The science of Rheumatoid Arthritis

Question 1

What are the functions of the synovium?

Answer 1

Maintenance of intact tissue surface

Production of synovial fluid => lubrication of cartilage
- control of synovial fluid volume and composition (hyaluronan, lubricin)

Nutrition of chondrocytes within joints

Question 2

What are the 2 layers of the synovium?

Answer 2

Intimal lining – very thin layer - consists of fibroblasts and macrophages

Sub-intimal tissue – contains blood vessels, fat cells, macrophages and fibroblasts

Question 3

How does rheumatoid arthritis affect a synovial joint?

Answer 3

A trigger (i.e smoking, genetics bacteria or synovial injury / infection of the joint causing inflammation etc) results in modification of auto-antigens (includes citrullination) i.e makes own antigens appear foreign.

APCs recognise these ‘foreign’ cells and trigger an IMMUNE RESPONSE. Plasma cells produce autoantibodies (i.e rheumatoid factor + anti-citrullinated protein antibody) which make their way to the joint + trigger inflammatory process via things like cytokine release (IL-1, IL-6, TNF alpha), activation of Fibroblast-like synoviocytes (Type B) within the synovium causing osteoclast activity (resulting in bone erosion) and production of proteases causing articular cartilage degradation.

Within the synovial fluid in the joint space there are neutrophils which become activated and also produce proteases and reactive O2 species causing bone and articular cartilage degradation too.

Question 4

What is the definition of RA?

Answer 4

A chronic, symmetric poly-articular inflammatory joint disease, which primarily affects the MCP and PIP joints of the hands and also small joints in the feet

Question 5

Which autoantibodies are associated with RA and are tested for as part of the diagnostic process? (2)

Answer 5

Rheumatoid factor - in 75% of people with R.A - you could have normal RF levels in R.A though so it is not very accurate / reliable.

Anti-citrullinated protein antibodies (ACPA) - directed against modified auto-antigens (citrullinated auto-antigens) such as fibrin and fillagrin - this is more sensitive and specific test for diagnosing R.A

Question 6

What are the 2 main classes of Rheumatoid Arthritis that helps to divide R.A patients into?

Answer 6

Seropositive rheumatoid arthritis - RF or ACP antibodies detected - associated with more progressive disease

Seronegative rheumatoid arthritis - antibodies are not detected in the blood - you could still be diagnosed as having R.A based on other symptoms but it could also be that you have another type of inflammatory arthritis

Question 7

What test is used clinically to detect Anti-citrullinated protein antibodies?

Answer 7

Diagnostic anti-cyclic citrullinated peptide (anti-CCP)

Question 8

What factors contribute to RA? (6)

Answer 8

Genetics
Smoking
Bacterial infection - Gingivitis
Viruses i.e EBV

Joint problems:
Infection within joint
Synovial injury / hyperplasia

Question 9

What would happen if a person who is genetically susceptible to RA had repeated insults either by smoking or infection?

Answer 9

The repeated insults can cause modification of auto-antigens which are then picked up by APCs and this triggers an Immune response.

Plasma cells produce auto-antibodies such as RF and ACP antibodies which move into the joint/joint space and creates inflammatory response etc

Question 10

Define ‘citrullination’

Answer 10

It’s a post-translational modification converting the amino acid arginine in a protein into the amino acid citrulline.

Citrullination happens normally but it can be abnormal in RA patients.

Question 11

Synovitis is the hallmark of RA, how is it characterised?

Answer 11

Villous hyperplasia

Infiltration of T cells, B cells, macrophages and plasma cells

Fibroblast-like synoviocyte proliferation

Production of cytokines and proteases which cause erosion of bone and articular cartilage

Increased vascularity

Self-amplifying process

Question 12

What do inflammatory cytokines do? (7)

Answer 12

Induce expression of endothelial-cell adhesion
molecules

Activate synovial fibroblasts, chondrocytes, osteoclasts

Promote angiogenesis

Suppress T-regs

Activate leukocytes

Promote autoAb production

IL-6 mediates systemic effects

Question 13

What things enhance blood vessel proliferation in the synovium?

Answer 13

Hypoxic conditions and angiogenic factors such as IL-8 and VEGF

Question 14

Systemic consequences of RA?

