Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Alterations in the Hypoxic Joint Environment and Blood Vessel Maturity Pre/Post Anti-Tnf Therapy
Kennedy, Aisling, Ng, Chin Teck, Biniecka, Monika, O'Sullivan, Jacintha, Veale, Douglas J., Fearon, Ursula
Angiogenesis is an early event in inflammatory arthritis. Persistent mature blood vessels within the synovial tissue following treatment of arthritis may be re-activated to induce a pro-inflammatory response. The aim of this study is to assess blood vessel maturity and stability pre/post anti-TNFa therapy and examine their relationship to in vivo tissue oxygen pO2, disease activity scores and angiogenic growth factor expression.
Twenty IA patients were assessed at baseline and three months post anti-TNFa therapy. Response to treatment was assessed using DAS28 and CRP scores. Using a specialist pO2 probe (Licox), pO2 levels in synovial tissue (ST) in vivo under direct visualisation at arthroscopy were assessed at baseline and 3 months post therapy. Matched serum, synovial fluid (SF) and ST were collected. Blood vessel (BV) maturity was assessed by dual immuno-fluorescent staining using Factor VIII (endothelial cell marker) and aSMA (pericyte marker). 8 dihydro 2'-deoxyguanosine (8-oxo-dG), a marker of pro-mutagenic lesions, was used to assess oxidative DNA damage in situ in ST by IHC. VEGF and Ang2 were measured by ELISA.
Seventy-five % of patients responded to anti-TNFa therapy, which reduced DAS from 4.49 (2.766.52) (median (range)) to 3.17 (1.544.48) (median (range)) (p<0.05). At baseline a significant number of immature vessels (showing no pericyte recruitment, indicating a loss of endothelial/pericyte cell-cell contact) was demonstrated in patients with inflammatory arthritis (p<0.01), in contrast to OA and normal tissue where all vessels had acquired pericytes and were mature. A significant reduction in number of synovial blood vessels (Factor VIII) was demonstrated post therapy (p<0.05), in contrast to aSMA, where there was no significant change. This resulted in a significant increase in BV maturity in responders (p<0.01) suggesting blood vessel stability and quiescence. This was coupled with a decrease in SF VEGF and Ang2. BV nuclear 8-oxo-dG expression was decreased post-therapy with a lower levels demonstrated in responders vs non-responders (p<0.05). pO2 levels in responders increased from 2.4% (median) at baseline to 3.4% (median) with the pO2 levels in non-responders decreasing from 3.7% to 2.5%. Significant inverse correlations were observed between DAS28-CRP and pO2 (r-0.36, p=0.009), DDAS28 and DBV-maturity (r=-0.606, p=0.008), 8-oxo-dG nuclear % and pO2 (r=-0.391, p=.007). DVEGF and DAng2 correlated with DDAS28 (r=0.39, p<0.05 and r=0.4, p<0.05 respectively).
Blood vessel maturity, stability and DNA damage are reduced post anti-TNFa therapy and associated with disease activity and in vivo pO2 levels. Blood vessel maturity may perpetuate a hypoxic environment within the synovial tissue, driving oxidative damage and maintaining angiogenic growth factor levels.
To cite this abstract, please use the following information:
Kennedy, Aisling, Ng, Chin Teck, Biniecka, Monika, O'Sullivan, Jacintha, Veale, Douglas J., Fearon, Ursula; Alterations in the Hypoxic Joint Environment and Blood Vessel Maturity Pre/Post Anti-Tnf Therapy [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1158