatoid arthritis?
Nerve ending irritation due to the chemicals produced by inflammation OR stretching of the joint capsule due to swelling
What are the signs/symptoms of rheumatoid arthritis?
Ulnar gift, swan neck (hyperextension of PIP, flexion of DIP), boutonniere (DIP), Z-shape thumb, knuckle subluxation
What are the common sites for rheumatoid arthritis?
Small joints of the hands and feet
Name some non-biological DMARDs
Gold, sulfasalazine, methotrexate and azathioprine
Name some biological DMARDs
Infliximab, anakinra, rituximab, abatacept and toclizumab
What are non-biological DMARDs?
These target immune cells non-selectively
What are biological DMARDs?
These target specific parts of the inflammatory cascade
Explain the mechanism of action of methotrexate.
Competitively binds to dihydrofolate reductase (to prevent folic acid production necessary for purine metabolism and RNA synthesis) and inhibits thymidylate synthesise which prevents DNA production; these prevent the cellular proliferation of immune cells.
What are the potential side effects of methotrexate?
Affects blood count, liver problems, neural tube defects if taken in pregnancy
How may sulfasalazine be used in the treatment of rheumatoid arthritis?
Form of non-biological DMARD, the mechanism of action of this antibiotic is poorly understood
How may azathioprine be used in the treatment of rheumatoid arthritis?
A non-biological DMARD which interferes with purnie synthesis which prevents DNA replication and cellular division of immune cells
What is the mechanism of action of infliximab?
TNF-alpha receptor antagonist
What is the mechanism of action of anakinra?
IL-1 receptor antagonist
What is the mechanism of action of abatacept?
T cell inhibitor (CTLA4 portion of antibody binds to CD28 on T cells to prevent costimulation)
What is the mechanism of action of toclizumab?
IL-6 inhibitor
What is the mechanism of action of rituximab?
B cell inhibitor (blocks CD20 receptor)
How may rheumatoid arthritis affect the vertebrae?
Can cause spondylolisthesis whereby the upper vertebra is able to slide forward on top of the one below
How may rheumatoid arthritis lead to complications of the C1/C2 vertebrae?
Rheumatoid arthritis can destroy the facet joints and ligaments which hold the odontoid process to the front of C1; ability of C1 to move forward and the process may start to push into the spinal cord
What is spondylolisthesis?
Where the upper vertebra is able to slide forward on top of the one below
How may rheumatoid arthritis lead to complications of the skull/C1 vertebrae?
Rheumatoid arthritis can destroy the joints between C1 and the skull leading to settling where the odontoid process begins to move up into the skull causing pressure on the spinal cord and arteries (causing occipital headaches)
How are vertebral complications of rheumatoid arthritis treated?
Conservative management (neck brace/monitoring), posterior cervical fusion (conducted through hole in neck using grafts from hip and wires), anterior cervical fusion (transoral approach if posterior approach is insufficient)
