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An adenosine-2A receptor agonist reduces joint inflammation and joint destruction following septic arthrosis (SS-40)

      Infectious arthritis can cause long-term joint morbidity regardless of appropriate early treatment. In addition to the bacteria, the inflammatory response appears to contribute to joint degradation through the production of cytokines (such as IL-8), superoxides, and metalloproteases. We have shown that an adenosine-2A receptor agonist (ATL146e) could be chondroprotective following joint infection with Staphylococcus aureus. The purpose of this study was to determine whether an adenosine agonist might augment the current treatment regimen to prevent the arthritic effects associated with joint sepsis. Methods: An infectious arthritis model was created in rabbit knees. S aureus bacteria were injected into both knees of each rabbit. Sixteen hours following infection (time zero), treatment or no treatment was begun. The 48 rabbits were divided into 4 treatment groups: no treatment (control), ATL146e only, antibiotics only, or antibiotics plus ATL146e (12 rabbits per group). At time zero, mini-osmotic pumps filled with saline (control) or ATL146e were implanted in each rabbit based on the treatment group. Rabbits in the antibiotic treatment groups were given 7 days of intramuscular ceftriaxone, and those in the ATL146e group were given the drug for 72 hours. Analysis at days 1, 3, and 7 consisted of gross appearance, synovial fluid analysis (WBC counts, culture, and interleukin-8 (IL-8) assay), serum WBC count and culture, histologic analysis, and biochemical analysis for glycosaminoglycan (GAG). Results were determined and compared among treatment groups and analyzed statistically by analysis of variance (ANOVA). Results: Serum WBC counts were within normal range for rabbits in all treatment groups. Blood cultures taken prior to euthanasia were negative in all groups despite bilateral knee infections. Synovial fluid cultures at day 7 were positive in 83% of the untreated knees and 100% of the ATL146e only treated knees, but negative in all antibiotic and antibiotic plus ATL146e treated knees indicating clearance of bacteria. Knees in the antibiotic plus ATL146e knees appeared normal with no effusion or loss of motion. Average WBC counts from the synovial fluid aspirates significantly decreased with treatment of antibiotics alone and antibiotics plus ATL146e. IL-8 assay results revealed considerably increased synovial fluid content compared to baseline values, but treatment with antibiotics plus ATL146e significantly decreased the IL-8 content when compared to other treatment groups (P < .001) indicating inflammatory response suppression. Histologic grading using Salter’s scale (0 = best, 15 = worst) resulted in significantly improved scores in the antibiotic plus ATL146e group (2.79) compared to no treatment (6.70), ATL146e only (6.61), and antibiotics only (5.10) (P < .00000001). GAG assay revealed no significant difference among treatment groups. Discussion: Results of this study show the addition of an adenosine-2A agonist to antibiotic therapy diminishes WBC chemotaxis and inflammation in the joint, while not compromising the clearance of intra-articular bacteria. Early bacterial clearance with modulation of the inflammatory response may prevent the long-term arthritic effects of joint sepsis. Results of this study influence the future treatment of septic arthritis and prevent the associated morbidity.