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

Purpose:

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.

Method:

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.

Results:

Seventy-five % of patients responded to anti-TNFa therapy, which reduced DAS from 4.49 (2.76–6.52) (median (range)) to 3.17 (1.54–4.48) (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).

Conclusion:

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
DOI: 10.1002/art.26232

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