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Hyperalgesia, synovitis, and multiple biomarkers of inflammation are suppressed by IL-1 inhibition in a novel animal model of gouty arthritis
  1. Richard Torres (richard.torres{at}regeneron.com)
  1. Regeneron Pharmaceuticals, United States
    1. Lynn MacDonald
    1. Regeneron Pharmaceuticals, United States
      1. Susan D Croll
      1. Regeneron Pharmaceuticals, Queens College of CUNY, United States
        1. Joel Reinhardt
        1. Regeneron Pharmaceuticals, United States
          1. Anthony Dore
          1. Regeneron Pharmaceuticals, United States
            1. Sean Stevens
            1. Regeneron Pharmaceuticals, United States
              1. Donna M Hylton
              1. Regeneron Pharmaceuticals, United States
                1. John S Rudge
                1. Regeneron Pharmaceuticals, United States
                  1. Ru Liu-Bryan
                  1. VA Medical Center and University of California at San Diego, United States
                    1. Robert A Terkeltaub
                    1. VA Medical Center and University of California at San Diego, United States
                      1. George D Yancopoulos
                      1. Regeneron Pharmaceuticals, United States
                        1. Andrew J Murphy
                        1. Regeneron Pharmaceuticals, United States

                          Abstract

                          Objective: Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced IL-1β release contributes to inflammation in subcutaneous air pouch and peritoneal models of acute gout and pseudogout. However, consequences of IL-1 inhibition have not been explored in more clinically relevant models of crystal-induced arthritis. In this study, we developed a novel mouse model of acute gouty ankle arthritis, and used it to assess the effects of genetic deletion of IL-1R1 and of exogenous mIL-1 Trap (a high-affinity blocker of mouse IL-1α and IL-1β) on pain, synovitis, and systemic inflammatory biomarkers.

                          Methods: MSU crystals were injected into the mouse ankle joint, and pain and ankle swelling were measured over 4 days. The effects of IL-1 inhibition were determined in this model, as well as in the comparator models of crystal-induced peritonitis and subcutaneous air pouch inflammation.

                          Results: Both IL-1R1-null mice and mice pre-treated with mIL-1 Trap showed reduced neutrophil influx in MSU and CPPD crystal-induced peritonitis and air pouch models (p<0.05). In the ankle joint model, both IL-1R1 knockout mice and pre-treatment with mIL-1 Trap were associated with significant reductions in MSU crystal-induced elevations in hyperalgesia, inflammation, SAA, and the levels of multiple inflammatory cytokines and chemokines (p<0.05). In addition, we observed that administration of mIL-1 Trap following MSU crystal injection reduced established hyperalgesia and ankle swelling.

                          Conclusions: IL-1 inhibition both prevented and relieved pain and ankle joint inflammation in response to intra-articular MSU crystals in mice. Results suggested that IL-1 Trap has the potential to both prevent and treat gouty arthritis.

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