RA and SS SGT

Question 1

is RA one disease?

Answer 1

• Very heterogeneous
• Fibroblast drive, myeloid driven, T cell driven
• Phenotypic description
• ACPA positive and negative

Question 2

what are the risk factors for ACPA+ RA?

Answer 2

• Shared epitope – shared peptide-binding groove in HLA-DRB4 that increases citrullinated peptide presentation
• PTPN22 controls TCR signal, variant loses TCR control
• Smoking
  These 3 risk factors increases ACPA

ACPA negative group lack this – they have HLA-DR3 variant

Question 3

what could be targeted in RA?

Answer 3

• Shift from pro to anti-inflammatory environment – increase pro-resolution pathway
• Could target fibroblasts that drive damage and inflammation
• Could inhibit inflammation and then remove pathogenic fibroblasts and increase resolution mechanisms

Question 4

why might Th17 targeting be useful in RA?

Answer 4

• IL-23 blockade can prevent TH17 development in psoriatic arthritis, but not effective in RA
• IL-23 works in preventing disease, but not in established disease
• IL-23 alters antibody glycosylation to make it more pathogenic
• Blockade prevents this

Question 5

what evidence is there for adaptive immunity playing a role in RA and SS?

Answer 5

• T and B cell infiltrates in both
• RA: ACPA, RF
• SS: anti-Ro, anti-La
• Abatacept targets T cells and works in ACPA+ patients

Question 6

why does SS lag behind RA in drug development?

Answer 6

• Lack of biomarkers
• Systemic disease whereas RA can be targeted at joint
• Cytokine networks: Anti-TNF didn’t work because it is protective
• too few patients and very heterogeneous

Question 7

why is drug development too difficult in some diseases?

Answer 7

• Trials focus on single diseases, not shared mechanisms
• Funding is key – if diseases are rare funding is scarce
• Sometimes patient populations are too small for large cohort trials
• Different science disciplines don’t share the mechanisms/therapy