SAT0051 BARICITINIB IMPROVES JOINT MOBILITY AFTER INJURY IN A RODENT FORCED-AMBULATION MODEL
Authors: Kelly Knopp, Akihiko Kato, Theron Wall, Jeff S. Mcdermott, Eric S. Nisenbaum, Benjamin Adams, Michael Johnson
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Movement-evoked pain and impaired joint mobility are common comorbidities in inflammatory diseases such as Rheumatoid Arthritis (RA) and Osteoarthritis. The Janus kinase (JAK) pathway has been implicated in both inflammation and chronic pain. Clinical data suggests that baricitinib, a selective JAK 1/2 inhibitor, can robustly and rapidly alleviate pain in RA.<sup>1</sup>Utilizing a rodent forced-ambulation model, we have previously shown attenuation of gait deficits with analgesics such as opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and an anti-NGF (Nerve Growth Factor) antibody.<sup>2</sup> However, in this same model a fusion protein blocker of TNFα (tumor necrosis factor alpha) signaling failed to demonstrate efficacy though inflammation was decreased. The present work investigated the potential of baricitinib, recently approved for treatment of RA, to reduce inflammagen-induced joint pain and gait impairment in this model of joint inflammation mediated pain. <h3>Objectives</h3> To determine if JAK 1/2 pathway inhibition is effective in treating inflammagen-induced joint pain and gait impairment. <h3>Methods</h3> Unilateral joint injury was induced in female Sprague Dawley rats (Harlan, Indianapolis, IN, USA) by unilateral intra-articular injection of 20 μg Complete Freund's Adjuvant (CFA). Using the GaitScan (CleverSys Inc., Reston, VA) treadmill system, a composite gait score comprising of range of motion, normalized stance distance, stance/swing ratio, and paw print size was evaluated over 3 days post-injection.<sup>2</sup> Rats were treated with vehicle, positive control (40 mg/kg Tramadol), or clinically relevant (based on plasma levels) increasing doses of baricitinib (1, 3, or 10 mg/kg p.o., 2-hrs prior to each test, q.d.). Dorsal root ganglion (DRG) were harvested post-gait evaluation and Total STAT3 (Cell Signaling, #4904) and phospho-STAT3 (Y705) (Cell Signaling, #9131) protein levels were examined via immunoblotting. The p-values were derived from repeated measures ANOVAs. <h3>Results</h3> In rat DRG homogenates, baricitinib significantly decreased phospho-STAT3 (Y705) protein levels in a dose-dependent manner (p&lt;0.01) with a significant effect after a 3 mg/kg dose and a maximal response after a 10 mg/kg in both the ipsilateral (right) and contralateral (left) sides. Total STAT3 protein levels remained unchanged. Similarly, treatment with baricitinib significantly improved composite gait score at the 10 mg/kg dose (p&lt;0.05) by Day 3. <h3>Conclusion</h3> These data indicate that treatment with baricitinib attenuates CFA-induced joint deficits, a surrogate measure of joint pain. This effect correlated with the pharmacodynamic inhibition of JAK-STAT signaling in DRGs. These data support a role for JAK-STAT signaling in pain signaling and provide an opportunity to investigate the potential mechanism of action of baricitinib in joint pain. <h3>References</h3> [1] Keystone. Ann Rheum Dis. 2017;76(11):1853-1861. [2] Adams. Osteoarthritis Cartilage. 2016;24(11):1928-1939. <h3>Disclosure of Interests</h3> Kelly Knopp Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Akihiko Kato Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Theron Wall Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jeff S Mcdermott Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Eric S Nisenbaum Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Benjamin Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Michael Johnson Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company