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Vincent the Lumper!
- 1. Tonia Vincent Kennedy Institute of Rheumatology University of Oxford Vincent the Lumper!
- 2. Disclosures Have consulted for GSC, UCB, Mundipharma over past 3 years.
- 4. “She’s ferocious…..” “Hope he’s strong; she’s the most argumentative woman I know…..” “She will never go with the tide if she can swim against it…..” Hilary Davan Wetton 2019 (Tonia’s husband)
- 5. Argument • There is currently no evidence that distinct endotypes exist – ‘Metabolic OA’ – ‘Post-traumatic OA’ – ‘Inflammatory OA’ – ‘Site-specific OA’ • There is currently no evidence that stratification in OA has clinical utility: – To identify new pathogenic pathways – To identify new treatments – To predict response to treatment – To predict course of disease
- 7. “Metabolic OA” • Metabolic syndrome: at least three of the following: – Obesity – Hypertension – Diabetes mellitus – High triglycerides – Low HDL
- 9. “METABOLIC OSTEOARTHRITIS” Is there evidence for a distinct endotype? Is there evidence that patient benefit could be gained by this knowledge? NO!
- 11. Evidence that PTOA and age-related OA are synonymous • Diseases resemble one another • Share general mechanism of pathogenesis • Pathogenic molecules/pathways, identified in mouse, influence human age-related disease
- 12. Extreme OA Non-OA SuperimposedIntroduction ative assessment of bone odelling in murine OA cognised player in the development and netically modified mouse models of OA are scovery in OA. throughput approaches for assessing bone and f OA combined with conventional molecular nalysis of subchondral bone on of osteophytogenesis cartilage xpression in subchondral bone Mantovani1,2, Anastasios Chanalaris2, Niharika Midha1, Tonia Vincent2, Massimo Marenzana1,2 , Imperial College London, 2The Kennedy Institute of Rheumatology, University of Oxford. DMM model of OA by alysis ORD CENTRE FOR OA PATHOGENESIS 3D imaging of hyaline cartilage by contrast-enhanced microCT Segmentation threshold Registration of DMM to Controlateral Lateral view Medial view SB.Pl. AC Marenzana, Vincent, unpublished
- 13. OCCUPATIONAL RISK OBESITY MALALIGNED JOINTS INCREASED LOAD ON NORMAL JOINT Mechanical injury is the common pathogenic pathway in OA ACUTE JOINT INJURY AGEING NORMAL LOAD ON A JOINT THAT HAS LOST ITS MECHANOPROTECTIVE MECHANISMS
- 14. “Mechanoflammation” PAIN Alexander et al, 2007, A&R Gruber et al, 2003, A&R Ismail et al, A&R, 2015 Ismail et al, A&R, 2016a Driscoll et al, 2014, A&R McNamee et al, 2010, A&R Inglis et al, 2008, Pain Von Loga et al, 2019, MATRIX DEGRADATION NFkB INFLAMMATORY GENES e.g. NGF REPAIR SMAD2/3 Vincent et al, 2002, PNAS Chia et al, 2012, A&R Vincent et al, 2004, A&R Tang et al, 2018, ARD Tang et al, 2016 A&R Madej et al, 2015, OAC Scharstuhl et al, 2002, J Imm CHONDROCYTE Mechanosensitive pathways drive OA FGF2 TGFbR FGFR3 Ion channels JNK2 TAK1 Wnts ? O’Conor et al, 2014, PNAS Lee et al, 2014, PNAS Nalesso et al, 2017, ARD Dell’Accio et al, 2008, A&R Putative Gene Developmental phenotype? Human OA risk factor Murine OA risk factor Predicted therapeutic target LTBP1 no Agonist LTBP3 no Agonist TBFb1 yes Agonist SMAD3 no Agonist GDF5 yes Agonist FGFR3 yes Agonist FGF18 yes Agonist
- 15. PAIN Alexander et al, 2007, A&R Gruber et al, 2003, A&R Ismail et al, A&R, 2015 Ismail et al, A&R, 2016a Driscoll et al, 2014, A&R McNamee et al, 2010, A&R Inglis et al, 2008, Pain Von Loga et al, 2019, MATRIX DEGRADATION NFkB INFLAMMATORY GENES e.g. NGF REPAIR SMAD2/3 Vincent et al, 2002, PNAS Chia et al, 2012, A&R Vincent et al, 2004, A&R Tang et al, 2018, ARD CHONDROCYTE FGF2 TGFbR FGFR3 Ion channels JNK2 TAK1 Wnts “MECHANOFLAMMATION” O’Conor et al, 2014, PNAS Lee et al, 2014, PNAS Nalesso et al, 2017, ARD Dell’Accio et al, 2008, A&R We ek 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 60 70 80 90 100 110 120 Pain levels after post injury vaccination weeks post surgery PercentageWeightBearing MOCK VAX pre vaccination time period: groups not randomized week 15 boost week 12 boost week 10 prime
- 16. “POST- TRAUMATIC OSTEOARTHRITIS” Is there evidence for a distinct endotype? Is there evidence that patient benefit could be gained by this knowledge? NO!
- 18. “Inflammatory OA” • 18-50% inflammatory ‘erosive’ hand OA according to XRay/MRI • Do anti-inflammatory treatments alter course of OA? • Do anti-inflammatory treatments alter course of OA in subset of patients with ‘more inflammatory’ OA? • 100% patients have synovitis by enhanced MRI
- 19. Does anti-inflammatory treatment work in OA?
- 20. Does targeting cytokines work in OA?
- 21. Does inflammation predict response to anti-inflammatory treatment??
- 22. • 140 symptomatic knee OA patients • RCT 12 weekly i.a. triamcinolone or saline • F/U 2 years; 3 monthly clinical outcomes, yearly MRI.
- 23. “INFLAMMATORY OSTEOARTHRITIS” Is there evidence for a distinct endotype? Is there evidence that patient benefit could be gained by this knowledge? NO!
- 26. Is Hand OA different? • Non weight-bearing joint • Strong hormonal association • Strong female preponderance (90%) • Distinct genetic association? Hip OA
- 27. “SITE-SPECIFIC OSTEOARTHRITIS” Is there evidence for a distinct endotype? Is there evidence that patient benefit could be gained by this knowledge? NO!
- 29. TRAUMA METABOLISM INFLAMMATION GENETIC FACTORS AGE DISTINCT PATHWAY COMMON PATHWAY OA
- 30. MECHANICAL INJURY AGE OA PROMOTING ”MECHANOFLAMMATION” REDUCING ABILITY TO REPAIR INFLAMMATION GENES COMMON PATHWAY OBESITY
- 31. DISCLAIMER ALERT: THESE INDIVIDUALS HAVE BEEN RUTHLESSLY EXPLOITED WITHOUT THEIR KNOWLEDGE…..
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