The Impact of Excluding Patients with End-Stage Knee Disease in Intra-Articular Hyaluronic Acid Trials: A Systematic Review and Meta-Analysis

IntroductionThe Kellgren-Lawrence (K-L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease.MethodsWe conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K-L grade criteria. The primary outcome was mean change in pain from baseline at 4-13weeks and 22-27weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE).ResultsTwenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4-13weeks [SMD=-0.30, 95% CI -0.44 to -0.15, p<0.0001] and within 22-27weeks [SMD=-0.27, 95% CI -0.39 to -0.16, p<0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR=1.76, 95% CI 1.16-2.67, p=0.008].ConclusionIA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort.FundingFerring Pharmaceuticals.