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 (KOOS4) 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 KOOS4. This study is registered with ClinicalTrials.gov, number NCT02667756.

Findings: We 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participants completed a KOOS4 at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable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 KOOS4 improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS4, medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS4 (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 KOOS4 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 associated with symptomatic outcomes but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process need to be better understood to make clinical progress.

Funding: Versus Arthritis, Kennedy Trust for Rheumatology Research, and NIHR Oxford Biomedical Research Centre.

Conflict of interest statement

TLV reports consultancy fees from GlaxoSmithKline, UCB, and Mundipharma and has also received research grants from Galapagos, Fidia, and Samumed. NKA reports consultancy fees from Pfizer/Lilly and received a grant in a related area of research from Merck. AJ reports consultancy fees from Freshfields Bruckhaus Deringer and from Anthera Pharmaceuticals. AW is a board member and holds stock in Fortius Clinic, has received research grants from Smith and Nephew, is a board member and shareholder in Innovate Orthopaedics, and a shareholder in DocComs. FEW has received clinical study grants from Pfizer and Astellas Pharma, reports consultancy fees from Pfizer, and is part of a consortium receiving some of its research funding from Galapagos, Fidia, and Samumed. All other authors report no competing interests.

© 2021 The Authors. Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

Figures

Figure 1

The primary outcome KOOS4, for all individuals in the 2-year dataset at baseline and at 2 years The KOOS4 is a composite score calculated from a patient-reported outcome measure, from 0 (extreme knee symptoms) to 100 (no knee symptoms). KOOS4=Knee Injury and Osteoarthritis Outcome Score based on a composite of four subscales (pain, symptoms, sports and recreation, and quality of life).

Figure 2

NHANES frequent knee pain and KOOS4 at 2 years, according to radiographic osteoarthritis status (A) NHANES frequent knee pain at 2 years in the 53 participants in the 2-year dataset also undergoing knee x-ray at 2 years. The percentage of patients reporting NHANES frequent knee pain for each category are printed above the relevant column. Fisher's exact test to test 2 × 2 contingency for no osteoarthritis versus new osteoarthritis, in the presence or absence of NHANES symptoms, showed no significant difference (two-sided test, p=0·20). Fisher's exact test to test 2 × 2 contingency for no progression versus progression or new osteoarthritis, in presence or absence of NHANES symptoms, showed no significant difference (two-sided test, p>0·99). (B) KOOS4 at 2 years in the 52 study participants in the 2-year dataset also undergoing knee x-ray at 2 years. The Kruskal Wallis test to test for differences between groups showed no significant difference (p=0·69). KOOS4=Knee Injury and Osteoarthritis Outcome Score based on a composite of four subscales (pain, symptoms, sports and recreation, and quality of life).NHANES=National Health and Nutrition Examination Survey. *No evidence of radiographic osteoarthritis at baseline or 2 years. †New radiographic osteoarthritis (Kellgren and Lawrence grade for osteoarthritis [KLG] ≥2) at 2 years (new osteoarthritis). ‡Evidence of KLG 1 or more at baseline with no progression (no progression). §This category includes new osteoarthritis (as previously defined) or progression (progression of at least 1 grade on KLG, where KLG is 1 or more at baseline).