Answer 14

Skin - Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation

CVD - cytokines and inflammation promote atherogenesis (plaque formation) - can lead to MI or stroke

Liver - increased CRP and ESR inflammatory markers and increased Hepcidin - which contributes to Anaemia

Neuro - Fatigue and depression caused by Anaemia

Muscles - inflammation causes insulin resistance - which results in muscle weakness

Bone - osteopenia which progresses to osteoporosis

Bone marrow - anaemia, thrombocytosis

Question 15

Which genes are associated with RA?

Answer 15

HLA DR4 (a gene often present in RF positive patients)
HLA DR1 (a gene occasionally present in RA patients)
PTPN22

Question 16

Which part of the IgG antibody does RF target?

Answer 16

The Fc portion

Question 17

What is the Fc portion of an antibody?

Answer 17

It is the constant part of antibodies, used to bind to cells of the immune system.

RF targets this portion on IgG causing activation of the immune system against the patients own IgG resulting in systemic inflammation

Question 18

How does R.A typically present?

Answer 18

It typically presents with a symmetrical distal polyarthropathy. 
The key symptoms are joint:
Pain
Swelling
Stiffness

These symptoms affect the MCP and PIP joints in the hands. And can also affect smaller joints in hands and feet such as wrist and ankle

Question 19

What is the key difference between osteoarthritis and rheumatoid arthritis in terms of pain?

Answer 19

Pain from an inflammatory arthritis (R.A) is worse after rest but improves with activity.

Pain from a mechanical problem such as osteoarthritis is worse with activity and improves with rest.

Question 20

Which joints are almost never affected in R.A?

Answer 20

Distal interphalangeal joints

Question 21

Key signs of R.A in the hands?

Answer 21

Swan hand - DIP flexed, PIP hyperextended

Boutonniere - DIP hyperextended, PIP flexed

Question 22

If you are seronegative it may be that you have another type of inflammatory arthritis. What else could you have?

Answer 22

Spondyloarthritis

Psoriasis - related arthritis

Question 23

What scoring system is useful in monitoring disease activity in R.A and response to treatment?

Answer 23

DAS28 = the Disease Activity Score.

It is based on the assessment for 28 joints and points are given for:

Swollen joints
Tender joints
ESR/CRP result

Question 24

Other than serology, what is looked for before diagnosing Rheumatoid Arthritis? (3)

Answer 24

The joints that are involved (more and smaller joints score higher)

Inflammatory markers (ESR and CRP)

Duration of symptoms (more or less than 6 weeks)

Question 25

Which imaging / scans are helpful in diagnosing R.A?

Answer 25

X-rays to see bony changes - look for joint destruction and deformity, soft tissue swelling, periarticular osteopenia and boney erosions

USS of the joints can be used to evaluate and confirm synovitis.

Question 26

Look

Answer 26

The exact trigger of the inflammation in R.A is unknown. However, we do know which cells are involved.

Question 27

Role of macrophages and fibroblast like synoviocytes in inflammatory process in R.A?

Answer 27

They secrete cytokines such as:
TNF alpha
IL-1 
IL-6 
Which promote inflammation

Question 28

How do cytokines affect the Fibroblast-like (type B) synoviocytes in the synovium?

Answer 28

They stimulate them which causes them to become activated and they then proliferate. They can also move joint-joint hence why you get symmetrical joint involvement.

At the same time, they begin assisting in RANKL expression which results in osteoclast activity

They also start to produce proteases which cause cartilage degradation. The cartilage then also produces proteases and it becomes a vicious cycle.

Question 29

RANKL expression together with cytokines stimulates what?

Answer 29

Osteoclast activity

which leads to bone erosion

Question 30

What is the T-cell involvement in inflammatory process in the joint space in R.A?

Answer 30

Promote inflammation

Secrete IL-17 which promotes macrophage activity as well as stimulate the fibroblast synoviocytes

Help in expression of RANKL which stimulates/speeds up osteoclast activity - bone erosion

Question 31

What is the plasma cell involvement in inflammatory process in the joint space in R.A?

Answer 31

There aren’t many plasma cells in the joint space in R.A

They assist in inflammation through cytokines and antibodies

Question 32

Where do you find immune complexes in R.A?

Answer 32

In the synovial fluid in the joint space

They promote inflammation

Question 33

How is Angiogenesis involved?

Answer 33

New blood vessels form during inflammatory process in order to recruit immune cells and provide nutrients to hyperplastic synovium

Cytokines help increase vascular impermeability etc allowing for more immune cells to migrate into the joints ( this is how the auto-antibodies such as RF and ACP and immune cells produced in lymph nodes elsewhere migrate into the joint)