Abstract 755: Mouse IL-1 Trap Reduces Pain and Inflammation in Animal Models of Gout
Assil Saleh, M.D.
Authors:
Richard Torres, Lynn Macdonald, Joel Reinhardt, Susan D. Croll, Donna M. Hylton, John S. Rudge, George D. Yancopoulos, Andrew J. Murphy.
Background:
Interleukin-1 (IL-1) may be a principal mediator of pain and inflammation in gout and pseudogout, and its release may be triggered by monosodium urate and calcium pyrophosphate dihydrate crystals. Blocking IL-1, therefore, may be a viable strategy to control pain and inflammation in these disorders. This hypothesis was addressed in a murine joint pain model of gout through the use of IL-1 receptor 1 knockout mice as well as mIL-1 Trap, a high-affinity mouse IL-1 blocker.
Methods:
The authors developed a novel joint pain model of gout by injecting monosodium urate into murine ankle joints and recording measures of pain and swelling. IL-1 receptor 1 knock-out mice and mice treated with mIL-1 Trap were studied. In addition, peritonitis induced by crystal injection as well as subcutaneous air pouch models of gout and pseudogout inflammation were also studied.
Results:
Crystal-induced peritonitis and subcutaneous air pouch models of gout and pseudogout inflammation in IL-1R1-knock out mice exhibited diminished neutrophil influx compared to controls (p<0.05).
Neutrophil infiltration was prevented in crystal-induced peritonitis mouse models by administering mIL-1 Trap (at 35 mg/kg) (p<0.05). This efficacy was equivalent to the effect of maximum dose colchicine (2mg/kg), and histology confirmed the abrogation of ankle inflammation by mIL-1 Trap.
Pain, inflammation, and SAA levels were significantly diminished in IL-1R1 knock-out mice, and mIL-1 Trap significantly diminished thermal and mechanical pain, swelling, and SAA rises in mice whose ankles were injected with monosodium urate crystals.
Conclusions:
The authors conclude that inhibiting IL-1 decreases inflammation and pain in mouse models of gout, suggesting that rilonacept (human IL-1 Trap) may be a viable therapeutic option for treating gout in humans.
Editorial:
This is a small and elegant proof-of-concept study that provides compelling evidence for the role of IL-1 in the pain and inflammation associated with gout. Two lines of study—a murine IL-1R1 knock-out model and an IL-1 inhibitor (mIL-1 Trap)—are employed to demonstrate the decrease in inflammation and pain seen in crystal-induced mouse gout. Evidence is presented suggesting comparable efficacy of mIL-1 Trap therapy with colchicine, suggesting that this approach may be just as effective, but probably not superior, to colchicine therapy in humans. Certainly, conclusions on the relevance of these data to human therapy with rilonacept await randomized clinical trials of this agent in humans. The identification of an alternative therapy for gout would certainly be a welcome development.
