Copyright © 2009 by The Journal of Bone and Joint Surgery, Inc.

Commentary & Perspective

Commentary & Perspective on
"Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain"
by Jason M. Cuellar, MD, PhD, et al.

Commentary & Perspective by
Michael A. Mont, MD*,
The Sinai Hospital of Baltimore, Baltimore, Maryland

Posted October 2009

Knee arthroscopy is one of the most common procedures that orthopaedic surgeons perform in the United States each year. Recently, the need for performing some of these procedures has been questioned1,2. One of the primary indications is clinically important meniscal tears. We typically rely on a combination of history, physical examination, and magnetic resonance imaging to diagnose these tears3,4. However, it is well-known that magnetic resonance imaging may diagnose meniscal injuries in more than 50% of the asymptomatic population, especially in patients who are more than forty years of age5,6. There have been few other laboratory or diagnostic tools that have been used to further evaluate symptomatic joints, except in the presence of infection or inflammatory conditions. It is not clear why some patients with meniscal injuries have clinically important pain while others remain asymptomatic.

In the study "Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain," Cuellar et al. analyzed thirty-two patients who had knee pain for less than six months and who had elected to undergo an arthroscopy after nonoperative treatment had failed. They analyzed the joint fluid aspirate from this group of knees (preoperatively) and from twenty-three of the contralateral noninvolved knees and compared the findings to those from fifteen asymptomatic control knees. They measured the concentrations of seventeen inflammatory cytokine-chemokines. They then compared magnetic resonance imaging findings with these assay results as well as with the intraoperative findings. The authors found that intra-articular concentrations of inflammatory cytokines correlated with pain in patients with symptomatic meniscal tears but were markedly lower in the asymptomatic normal knees and in asymptomatic knees with meniscal tears. On the basis of this study, they concluded that the cytokines may be involved in the generation of pain following meniscal injury.

The importance of this work is that this may be a first step in the development of a more sensitive and specific test for symptomatic meniscal tears. The sensitivity and specificity of using history, physical examination, and magnetic resonance imaging are extremely low. It appears that, on the basis of the results of this preliminary study, (in this reviewer's opinion) these tests could lead to a much better differentiation of asymptomatic and symptomatic individuals, and perhaps more clearly define the indications for surgery. Therefore, these types of tests might determine which patients are best suited for continued nonoperative treatment and which may be best served by surgical intervention. In this study, the tests were 100% sensitive and specific for symptomatic meniscal tears.

In addition, knowledge of the specific cytokines that are involved in meniscal injuries, as well as the pain pathway, may lead to further insights concerning meniscal or cartilage pathophysiology. Various inflammatory cytokines have been implicated in the local production of knee pain. Some of these cytokines may sensitize nociceptors, resulting in pain. In addition, blockade of tumor necrosis factor-alpha leads to pain relief in patients with rheumatoid arthritis7. These various cytokines may be related to the inflammatory or healing process in the knee8.

A strength of this study is that it was performed prospectively on a well-defined cohort of patients. All thirty-two patients had magnetic resonance imaging of the lavaged knee preoperatively along with the performance of appropriate tests, and the results could easily be compared with the intraoperative findings. The study was well planned, with independent observation of the magnetic resonance imaging scans as well as the intraoperative findings.

There were certain limitations of the study, including that this was a small sampling of patients (n = 32) from a single center. Two of the patients who underwent surgery did not have meniscal injury despite positive findings on magnetic resonance imaging and, in some cases, there was sample loss. In addition, what could be a major problem is that it may be hard to create a standardized system for lavaging and aspirating joints. Certainly, sometimes one patient may have a much larger effusion in the knee joint than another patient does (by an order of tenfold or more), which can certainly dilute any cytokines. For this test to be clinically useful, a much more sophisticated analysis of the concentration of the cytokines, corrected for the amount of effusion that is present, will need to be performed. This may not be only a concentration effect, but it may also be a function of the total amount of cytokines that are present, which would be overexpressed as a concentration in joints that have a minimal amount of fluid. In some patients, the joint aspirations may be contaminated with blood, which may affect the measurements. It is good that the authors have pointed out many of the potential biases in their study, such as the possibility of greater dilution of cytokines in patients with an effusion than in patients without an effusion.

In summary, the authors have found a greater concentration of four inflammatory cytokines and/or chemokines from intra-articular aspirates from painful knees with operatively confirmed meniscal injuries as compared with the concentrations found in nonpainful control knees as well as age-matched atraumatic control knees. These tests might be useful in the future to add information about clinical judgments concerning meniscal injuries and the further development of a diagnostic test. In addition, it is possible that increased understanding of these cytokine factors in the knee may lead to the development of additional antinociceptives, pain medications, or other intra-articular reagents for treatment.

*The author did not receive any outside funding or grants in support of his research for or preparation of this work. The author, or a member of his 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 (Stryker, Wright Medical).


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