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Editorial Commentary: Serum Cartilage Oligomeric Matrix Protein Appears to Be the Most Useful Biomarker for Tracking Early Osteoarthritis of the Knee in Anterior Cruciate Ligament Deficient Patients (But May Also Reflect Synovitis)

      Abstract

      Owing to chondral or meniscal pathology sustained at the time of injury, patients who sustain anterior cruciate ligament injury are at risk of knee osteoarthritis (OA). Thus, recognition of early OA is critical. Detection of joint space narrowing on radiography has been described as outdated, and furthermore, the different descriptions of the Kellgren-Lawrence criteria have an impact on the classification of OA of the lowest grade (Kellgren-Lawrence grade ≥ 1). Serum cartilage oligomeric matrix protein (COMP) may allow detection of early OA in patients with anterior cruciate ligament deficiency because significantly higher levels have been observed in patients with early OA than in patients with non-early OA. Serum COMP appears to be the most useful of the biomarkers studied. Prior studies have shown correlations with OA in animal models and via magnetic resonance imaging evaluation. However, I would be hesitant about widespread use. It is possible that the serum COMP level reflects not only cartilage damage but also synovitis. This may be particularly misleading in patients with diagnoses of rheumatologic disorders and/or undiagnosed genetic HLA-B27 variants.
      Owing to chondral or meniscal pathology sustained at the time of injury, patients who sustain anterior cruciate ligament (ACL) injury are at risk of knee osteoarthritis (OA).
      • Keays S.L.
      • Newcombe P.A.
      • Bullock-Saxton J.E.
      • Bullock M.I.
      • Keays A.C.
      Factors involved in the development of osteoarthritis after anterior cruciate ligament surgery.
      Because of a high prevalence of symptomatic cartilage lesions in the knee compared with other joints and underlying substantial economic implications,
      • Jackson D.W.
      • Simon T.M.
      • Aberman H.M.
      Symptomatic articular cartilage degeneration: The impact in the new millennium.
      much attention has been given to this topic. Typical modalities for identification and diagnosis of OA including physical examination and radiographic imaging may only show positive findings after substantial and irreparable disease progression has already occurred and the ideal time for early treatment has been missed.
      • Marijnissen A.C.
      • Vincken K.L.
      • Vos P.A.
      • et al.
      Knee Images Digital Analysis (KIDA): A novel method to quantify individual radiographic features of knee osteoarthritis in detail.
      This implies recognition of early OA to be critical. Detection of joint space narrowing on radiography has been described as outdated,
      • Guermazi A.
      • Roemer F.W.
      • Burstein D.
      • Hayashi D.
      Why radiography should no longer be considered a surrogate outcome measure for longitudinal assessment of cartilage in knee osteoarthritis.
      and furthermore, the different descriptions of the Kellgren-Lawrence criteria have an impact on the classification of OA of the lowest grade (Kellgren-Lawrence grade ≥ 1).
      • Schiphof D.
      • de Klerk B.M.
      • Kerkhof H.J.
      • et al.
      Impact of different descriptions of the Kellgren and Lawrence classification criteria on the diagnosis of knee osteoarthritis.
      In the diagnosis of early OA, magnetic resonance imaging (MRI) enables measurement of longitudinal changes in quantitative cartilage morphology in knee OA
      • Guermazi A.
      • Roemer F.W.
      • Burstein D.
      • Hayashi D.
      Why radiography should no longer be considered a surrogate outcome measure for longitudinal assessment of cartilage in knee osteoarthritis.
      ; however, it has limitations such as invasiveness and lack of cost-effectiveness. In their elegant study “Serum Cartilage Oligomeric Matrix Protein Detects Early Osteoarthritis in Patients With Anterior Cruciate Ligament Deficiency,” Nishida, Hashimoto, Orita, Nishino, Kinoshita, and Nakamura
      • Nishida Y.
      • Hashimoto Y.
      • Orita K.
      • Nishino K.
      • Kinoshita T.
      • Nakamura H.
      Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency.
      not only showed that serum cartilage oligomeric matrix protein (COMP) levels were significantly higher in the early OA group than in the non-early OA group but also were able to define an optimum cutoff value for the serum COMP level of 152 ng/mL, which may be used to detect early cartilage change in patients with ACL deficiency. Nishida et al. provide an interesting and clinically relevant study in a well-written article advocating the use of serum COMP in an effort to track changes over time in the same patient, thus allowing any potential progression of cartilage degeneration to be identified without the need for arthroscopic evaluation or repeated costly MRI.
      The message is interesting because it focuses on the use of blood work, namely the serum COMP level, for tracking of the progression of early OA. Nishida et al.
