Science of Rheumatic arthritis

Question 1

What are the functions of the synovial membrane (Synovium)?

Answer 1

Functions of synovium:
> Maintenance of intact tissue surface

> Lubrication of cartilage

> Control of synovial fluid volume and composition (hyaluronan, lubricin)

> Nutrition of chondrocytes within joints

Question 2

Which cell types are there in the synovium?

Answer 2

Two cell types:

• Macrophage
• Fibroblast = Produce the components of synovial fluid

Question 3

In Rheumatoid arthritis what does the synovium thicken to form?

Answer 3

The pannus

Question 4

What is Rheumatic arthritis?

Answer 4

Rheumatoid arthritis is a chronic symmetric polyarticular inflammatory joint disease, which primarily affects the small joints of the hands and feet

Question 5

What is rheumatoid synovitis (Pannus) characterised by?

Answer 5

The rheumatoid synovitis (pannus) is characterised by inflammatory cell infiltration, synoviocyte proliferation and neoangiogenesis

Question 6

What does the synovial fluid in the joint cavity contain during Rheumatoid arthritis?

Answer 6

The synovial fluid in the joint cavity contains neutrophils, particularly during acute flares of RA

Question 7

What does the pannus causes?

Answer 7

Bone and cartilage destruction (Deformities)

Question 8

Which autoantibodies are usually present in RA?

Answer 8

Autoantibodies, such as RFs and anti-citrullinated protein antibodies, are commonly associated with RA (Most Common)

Question 9

Which secondary autoantibodies are usually present in RA?

Answer 9

Autoantibodies occur in RA that recognise either joint antigens, such as type II collagen, or systemic antigens, such as glucose phosphate isomerase (Secondary Aa)

Question 10

Seropositive rheumatoid arthritis?

Answer 10

Seropositive rheumatoid arthritis:
> Rheumatoid factor

> Anti-citrullinated protein antibody (ACPA)

> Diagnostic anti-CCP assays recognise citrullinated self-proteins
- α-enolase, keratin, fibrinogen, fibronectin, collagen, vimentin

> Patients with ACPA+ disease have a less favourable prognosis

Question 11

Which serotype is associated with genetic factors leading to RA?

Answer 11

Alleles containing a common amino acid motif (QKRAA – shared epitope) in the HLA-DRB1 region (HLA-DR4 serotype) confer susceptibility:

• Role in promoting autoimmunity (e.g. altered antigen presentation)
• Molecular mimicry (e.g. with microbial proteins)

Other associations = PTPN22, CTLA4, c-REL etc

Question 12

Environmental factors leading to RA?

Answer 12

> Smoking and bronchial stress (exposure to silica)

> Infectious agents have been associated with RA:
Viruses (EBV, CMV)
- E. Coli
- Mycoplasma
- Periodontal disease (Porphyromonas gingivalis)
- Microbiome (gut microbes)

Question 13

What occurs in individuals who are highly susceptible to RA and receive repeated insults of environmental factors?

Answer 13

> Formation of immune complexes and rheumatoid factor (high-affinity autoAb against the Fc portion of Ig)

> Altered citrullination of proteins and breakdown of tolerance, with resulting ACPA response

Question 14

What is synovitis?

Answer 14

Inflammation of the synovium

Question 15

Pathogenesis of RA?

Answer 15

> Villous hyperplasia
Infiltration of T cells, B cells, macrophages and plasma cells
Intimal cell proliferation (fibroblasts)
Production of cytokines and proteases
Increased vascularity
Self-amplifying process

Question 16

How is pathogenicity of CD20+ cells confirmed in RA?

Answer 16

Efficacy of rituximab

Question 17

Role of B cells in RA?

Answer 17

Role of B cells goes beyond production of autoAb
> Autoantigen presentation
> Cytokines (IL-6, TNF-α)

Question 18

What do inflammatory cytokines activate in RA?

Answer 18

> Activate synovial fibroblasts, chondrocytes, osteoclasts

> Promote angiogenesis

> Suppress T-regs

> Activate leukocytes

> Promote autoAb production

> IL-6 mediates systemic effects

Question 19

Which interleukin mediates the systemic effects in RA?

Answer 19

IL-6 mediates systemic effects:
> Acute-phase response
> Anaemia
> Cognitive dysfunction
> Lipid metabolism dysregulation

Question 20

Which interleukin mediates the systemic effects in RA?

Answer 20

IL-6 mediates systemic effects:
> Acute-phase response
> Anaemia
> Cognitive dysfunction
> Lipid metabolism dysregulation

Question 21

Bone destruction in RA?

Answer 21

Bone destruction is mediated by osteoclasts that are activated under the influence of RANKL produced by RA synovium

Question 22

Cartilage destruction in RA?

Answer 22

> Several classes of proteases, including metalloproteinases and aggrecanases are produced by FLS in the intimal lining layer

> Synovial lining cells, especially FLS, can attach to and invade cartilage in RA

Question 23

Key cytokines in RA?

Answer 23

Key cytokines:
TNF-a*
IL-1
IL-6*
RANKL M-CSF

Question 24

Systemic consequences of RA?

Answer 24

> Vasculitis, nodules, scleritis, amyloidosis = secondary to uncontrolled chronic inflammation

> Cardiovascular disease

• Altered lipid metabolism
• Elevated acute-phase reactants
• Increased endothelial activation

> Fatigue and reduced cognitive function (secondary fibromyalgia)
- Dysregulation of the HPA axis

> Liver

• Elevated acute-phase response
• Anaemia of chronic disease (IL-6 increases hepatocyte production of hepcidin, an iron-regulatory hormone)

> Lungs (interstitial lung disease, fibrosis)

> Muscles (sarcopoenia)

> Bone (osteoporosis)

> Secondary Sjogren’s syndrome