Abstract
Background: Joint Injury is a major risk factor for osteoarthritis (OA) and an opportunity to prospectively examine its early processes. We investigated whether predefined baseline factors including demographic, clinical factors and protein analytes in knee synovial fluid (sf/SF) and in plasma/serum were associated with clinically relevant outcomes at two years after knee injury.
Methods: This was a longitudinal cohort study (REC10/H0805/39;NCT02667756) with 150 individuals aged 16-50 recruited within 8 weeks of a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically being treated surgically. Twelve SF and four plasma/serum biomarkers were measured by immunoassay as the exposures of interest. Primary outcome was “Knee Injury and Osteoarthritis Outcome Score” (KOOS)4. X-ray/3T-MRI knees were taken at baseline and two years. Linear and logistic regression models adjusting for predefined covariates assessed associations with 2year KOOS4 and secondary endpoints including new symptomatic (regular knee symptoms), tibio-femoral radiographic OA (TFROA, Kellgren Lawrence Grade 2 or more on an X-ray) respectively.
Findings: Baseline KOOS4, medium/large knee effusion and moderate/severe SF blood staining and their interaction significantly predicted 2year KOOS4 (Coeff. -20·5 [95% confidence interval -34·8, -6·18]. Of the predefined markers, only sfMCP-1 and sfIL-6 -showed independent associations with 2year KOOS4 (-0.015[0.027,-0.004] and -0.0005[-0.0009,-0.0001] per change in 1 pg/ml units respectively), jointly with the interaction of effusion and blood staining accounting for 39% of outcome variability. New TFROA at two years was associated with baseline meniscal tear (OR5·7[1·25,25·92]). 13/22(59·1%) with new TFROA had no NHANES frequent knee symptoms. Only 3month medium/large effusion was associated with new symptomatic TFROA at two years (OR14·0[1·86,105·27]). No sf/blood markers were associated with predefined structural/symptomatic outcomes.
Interpretation: Effusion-haemarthrosis was strongly associated with symptomatic outcomes after acute knee injury. The SF molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic 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 needs to be better understood to make clinical progress.
Methods: This was a longitudinal cohort study (REC10/H0805/39;NCT02667756) with 150 individuals aged 16-50 recruited within 8 weeks of a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically being treated surgically. Twelve SF and four plasma/serum biomarkers were measured by immunoassay as the exposures of interest. Primary outcome was “Knee Injury and Osteoarthritis Outcome Score” (KOOS)4. X-ray/3T-MRI knees were taken at baseline and two years. Linear and logistic regression models adjusting for predefined covariates assessed associations with 2year KOOS4 and secondary endpoints including new symptomatic (regular knee symptoms), tibio-femoral radiographic OA (TFROA, Kellgren Lawrence Grade 2 or more on an X-ray) respectively.
Findings: Baseline KOOS4, medium/large knee effusion and moderate/severe SF blood staining and their interaction significantly predicted 2year KOOS4 (Coeff. -20·5 [95% confidence interval -34·8, -6·18]. Of the predefined markers, only sfMCP-1 and sfIL-6 -showed independent associations with 2year KOOS4 (-0.015[0.027,-0.004] and -0.0005[-0.0009,-0.0001] per change in 1 pg/ml units respectively), jointly with the interaction of effusion and blood staining accounting for 39% of outcome variability. New TFROA at two years was associated with baseline meniscal tear (OR5·7[1·25,25·92]). 13/22(59·1%) with new TFROA had no NHANES frequent knee symptoms. Only 3month medium/large effusion was associated with new symptomatic TFROA at two years (OR14·0[1·86,105·27]). No sf/blood markers were associated with predefined structural/symptomatic outcomes.
Interpretation: Effusion-haemarthrosis was strongly associated with symptomatic outcomes after acute knee injury. The SF molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic 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 needs to be better understood to make clinical progress.
| Original language | English |
|---|---|
| Article number | E648-E658 |
| Pages (from-to) | e648-e658 |
| Number of pages | 11 |
| Journal | Lancet Rheumatology |
| Volume | 3 |
| Issue number | 9 |
| Early online date | 24 Jun 2021 |
| DOIs | |
| Publication status | E-pub ahead of print - 24 Jun 2021 |
Bibliographical note
Funding Information: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.
Funding Information:
This work was supported by project grants from the Kennedy Trust for Rheumatology Research , Versus Arthritis ‘Pain Challenge' project grant ( 21509 ), and Centre for OA Pathogenesis Versus Arthritis ( grants 20205 and 21621 ). FEW is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship ( MR/S016538/1 ) and was also supported during this work in part by the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. FEW and NKA are members of the Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, University of Oxford (grant 21595). AJ was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are our own and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. We have not been paid to write this article by a pharmaceutical company or other agency. We thank Versus Arthritis for funding this work and the Kennedy Trust for Rheumatology Research and UKRI for supporting the KICK cohort and FEW. We wish to thank Jeremy Saklatvala for his role in the conception of the study. We also thank Charlotte Kerr and Gretchen Brewer for administrative support, Joanne Milligan for technical support, and Brian Marsden, Vinod Kumar, and Andrew Freidin for database and data management support. We also thank KICK study participants and sites, particularly the Fortius Clinic for their assistance.
Funding Information:
This work was supported by project grants from the Kennedy Trust for Rheumatology Research, Versus Arthritis ?Pain Challenge' project grant (21509), and Centre for OA Pathogenesis Versus Arthritis (grants 20205 and 21621). FEW is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S016538/1) and was also supported during this work in part by the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. FEW and NKA are members of the Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, University of Oxford (grant 21595). AJ was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are our own and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. We have not been paid to write this article by a pharmaceutical company or other agency. We thank Versus Arthritis for funding this work and the Kennedy Trust for Rheumatology Research and UKRI for supporting the KICK cohort and FEW. We wish to thank Jeremy Saklatvala for his role in the conception of the study. We also thank Charlotte Kerr and Gretchen Brewer for administrative support, Joanne Milligan for technical support, and Brian Marsden, Vinod Kumar, and Andrew Freidin for database and data management support. We also thank KICK study participants and sites, particularly the Fortius Clinic for their assistance.
Publisher Copyright:
© 2021 The Authors. Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license