BARICITINIB IMPROVES JOINT MOBILITY AFTER INJURY IN A RODENT FORCED-AMBULATION MODEL

Background: 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. 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. 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. Objectives: To determine if JAK 1/2 pathway inhibition is effective in treating inflammagen-induced joint pain and gait impairment. Methods: 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. 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. Results: In rat DRG homogenates, baricitinib significantly decreased phospho-STAT3 (Y705) protein levels in a dose-dependent manner (p<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<0.05) by Day 3. Conclusion: 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. Figure 1 Representative still images from video recordings of animals during gait analysis at baseline (Top Panel), 3 Days post-CFA and vehicle treatment (Middle Panel) and 3 Days post-CFA with 10 mg/kg daily baricitinib treatment (Bottom panel). The ventral image of the rat illustrates the same part of the gait cycle (ipsilateral stance phase initiation) across treatment groups to highlight impairment in the CFA-injected limb (Red Box) vs Baseline and apparent improvement following 10 mg/kg baricitinib treatment. The panels on the left provide examples of software-detected paw prints for each treatment group which show that CFA + vehicle treatment produced a small, closed-toed paw print (Middle) which appears restored to near baseline levels following baricitinib treatment (Bottom). REFERENCES: [1] Keystone. Ann Rheum Dis. 2017;76(11):1853-1861. [2] Adams. Osteoarthritis Cartilage. 2016;24(11):1928-1939. Disclosure of Interests: 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 DOI: 10.1136/annrheumdis-2019-eular.1751Citation: Ann Rheum Dis, volume 78, supplement 2, year 2019, page A1089Session: Rheumatoid arthritis - etiology, pathogenesis and animal models (Scientific Abstracts)