Clinical and molecular associations with outcomes at 2 years after acute knee injury: a longitudinal study in the Knee Injury Cohort at the Kennedy (KICK)

Abstract

Background Joint injury is a major risk factor for osteoarthritis and provides an opportunity to prospectively examine early processes associated with osteoarthritis. We investigated whether predefined baseline demographic and clinical factors, and protein analytes in knee synovial fluid and in plasma or serum, were associated with clinically relevant outcomes at 2 years after knee injury.Methods This longitudinal cohort study recruited individuals aged 16-50 years between Nov 1, 2010, and Nov 28, 2014, across six hospitals and clinics in London, UK. Participants were recruited within 8 weeks of having a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically treated surgically. We measured several predefined clinical variables at baseline (eg, time from injury to sampling, extent and type of joint injury, synovial fluid blood staining, presence of effusion, self-reported sex, age, and BMI), and measured 12 synovial fluid and four plasma or serum biomarkers by immunoassay at baseline and 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS 4 ) at 2 years, adjusted for baseline score, assessed in all patients. Linear and logistic regression models adjusting for predefined covariates were used to assess associations between baseline variables and 2-year KOOS 4 . This study is registered with ClinicalTrials.gov, number NCT02667756. FindingsWe enrolled 150 patients at a median of 17 days (range 1-59, IQR 9-26) after knee injury. 123 (82%) were male, with a median age of 25 years (range 16-50, IQR 21-30). 98 (65%) of 150 participants completed a KOOS 4 at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable adjusted analysis. In the 2-year dataset mean KOOS 4 improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS 4, medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS 4 (n=77; coefficient -20•5, 95% CI -34•8 to -6•18; p=0•0060). The only predefined biomarkers that showed independent associations with 2-year KOOS 4 were synovial fluid MCP-1 (n=77; -0•015, 0•027 to -0•004 per change in 1 pg/mL units; p=0•011) and IL-6 (n=77; -0•0005, -0•0009 to -0•0001 per change in 1 pg/mL units; p=0•017). These biomarkers, combined with the interaction of effusion and blood staining, accounted for 39% of outcome variability. Two adverse events occurred that were linked to study participation, both at the time of blood sampling (one presyncopal episode, one tenderness and pain at the site of venepuncture).Interpretation The combination of effusion and haemarthrosis was significantly associated with symptomatic outcomes after acute knee injury. The synovial fluid molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently as...

Human synovial fluid interleukin‐6, but not type II collagen breakdown, positively correlated with pain after anterior cruciate ligament injury and reconstruction

“…In a study by Watt et al, higher preoperative synovial fluid IL‐6 was associated with a lower (worse) Knee Injury and Osteoarthritis Outcome Score 4 (KOOS 4 ) measured at baseline 21 . Another study of patients with acute knee injuries found a significant negative correlation ( p = 0.017) between synovial fluid IL‐6 and KOOS 4 scores at 2 years following surgery 22 . The pain subdomain of the KOOS 4 score (KOOS pain) highly correlated with overall KOOS 4 scores at 2 years, 22 indicating a likely positive correlation between IL‐6 and pain, agreeing with the results of the present study.…”

Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis

“…Mounting data have highlighted the importance of chemokines in acute knee injuries and osteoarthritis (OA) in both clinical [ 4 – 6 ] and preclinical studies [ 7 – 9 ]. The chemokine family comprises several protein members, including the chemokine (C–C motif) ligand type 2 (CCL2), which binds the same C–C chemokine receptor 2 (CCR2) [ 10 ], and they are known to be involved in the recruitment of immune cells at sites of inflammation [ 9 , 11 ].…”

Harmonising knee pain patient-reported outcomes: a systematic literature review and meta-analysis of Patient Acceptable Symptom State (PASS) and individual participant data (IPD)

“…Web-Based Exercises for Treating Knee Osteoarthritis (WebEx) (NCT03545048) was an RCT exploring the effectiveness of internet-based exercises in individuals with a diagnosis of knee osteoarthritis, which reported NRS and WOMAC pain scales 13 . Knee Injury Cohort at the Kennedy (KICK) (NCT02667756) was a longitudinal cohort study aiming to identify biomarkers predicting outcomes in individuals with a clinically significant acute knee injury, which collected NRS and KOOS pain scales 14 . Meniscal Tear and Osteoarthritis Risk (MenTOR) (NCT02684864/REC15/SC/0551) is an active observational cohort study exploring clinical outcome prediction by knee synovial fluid biomarkers in individuals with degenerative meniscal tear, which also collected NRS and KOOS pain scales.…”