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Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain

¹ Department of Orthopaedic Surgery, NYU-Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10033
² Department of Orthopaedic Surgery, Stanford University, 450 Broadway, Pavilion C, Redwood City, CA 94063
³ Department of Anesthesia, Stanford University, 300 Pasteur Drive, Stanford, CA 94305-5117. E-mail address: dcyeomans{at}stanford.edu

Investigation performed at Jackson North Medical Center, North Miami Beach, Florida, and Stanford University Medical Center, Stanford, California

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from Cytonics Corporation. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Cytonics Corporation). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

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Methods: This prospective cohort study included thirty-two patients without rheumatoid arthritis who had knee pain for less than six months, with either an acute or insidious onset, and elected to have arthroscopic treatment after nonoperative management had failed. Twenty-three of these patients elected to have the contralateral, nonoperatively treated knee lavaged at the time of arthroscopy. Fifteen asymptomatic control subjects also contributed samples of knee joint fluid, for a total of seventy samples from forty-seven subjects. Lavage of the operatively treated, contralateral, and control knees was performed with the patient under regional anesthesia prior to arthroscopy, if applicable, by the infusion of sterile saline solution into the knee followed by the immediate withdrawal into a syringe. The concentrations of seventeen inflammatory cytokines and chemokines were measured with use of a multiplexed immunoassay panel. Preoperative magnetic resonance imaging findings and cytokine assay results were compared with intraoperative findings.

Results: Multivariate analysis of variance detected significantly greater concentrations of interferon gamma (IFN-); interleukins 2, 4, 6, 10, and 13 (IL-2, IL-4, IL-6, IL-10, and IL-13); monocyte chemotactic protein-1 (MCP-1); and macrophage inflammatory protein-1 beta (MIP-1β) in fluid samples from painful knees than in samples from nonpainful knees. Correlation analysis demonstrated a significant positive correlation between patient-reported pain scores and concentrations of IL-6 (Spearman = 0.7), MCP-1 ( = 0.8), MIP-1β ( = 0.6), and IFN- ( = 0.6). These four cytokines also demonstrated a positive correlation with each other ( = 0.5 to 0.7). The presence of IFN-, IL-6, MCP-1, or MIP-1β performed as well as magnetic resonance imaging in the prediction of intraoperative findings.

Conclusions: Intra-articular concentrations of four inflammatory cytokines IFN-, IL-6, MCP-1, and MIP-1β correlated to pain in patients with symptomatic meniscal tears in the knee but were markedly lower in asymptomatic normal knees and in asymptomatic knees with meniscal tears. These cytokines may be involved in the generation of pain following meniscal injury.

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