Loco PBL 4: Rheumatoid Arthritis

Question 1

What is the cause of flexion contractures in rheumatoid arthritis?

Answer 1

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

Question 2

What are occipital headaches (C2 neuralgia)?

Answer 2

Where the occipital nerves are inflamed or injured and pain is felt in the base of the skull

Question 3

What are the risk factors for developing rheumatoid arthritis?

Answer 3

Genetics (HLA-DR1/DR4/PTPN22, TRAF5), infections (EBV, porophyromonas gingivitis, ruebella) and hormones (reduced RA in pregnancy)

Question 4

What genetics are associated with rheumatoid arthritis?

Answer 4

HLA DR-1, HLA-DR4, PTPN22, TRAF5

Question 5

How may imprinting be associated with rheumatoid arthritis?

Answer 5

Differential methylationof chromosomes by the parent of origin may play a role in explaining why RA is more common in women

Question 6

How are infections associated with rheumatoid arthritis?

Answer 6

Mycoplasma, EBV, porphyromonas gingivalis (periodontal infection) and rubella virus

Question 7

How are hormones thought to be associated with rheumatoid arthritis?

Answer 7

In pregnancy there seems to be a reduction in rheumatoid arthritis

Question 8

What inflammatory cytokines are involved in rheumatoid arthritis?

Answer 8

IL-17, IL,-1, IL-6, TNF

Question 9

Explain the pathophysiology of rheumatoid arthritis

Answer 9

> 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)

Question 10

Which cell mediates the inflammatory process of rheumatoid arthritis?

Answer 10

Th17 cells

Question 11

How do type A synoviocytes contribute to the degradation of tissues rheumatoid arthritis?

Answer 11

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

Question 12

How do type B synoviocytes contribute to the degradation of tissues rheumatoid arthritis?

Answer 12

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

Question 13

How do B cells contribute to the degradation of tissues rheumatoid arthritis?

Answer 13

B cells produce autoantibodies such as anti-citrullinated protein and rheumatoid factors which may stimulate the initial osteoclastic activity and initial bone loss

Question 14

How is synovial fluid affected by rheumatoid arthritis?

Answer 14

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)

Question 15

Why are synovial joints most susceptible to inflammation?

Answer 15

They have a rich network of fenestrated capillaries and a limited number of ways in which they can respond.

Question 16

How do type A synoviocytes affect sclerostin production in rheumatoid arthritis?

Answer 16

Induces sclerostin expression by osteocytes to further inhibit osteoblasts

Question 17

Why is there an increased production of synovial fluid in rheumatoid arthritis?

Answer 17

Due to an increased leakiness/permeability of the blood vessels

Question 18

What is pannus?

Answer 18

Growing and proliferating synovial membrane which grows into the articular cartilage and underlying bone causing damage

Question 19

What causes the pain of rheumatoid arthritis?

Answer 19

Nerve ending irritation due to the chemicals produced by inflammation OR stretching of the joint capsule due to swelling

Question 20

What are the signs/symptoms of rheumatoid arthritis?

Answer 20

Ulnar gift, swan neck (hyperextension of PIP, flexion of DIP), boutonniere (DIP), Z-shape thumb, knuckle subluxation

Question 21

What are the common sites for rheumatoid arthritis?

Answer 21

Small joints of the hands and feet

Question 22

Name some non-biological DMARDs

Answer 22

Gold, sulfasalazine, methotrexate and azathioprine

Question 23

Name some biological DMARDs

Answer 23

Infliximab, anakinra, rituximab, abatacept and toclizumab

Question 24

What are non-biological DMARDs?

Answer 24

These target immune cells non-selectively

Question 25

What are biological DMARDs?

Answer 25

These target specific parts of the inflammatory cascade

Question 26

Explain the mechanism of action of methotrexate.

Answer 26

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.

Question 27

What are the potential side effects of methotrexate?

Answer 27

Affects blood count, liver problems, neural tube defects if taken in pregnancy

Question 28

How may sulfasalazine be used in the treatment of rheumatoid arthritis?

Answer 28

Form of non-biological DMARD, the mechanism of action of this antibiotic is poorly understood

Question 29

How may azathioprine be used in the treatment of rheumatoid arthritis?

Answer 29

A non-biological DMARD which interferes with purnie synthesis which prevents DNA replication and cellular division of immune cells

Question 30

What is the mechanism of action of infliximab?

Answer 30

TNF-alpha receptor antagonist

Question 31

What is the mechanism of action of anakinra?

Answer 31

IL-1 receptor antagonist

Question 32

What is the mechanism of action of abatacept?

Answer 32

T cell inhibitor (CTLA4 portion of antibody binds to CD28 on T cells to prevent costimulation)

Question 33

What is the mechanism of action of toclizumab?

Answer 33

IL-6 inhibitor

Question 34

What is the mechanism of action of rituximab?

Answer 34

B cell inhibitor (blocks CD20 receptor)

Question 35

How may rheumatoid arthritis affect the vertebrae?

Answer 35

Can cause spondylolisthesis whereby the upper vertebra is able to slide forward on top of the one below

Question 36

How may rheumatoid arthritis lead to complications of the C1/C2 vertebrae?

Answer 36

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

Question 37

What is spondylolisthesis?

Answer 37

Where the upper vertebra is able to slide forward on top of the one below

Question 38

How may rheumatoid arthritis lead to complications of the skull/C1 vertebrae?

Answer 38

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)

Question 39

How are vertebral complications of rheumatoid arthritis treated?

Answer 39

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)