Real-World Effectiveness and Safety of Intra-Articular Polynucleotide for Knee Osteoarthritis: Large Multicenter Observational Study with Repeated Treatment

Background/Objectives: Intra-articular polynucleotide (PN) has emerged as an alternative to hyaluronic acid (HA) for treating knee osteoarthritis (OA), with randomized controlled trials (RCTs) reporting similar or greater pain reduction. Real-world evidence on both single- and repeated-cycle outcomes remains limited. This study evaluated PN’s real-world effectiveness and safety and whether its pain reduction falls within ranges reported in previous PN–HA RCTs, and evaluated repeated-cycle outcomes. Methods: Clinical data from 1048 PN-treated OA patients were retrospectively reviewed. The safety set comprised 1024 patients with follow-up visits. The efficacy set included 975 patients who completed 3–5 weekly PN injections with evaluable VAS, CGI, and PGI data at baseline, 3, and 6 months. A repeated-treatment subgroup (n = 45) received a second PN cycle 6 months later. First-cycle outcomes were compared with PN–HA RCTs. Results: In the first-cycle (n = 975), VAS decreased from 50.30 mm to 23.02 and 22.43 mm at 3 and 6 months (−27.28 and −27.87 mm; p < 0.0001), showing a comparable magnitude to RCT-reported ranges (~27–41 mm). CGI improvement was 81.0% and 79.6%, and PGI improvement 78.8% and 78.1% at 3 and 6 months. In the repeated-treatment subgroup (n = 45), despite a lower second-cycle baseline VAS of 31.00 mm (vs. 50.30 mm at first-cycle baseline), VAS decreased to 14.07 mm and 17.33 mm at 3 and 6 months (−16.93 and −13.67 mm; p < 0.001), achieving comparable absolute post-treatment pain levels. Among 1024 patients, three mild-to-moderate arthralgia events (0.29%) occurred, with no serious device-related adverse events in either cycle. Conclusions: PN provided meaningful 6-month pain reduction in a comparable magnitude to previous RCTs and showed consistent benefit with repeated administration without new safety concerns.