478 C OPYRIGHT Ó 2015
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
A commentary by Edward Joseph Harvey, MDCM, MSc, is linked to the online version of this article at jbjs.org.
Inflammatory Cytokine Response Following Acute Tibial Plateau Fracture Justin M. Haller, MD, Molly McFadden, MS, Erik N. Kubiak, MD, and Thomas F. Higgins, MD Investigation performed at the Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah
Background: The objective of the present study was to evaluate human synovial fluid for inflammatory cytokine concentrations following acute tibial plateau fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture, and that the inflammatory response would be greater after high-energy compared with low-energy injuries. Methods: Between December 2011 and June 2013, we prospectively enrolled forty-five patients with an acute tibial plateau fracture. Synovial fluid aspirations were performed on the injured and uninjured knees. Twenty patients who required an external fixator followed by delayed fixation underwent aspiration at both surgical procedures. The concentrations of interferon-gamma (IFN-g), interleukin-1 beta (IL-1b), interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, tumor necrosis factor-alpha (TNF-a), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1b) were quantified with use of multiplex assays. Results: The forty-five patients had an average age of forty-two years (range, twenty to sixty years). There were twenty-four lowenergy and twenty-one high-energy tibial plateau injuries. There was a significant difference between injured and uninjured knees (p < 0.001) with regard to concentrations of IL-1b, IL-6, IL-8, IL-10, IL-1RA, and MCP-1. There was not a detectable difference in synovial fluid cytokine concentrations between high and low-energy injuries. The concentrations of IL-10 (p < 0.001), IL-1RA (p = 0.002), IL-6 (p < 0.001), IL-8 (p < 0.001), and MCP-1 (p = 0.002) were significantly greater in the injured knee than in the uninjured knee at the second aspiration, at a mean of 9.5 days (range, three to twenty-one days) after the initial injury. Conclusions: There was a significant local inflammatory response following acute tibial plateau fracture. There was not a detectable difference in inflammatory cytokine concentration between high and low-energy injuries. Synovial fluid concentrations of IL-10, IL-8, IL-6, IL-1RA, and MCP-1 remained elevated at the second aspiration. Clinical Relevance: The articular surface is exposed to acute and sustained concentrations of multiple inflammatory cytokines following intra-articular fracture. Inflammatory cytokines have been associated with the development of primary and inflammatory arthritis, and this research indicates that these factors could also play a role in the development of posttraumatic osteoarthritis.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
P
osttraumatic osteoarthritis is a common cause of disability following intra-articular fracture. It is estimated that posttraumatic osteoarthritis accounts for up to 12% of the cases of symptomatic osteoarthritis, and it is associated
with substantial cost to the health-care system1. Given that the majority of trauma patients are younger, the impact of this condition can be particularly devastating for those in the prime of their working careers2.
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2015;97:478-83
d
http://dx.doi.org/10.2106/JBJS.N.00200
479 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O L U M E 97-A N U M B E R 6 M A R C H 18, 2 015 d
d
d
Posttraumatic osteoarthritis can develop following a variety of joint injuries, but it most predictably occurs after intra-articular fracture. The initial traumatic injury involves a complex process of articular impaction and/or displacement and soft-tissue disruption that leads to exposure of the articular surface to blood and marrow, a local inflammatory response, abnormal joint loading, and chondrocyte necrosis and apoptosis3. However, the exact mechanism(s) that lead to progression from the initial injury to end-stage posttraumatic osteoarthritis are poorly understood. Inflammation can have deleterious effects on a joint. Although inflammatory cytokines have been shown to stimulate osseous repair through osteoclastogenesis and recruitment of osteoblastic cells, multiple studies have demonstrated that these same cytokines also play a role in cartilage degradation4-9. Increased interleukin-1 beta (IL-1b) and tumor necrosis factoralpha (TNF-a) expression has been found in the cartilage of patients with degenerative osteoarthritis, and these cytokines are transiently increased after traumatic injury10,11. The effect of the initial inflammatory response after intraarticular fracture on the development of posttraumatic osteoarthritis remains unknown. Several authors have found elevated levels of cytokines in joints affected by injury12-14. However, they all evaluated patients following an anterior cruciate ligament (ACL) injury. It seemed to us that intra-articular