Published 11/21/2020
Kerri Fitzgerald

Three Biomarkers Predict Postoperative Pain, Osteoarthritis after Knee Injury

Editor’s note: The following content was originally scheduled for the AAOS Now Daily Edition, which publishes each year onsite at the AAOS Annual Meeting, but this year’s meeting in March was canceled due to COVID-19. Despite the cancellation, members can access virtual content from the Annual Meeting by visiting the Academy’s Annual Meeting Virtual Experience webpage at aaos.org/VirtualAAOS2020.

Following injury to the articular surface of the knee, measurable changes in the joint microenvironment can occur, including altered expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), aggrecanases, growth factors, and apoptotic factors. A study that was presented by Matthew Thomas Kingery, MD, a post-graduate year-1 resident at NYU Langone Orthopedic Hospital, as part of the Annual Meeting Virtual Experience assessed the impact of 10 synovial fluid biomarkers at the time of knee injury and found that three specific biomarkers can predict with moderate accuracy functional outcomes and level of pain at five years postoperatively.

“The development of post-traumatic osteoarthritis (PTOA) affects a large percentage of patients with anterior cruciate ligament (ACL) tears, meniscus tears, and other knee injuries,” Dr. Kingery told AAOS Now. “Even when an injury is surgically treated, the joint is at a significantly increased risk of PTOA 10 or more years following the initial insult. It is believed that the accelerated cartilage degradation associated with PTOA is the result of inflammatory chemokines released into the joint space at the time of injury. In other words, the initial seed of PTOA is planted at the time of the injury, and there may be a specific pattern of molecular biomarkers in the synovial fluid (i.e., an inflammatory phenotype) that is able to predict which patients are at the highest risk of diminished function and development of OA as a result of their knee trauma.”

The study prospectively enrolled 39 patients (mean age at time of surgery, 41.56 years) undergoing primary knee arthroscopy for ACL injury, meniscus injury, and/or focal chondral lesion beginning in October 2011. Patients were excluded if they had any additional associated ligament injury, systemic inflammatory disease, autoimmune disease, intra-articular corticosteroid injection in the three months before surgery, prior knee surgery, immunomodulatory drug use, chemotherapy within the past year, insufficient synovial fluid aspiration, or cartilage/meniscal transplantation in addition to arthroscopy. Those aged 18 years or younger also were excluded.

Immediately prior to surgical incision, synovial fluid was aspirated from the operative knee and transferred to sterile tubes containing a protease inhibitor cocktail solution. The samples were centrifuged at 3,820 rpm for 10 minutes, and the supernatant was aliquoted into sterile tubes before storage at –80 degrees Celsius. After thawing, the samples were assayed with a multiplex magnetic bead immunoassay, and researchers assessed the concentration of 10 cytokines and chemokines that have previously been suggested to play a role in cartilage degradation and inflammation in the joint space.

Patients with a minimum of five years of postoperative follow-up were contacted and asked to complete the visual analog scale (VAS) pain score, Lysholm Knee Scoring Scale, and Knee Injury and Osteoarthritis Outcome Score Physical Function Short-form (KOOS-PS).

Five patients (12.8 percent) had isolated ACL injuries, 15 (38.5 percent) had isolated meniscus injuries, 15 (38.5 percent) had combined ACL and meniscus injuries, and four (10.3 percent) had focal chondral defects. The mean time from surgery to follow-up was 6.79 years. Eleven patients (28.2 percent) underwent further ipsilateral knee surgery during follow-up.

At final follow-up, mean Lysholm score was 83.67, mean KOOS-PS score was 88.37, and mean VAS pain score was 11.03.

Among 28 patients who did not undergo further surgery since the time of synovial fluid sampling, the biomarkers MMP-3 (a proinflammatory enzyme), TIMP-2 (an anti-inflammatory inhibitor of MMPs), and vascular endothelial growth factor (an angiogenesis-inducing growth factor) most accurately predicted functional outcomes at five years postoperatively. Regardless of the type of injury and degree of cartilage damage observed at the time of surgery, those three biomarkers could explain 60.35 percent of the variability in Lysholm score, 34.75 percent of the variability in KOOS-PS score, and 39.38 percent of the variability in VAS pain score at five years postoperatively. Dr. Kingery told AAOS Now that these findings “support the idea that the specific constitution of the intra-articular microenvironment following injury at the time of surgery may play an important role in the development and progression of associated joint degradation over time.”

“We will continue to follow the functional status of the patients enrolled in this study,” he continued. “In 10 to 15 years, a subset of the patients will have developed end-stage OA requiring arthroplasty, and we will be able to develop further models that predict not only diminished function but also the eventual development of PTOA. We hope that further investigation will allow us to describe changes in the synovial fluid microenvironment over time as cartilage degradation takes place and OA develops. The ultimate goal is to be able to sample a patient’s synovial fluid at the time of injury and accurately predict who is at the highest risk of developing PTOA in the future. Additionally, the identified cytokines may serve as potential targets for therapeutic intervention in the acute injury period to slow the degeneration of cartilage.”

The study is limited by its small patient cohort and limited follow-up for some patients. In addition, the study assessed only 10 biomarkers; additional cytokines may be found in synovial fluid that may have equal or greater predictive ability, according to Dr. Kingery.

Dr. Kingery’s coauthors of “Synovial Fluid Biomarkers at the Time of Arthroscopy Predict Five-Year Outcomes” are Amit Koushik Manjunath, Danielle Heather Markus, Elyse Jordan Berlinberg, Lena Kenny, and Eric Jason Strauss.

Kerri Fitzgerald is the managing editor of AAOS Now. She can be reached at kefitzgerald@aaos.org.