25. Introduction to RA

Question 1

What is arthritis?

Answer 1

• arthron* = joint
• itis* = inflammation

Arthritis = inflammed joint

• Umbrella term for >100 different types of arthritis currently identified
• Disability & reduced quality of life (elderly)

Question 2

Facts & figures for Arthritis in the Australian population

Answer 2

2011-12

• approx. 3.3 milion (1 in 6; 15%) had arthritis
• prevalence higher in indigenous than non-indigenous
• 95% cases due to OA, RA, gout (chrystalline disease)
• 2012 - total cost of arthritis & musculoskeletal conditions = $55.1 billion
• predicted by 2050, 7 million Australians expected to suffer some form of arthritis (roughly 1 in 3)

Question 3

Define RA and what does it lead to?

Answer 3

• Chronic inflammatory autoimmune disease of unknown aetiology
• associated with articular menifestations (dominant feature), and systemic (extra-articular) complications

Leads to:

• progressive disability (wheelchair bound w/in 20 yrs)
• reduced life expectancy
• significant socioeconomic costs

Question 4

What is the primary manifestation of RA?

Answer 4

Primary manifestation = synovial inflammation (synovitis)

⇒ erosion of bone, cartilage, peri-articular structures

Question 5

Epidemiology of RA

Answer 5

In adult Caucasian populations:

• Incidence = 8-98 cases per 100,000/annum
• Prevalence = 0.5 to 1.0% (# of existing cases at any given time)
• 2-3x more common in females than males
• peak age of onset = 40 (40-70 range)

Question 6

Describe the principle of all autoimmune diseases

Answer 6

Genetic susceptibility

+

Environmental trigger

⇒

break down of immune tolerance (self reactive Ab or T cells)

⇒

AUTOIMMUNE DISEASE

Question 7

What are the genetic risk factors for RA?

Answer 7

HLA

• in studies of identical twins, genetics accounts for 50-60% disease susceptibility
• Genetic risk factors
  
  • human leukocyte antigen (HLA) ~12.7%
  • non-HLA ~4%
• HLA Class II (most important) - located on c’some 6
  
  • DRB1 gene - encodes HLA-DR antigen presenting molecule
  • allelic variants: DRB1*0401, DRB1*0404

Question 8

What is the ‘shared epitope’?

Answer 8

HLA-DRB1 alleles which confer RA risk encode a 5 amino acid sequence (shared epitope)

*highly conserved sequence

• QKRAA
• occupies positions 70-74 of HLA-DRß chain
• surrounds peptide binding groove (determines Ag-binding specificity & presentaiton to CD4+ Th cells)

Question 9

Shared epitope in RA susceptibility

Answer 9

Proposed role of SE

• efficient binding of arthritogenic (citrulline) peptides
• thymic selection of autoimmune T cells (+ve or -ve)
• target for T cells
  
  • molecular mimicry - SE & microbes (eg. Epstein-Barr virus)
• marker of immunoreactivity
  
  • anti-citrulline protein antibodies (ACPA) expression
• polarises T-cell differentiation to Th type 17 (autoimmunity)

does not necessarily predict progression

• cohort with recent onset undifferentiated (ACPA+) arthritis, progression to RA occurred regardless of HLA-DR genotype

may predict RA severity

• increased joint damage (eg. erosions - two copies)
• increased prevalance extra-articular manifestations

Question 10

Non HLA genetic risk factors

Answer 10

PTPN22

• 2 fold
• encodes lymphoid tyrosine phosphatase
• role in T and B cell signaling
• no role in RA risk in asians

PADI4

• 2 fold
• primarily in asian populations

Question 11

MIcrochimerism

Answer 11

• possibly explains why SE is not associated with RA in certain ethnic and racial groups
• maternal cells of SE-expressing women persist in their children’s circulation throughout adulthood
  
  • confers increased RA risk
• termed non-inheritable maternal antigens (NIMA)