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SAT0039 In vivo fluorescence-imaging of matrix metalloproteinase activity and response to therapy in an animal model of rheumatoid arthritis
  1. I.H. Tarner1,
  2. F. Werner2,
  3. C. Schimmelpfennig2,
  4. A. Deten2,
  5. C. Oelkrug2,
  6. U. Müller-Ladner1,
  7. J. Boltze2,
  8. A. Kranz2,
  9. E. Neumann1
  1. 1Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Bad Nauheim
  2. 2Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany

Abstract

Background Prevention of joint destruction and thus patient disability is the most important long-term goal of rheumatoid arthritis (RA) therapy. However, despite intensive treatment efforts this goal is frequently not achieved. A non-invasive imaging technique that facilitates in vivo monitoring of the destructive process and the anti-destructive efficacy of anti-rheumatic drugs would be highly beneficial to improve RA therapy.

Objectives For this purpose, we evaluated fluorescence-based in vivo molecular imaging of matrix metalloproteinase (MMP) activity in an animal model of RA to assess the process of inflammatory joint destruction, the efficacy of different anti-rheumatic drugs, and the optimal time point for treatment initiation.

Methods MMP activity was detected by in vivo imaging of an MMP-activated, fluorescenctly labeled smart probe (MMPsense-680, PerkinElmer) in arthritic joints of mice with collagen-induced arthritis (CIA). Animals were imaged weekly 24 hours after intravenous probe injection for 4 weeks. Drug treatment included placebo (NaCl), dexamethasone (DXA, 0.5 μg/g body weight), etanercept (ETC, 5 μg/g) methotrexate (MTX, 10 μg/g) and ETC + MTX, starting either on day 28 (early) or on day 35 (late).

Results In vivo fluorescence imaging showed a steep increase in MMP activity in placebo treated mice at the time of clinical arthritis manifestation that correlated well with the degree of clinical arthritis severity (r=0.715, p<0.05) and slowly decreased over the following 3 weeks. DXA (n=8) and early ETC + MTX (n=9) treatment resulted in significantly lower clinical severity of arthritis compared with placebo, whereas early and late ETC monotherapy (n=9 and n=10, respectively), early and late MTX monotherapy (n=7 and n=9, respectively) as well as late ETC + MTX (n=9) had no significant effect. Correspondingly, MMP activity was found to increase only mildly from baseline at the time of clinical arthritis onset in the DXA and early ETC + MTX therapy groups and declined more rapidly compared with placebo and all other treatment groups. By contrast, MMP activity in the placebo and all other treatment groups reached significantly higher fluorescence values than DXA and early ETC + MTX. Interestingly, while MMP activity declined in all groups over time, it only returned to near-baseline levels in DXA treated animals.

Conclusions In vivo fluorescence imaging of MMP activity in CIA allows effective monitoring of disease activity and treatment response. Early ETC + MTX and DXA therapies are superior to other treatment regimens.

Disclosure of Interest None Declared

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