fracture would generate a more robust inflammatory response and may place the joint at greater risk for the development of posttraumatic osteoarthritis. Thus, we thought that investigating the cytokine profile in a joint immediately following intra-articular injury could lead to early-targeted drug therapy with cytokine inhibitors to modify the progression of posttraumatic osteoarthritis or offer prognostic information to guide patient treatment. We are not aware of any studies that demonstrated elevated levels of the inflammatory cytokines and chemokines in the setting of intra-articular fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture and that the inflammatory response would be greater in high-energy injuries than in low-energy injuries. Materials and Methods
A
fter receiving institutional review board approval, we prospectively enrolled all patients older than eighteen years of age who presented to our level-1 trauma center with a tibial plateau fracture from December 15, 2011, through June 30, 2013. Exclusion criteria included an age of more than sixty years; any history of knee osteoarthritis based on previous diagnosis, suggestive history, or radiographic findings; regular use of nonsteroidal anti-inflammatory drugs; any history of autoimmune disease; acute contralateral intra-articular knee injury; open fracture; an inability to speak English; and injury more than twenty-four hours prior to evaluation. Basic patient demographic and socioeconomic data, including age, sex, and comorbidities, were obtained. Fractures were classified according to the AO/OTA 15 16 system and the Schatzker system . Injury Severity Scores (ISSs) were recorded for 17 all patients . Nonosteopenic plateau fractures that were classified as Schatzker type IV, V, or VI were considered high-energy injuries. Additionally, the percentage of articular comminution was calculated. This was done, with use of the freehand region of interest tool in the electronic PACS system (iSite PACS, version 3.6.261.0; Koninklijke Philips Electronics, Foster City, California), by determining the area of the intact tibial plateau on the injured side and comparing it with the area of the intact plateau on the uninjured side. Fragments
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
A commentary by Edward Joseph Harvey, MDCM, MSc, is linked to the online version of this article at jbjs.org.
Inflammatory Cytokine Response Following Acute Tibial Plateau Fracture Justin M. Haller, MD, Molly McFadden, MS, Erik N. Kubiak, MD, and Thomas F. Higgins, MD Investigation performed at the Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah
Background: The objective of the present study was to evaluate human synovial fluid for inflammatory cytokine concentrations following acute tibial plateau fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture, and that the inflammatory response would be greater after high-energy compared with low-energy injuries. Methods: Between December 2011 and June 2013, we prospectively enrolled forty-five patients with an acute tibial plateau fracture. Synovial fluid aspirations were performed on the injured and uninjured knees. Twenty patients who required an external fixator followed by delayed fixation underwent aspiration at both surgical procedures. The concentrations of interferon-gamma (IFN-g), interleukin-1 beta (IL-1b), interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, tumor necrosis factor-alpha (TNF-a), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1b) were quantified with use of multiplex assays. Results: The forty-five patients had an average age of forty-two years (range, twenty to sixty years). There were twenty-four lowenergy and twenty-one high-energy tibial plateau injuries. There was a significant difference between injured and uninjured knees (p < 0.001) with regard to concentrations of IL-1b, IL-6, IL-8, IL-10, IL-1RA, and MCP-1. There was not a detectable difference in synovial fluid cytokine concentrations between high and low-energy injuries. The concentrations of IL-10 (p < 0.001), IL-1RA (p = 0.002), IL-6 (p < 0.001), IL-8 (p < 0.001), and MCP-1 (p = 0.002) were significantly greater in the injured knee than in the uninjured knee at the second aspiration, at a mean of 9.5 days (range, three to twenty-one days) after the initial injury. Conclusions: There was a significant local inflammatory response following acute tibial plateau fracture. There was not a detectable difference in inflammatory cytokine concentration between high and low-energy injuries. Synovial fluid concentrations of IL-10, IL-8, IL-6, IL-1RA, and MCP-1 remained elevated at the second aspiration. Clinical Relevance: The articular surface is exposed to acute and sustained concentrations of multiple inflammatory cytokines following intra-articular fracture. Inflammatory cytokines have been associated with the development of primary and inflammatory arthritis, and this research indicates that these factors could also play a role in the development of posttraumatic osteoarthritis.
Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
P
osttraumatic osteoarthritis is a common cause of disability following intra-articular fracture. It is estimated that posttraumatic osteoarthritis accounts for up to 12% of the cases of symptomatic osteoarthritis, and it is associated
with substantial cost to the health-care system1. Given that the majority of trauma patients are younger, the impact of this condition can be particularly devastating for those in the prime of their working careers2.
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
J Bone Joint Surg Am. 2015;97:478-83
d
http://dx.doi.org/10.2106/JBJS.N.00200
479 TH E JO U R NA L O F B O N E & JO I N T SU RG E RY J B J S . O RG V O L U M E 97-A N U M B E R 6 M A R C H 18, 2 015 d
d
d
Posttraumatic osteoarthritis can develop following a variety of joint injuries, but it most predictably occurs after intra-articular fracture. The initial traumatic injury involves a complex process of articular impaction and/or displacement and soft-tissue disruption that leads to exposure of the articular surface to blood and marrow, a local inflammatory response, abnormal joint loading, and chondrocyte necrosis and apoptosis3. However, the exact mechanism(s) that lead to progression from the initial injury to end-stage posttraumatic osteoarthritis are poorly understood. Inflammation can have deleterious effects on a joint. Although inflammatory cytokines have been shown to stimulate osseous repair through osteoclastogenesis and recruitment of osteoblastic cells, multiple studies have demonstrated that these same cytokines also play a role in cartilage degradation4-9. Increased interleukin-1 beta (IL-1b) and tumor necrosis factoralpha (TNF-a) expression has been found in the cartilage of patients with degenerative osteoarthritis, and these cytokines are transiently increased after traumatic injury10,11. The effect of the initial inflammatory response after intraarticular fracture on the development of posttraumatic osteoarthritis remains unknown. Several authors have found elevated levels of cytokines in joints affected by injury12-14. However, they all evaluated patients following an anterior cruciate ligament (ACL) injury. It seemed to us that intra-articular fracture would generate a more robust inflammatory response and may place the joint at greater risk for the development of posttraumatic osteoarthritis. Thus, we thought that investigating the cytokine profile in a joint immediately following intra-articular injury could lead to early-targeted drug therapy with cytokine inhibitors to modify the progression of posttraumatic osteoarthritis or offer prognostic information to guide patient treatment. We are not aware of any studies that demonstrated elevated levels of the inflammatory cytokines and chemokines in the setting of intra-articular fracture. Our hypothesis was that there would be an elevated inflammatory response following intra-articular fracture and that the inflammatory response would be greater in high-energy injuries than in low-energy injuries. Materials and Methods
A
fter receiving institutional review board approval, we prospectively enrolled all patients older than eighteen years of age who presented to our level-1 trauma center with a tibial plateau fracture from December 15, 2011, through June 30, 2013. Exclusion criteria included an age of more than sixty years; any history of knee osteoarthritis based on previous diagnosis, suggestive history, or radiographic findings; regular use of nonsteroidal anti-inflammatory drugs; any history of autoimmune disease; acute contralateral intra-articular knee injury; open fracture; an inability to speak English; and injury more than twenty-four hours prior to evaluation. Basic patient demographic and socioeconomic data, including age, sex, and comorbidities, were obtained. Fractures were classified according to the AO/OTA 15 16 system and the Schatzker system . Injury Severity Scores (ISSs) were recorded for 17 all patients . Nonosteopenic plateau fractures that were classified as Schatzker type IV, V, or VI were considered high-energy injuries. Additionally, the percentage of articular comminution was calculated. This was done, with use of the freehand region of interest tool in the electronic PACS system (iSite PACS, version 3.6.261.0; Koninklijke Philips Electronics, Foster City, California), by determining the area of the intact tibial plateau on the injured side and comparing it with the area of the intact plateau on the uninjured side. Fragments
