Christian Lattermann1, Cale A Jacobs1, Mary Proffitt Bunnell2, Laura J Huston3, Lee G Gammon4, Darren L Johnson1, Emily K Reinke3, Janet L Huebner5, Virginia B Kraus5, Kurt P Spindler6. 1. Department of Orthopedic Surgery and Sports Medicine, University of Kentucky, Lexington, Kentucky, USA. 2. Division of Physical Therapy, University of Kentucky, Lexington, Kentucky, USA. 3. Vanderbilt Orthopaedic Institute, Nashville, Tennessee, USA. 4. University of Kentucky College of Medicine, Lexington, Kentucky, USA. 5. Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA. 6. Cleveland Clinic Sports Health Center, Garfield Heights, Ohio, USA.
Abstract
BACKGROUND: It is increasingly recognized that biochemical abnormalities of the joint precede radiographic abnormalities of posttraumatic osteoarthritis (PTOA) by as much as decades. A growing body of evidence strongly suggests that the progression from anterior cruciate ligament (ACL) injury to PTOA is multifactorial, involving the interplay between biomechanical disturbances and biochemical homeostasis of articular cartilage. PURPOSE: The purposes of this randomized study using an acute ACL injury model were to (1) evaluate the natural progression of inflammatory and chondrodegenerative biomarkers, (2) evaluate the relationship between subjective reports of pain and inflammatory and chondrodegenerative biomarkers, and (3) determine if postinjury arthrocentesis and corticosteroid injection offer the ability to alter this biochemical cascade. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 49 patients were randomized to 4 groups: group 1 (corticosteroid at 4 days after ACL injury, placebo injection of saline at 2 weeks), group 2 (placebo at 4 days after ACL injury, corticosteroid at 2 weeks), group 3 (corticosteroid at both time intervals), or a placebo group (saline injections at both time intervals). Patient-reported outcome measures and synovial biomarkers were collected at approximately 4 days, 11 days, and 5 weeks after injury. The change between the time points was assessed for all variables using Wilcoxon tests, and the relationship between changes in outcome scores and biomarkers were assessed by calculating Spearman ρ. Outcomes and biomarkers were also compared between the 4 groups using Kruskal-Wallis tests. RESULTS: No adverse events or infections were observed in any study patients. With the exception of matrix metalloproteinase 1 (MMP-1) and tumor necrosis factor-inducible gene 6 (TSG-6), chondrodegenerative markers worsened over the first 5 weeks while all patient-reported outcomes improved during this time, regardless of treatment group. Patient-reported outcomes did not differ between patients receiving corticosteroid injections and the placebo group. However, increases in C-telopeptide of type II collagen (CTX-II), associated with collagen type II breakdown, were significantly greater in the placebo group (1.32 ± 1.10 ng/mL) than in either of the groups that received the corticosteroid injection within the first several days after injury (group 1: 0.23 ± 0.27 ng/mL [ P = .01]; group 3: 0.19 ± 0.34 ng/mL [ P = .01]). CONCLUSION: PTOA begins at the time of injury and results early on in dramatic matrix changes in the knee. However, it is encouraging that early intervention with an anti-inflammatory agent was able to affect biomarkers of chondral degeneration. Should early intervention lead to meaningful changes in either the onset or severity of symptomatic PTOA, the current treatment paradigm for patients with ACL injury may have to be restructured to include early aspiration and intra-articular intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01692756.
RCT Entities:
BACKGROUND: It is increasingly recognized that biochemical abnormalities of the joint precede radiographic abnormalities of posttraumatic osteoarthritis (PTOA) by as much as decades. A growing body of evidence strongly suggests that the progression from anterior cruciate ligament (ACL) injury to PTOA is multifactorial, involving the interplay between biomechanical disturbances and biochemical homeostasis of articular cartilage. PURPOSE: The purposes of this randomized study using an acute ACL injury model were to (1) evaluate the natural progression of inflammatory and chondrodegenerative biomarkers, (2) evaluate the relationship between subjective reports of pain and inflammatory and chondrodegenerative biomarkers, and (3) determine if postinjury arthrocentesis and corticosteroid injection offer the ability to alter this biochemical cascade. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 49 patients were randomized to 4 groups: group 1 (corticosteroid at 4 days after ACL injury, placebo injection of saline at 2 weeks), group 2 (placebo at 4 days after ACL injury, corticosteroid at 2 weeks), group 3 (corticosteroid at both time intervals), or a placebo group (saline injections at both time intervals). Patient-reported outcome measures and synovial biomarkers were collected at approximately 4 days, 11 days, and 5 weeks after injury. The change between the time points was assessed for all variables using Wilcoxon tests, and the relationship between changes in outcome scores and biomarkers were assessed by calculating Spearman ρ. Outcomes and biomarkers were also compared between the 4 groups using Kruskal-Wallis tests. RESULTS: No adverse events or infections were observed in any study patients. With the exception of matrix metalloproteinase 1 (MMP-1) and tumor necrosis factor-inducible gene 6 (TSG-6), chondrodegenerative markers worsened over the first 5 weeks while all patient-reported outcomes improved during this time, regardless of treatment group. Patient-reported outcomes did not differ between patients receiving corticosteroid injections and the placebo group. However, increases in C-telopeptide of type II collagen (CTX-II), associated with collagen type II breakdown, were significantly greater in the placebo group (1.32 ± 1.10 ng/mL) than in either of the groups that received the corticosteroid injection within the first several days after injury (group 1: 0.23 ± 0.27 ng/mL [ P = .01]; group 3: 0.19 ± 0.34 ng/mL [ P = .01]). CONCLUSION: PTOA begins at the time of injury and results early on in dramatic matrix changes in the knee. However, it is encouraging that early intervention with an anti-inflammatory agent was able to affect biomarkers of chondral degeneration. Should early intervention lead to meaningful changes in either the onset or severity of symptomatic PTOA, the current treatment paradigm for patients with ACL injury may have to be restructured to include early aspiration and intra-articular intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01692756.
Authors: John D King; Grant Rowland; Alejandro G Villasante Tezanos; James Warwick; Virginia B Kraus; Christian Lattermann; Cale A Jacobs Journal: Cartilage Date: 2018-07-22 Impact factor: 4.634
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