      • Nishida Y.
      • Hashimoto Y.
      • Orita K.
      • Nishino K.
      • Kinoshita T.
      • Nakamura H.
      Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency.
      showed significantly higher serum COMP levels in patients graded as having early OA versus non-early OA (187.4 ng/mL vs 130.8 ng/mL, P < .001). Appropriately, the criteria used for the determination of early OA included International Cartilage Repair Society grade I to IV in at least 2 compartments or grade II to IV in 1 compartment with at least surrounding softening and swelling of the cartilage. Furthermore, the results via multiple logistic regression analysis showed age (odds ratio, 1.09; 95% confidence interval, 1.02-1.16; P = .01) and serum COMP level (odds ratio, 1.02; 95% confidence interval, 1.01-1.04; P < .001) to be independent factors for the presence of early OA arthroscopic cartilage findings. These objective data are valuable especially in counseling, suggesting that it is possible to detect and track early OA in these high-risk patients.
      As with any study, there are limitations. Pre-existing lesions may be a confounding factor. On multivariate analysis, age and serum COMP level were both factors for the detection of early OA. Furthermore, within the study cohort, patients in the early OA group had a relatively high age (mean, 28.6 years), which was statistically significantly higher than the age in the non-OA group. Finally, although a post hoc analysis was performed, showing that 10 subjects in each group would be required for a small effect size for age and serum COMP level, the relatively small sample size was underpowered to detect differences in body mass index and preoperative Tegner Activity Scale score between the 2 groups.
      The study by Nishida et al.
      • Nishida Y.
      • Hashimoto Y.
      • Orita K.
      • Nishino K.
      • Kinoshita T.
      • Nakamura H.
      Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency.
      provides evidence for a relatively benign and cost-effective strategy for identifying early OA in patients with ACL deficiency. Although I am cautiously optimistic regarding the use of serum COMP levels for the detection of early OA, I would be hesitant regarding widespread use. Among biomarkers, many have been studied, such as serum N-propeptide of collagen IIA and urinary C-telopeptide fragments of type II collagen, which can detect the uncoupling of type II collagen synthesis and degradation.
      • Garnero P.
      • Ayral X.
      • Rousseau J.C.
      • et al.
      Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis.
      Although serum COMP appears to be the most useful given that prior studies have shown correlations with OA in animal models
      • Lai Y.
      • Yu X.P.
      • Zhang Y.
      • et al.
      Enhanced COMP catabolism detected in serum of patients with arthritis and animal disease models through a novel capture ELISA.
      and via MRI evaluation,
      • Streich N.A.
      • Zimmermann D.
      • Schmitt H.
      • Bode G.
      Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
      there may be concerns. It is possible that the serum COMP level reflects not only cartilage damage but also synovitis.
      • Zivanovic S.
      • Rackov L.P.
      • Zivanovic A.
      • Jevtic M.
      • Nikolic S.
      • Kocic S.
      Cartilage oligomeric matrix protein—Inflammation biomarker in knee osteoarthritis.
      This may be particularly misleading in patients with diagnoses of rheumatologic disorders and/or undiagnosed genetic HLA-B27 variants.
      As surgeons, we need to continue to push the limits in terms of earlier diagnosis to optimize outcomes for our patients while also not being the first or last to adapt to innovation. This study is a great example. Nishida et al.
      • Nishida Y.
      • Hashimoto Y.
      • Orita K.
      • Nishino K.
      • Kinoshita T.
      • Nakamura H.
      Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency.
      were able to identify an optimum cutoff value for the serum COMP level that may be used to detect early cartilage change in patients with ACL deficiency. Further longitudinal studies are required; however, serum COMP levels may be used to follow variations over time indicating progression of cartilage degeneration without a need for costly MRI or physically invasive arthroscopy.

      Supplementary Data

      References

        • Keays S.L.
        • Newcombe P.A.
        • Bullock-Saxton J.E.
        • Bullock M.I.
        • Keays A.C.
        Factors involved in the development of osteoarthritis after anterior cruciate ligament surgery.
        Am J Sports Med. 2010; 38: 455-463
        • Jackson D.W.
        • Simon T.M.
        • Aberman H.M.
        Symptomatic articular cartilage degeneration: The impact in the new millennium.
        Clin Orthop Relat Res. 2001; : S14-S25
        • Marijnissen A.C.
        • Vincken K.L.
        • Vos P.A.
        • et al.
        Knee Images Digital Analysis (KIDA): A novel method to quantify individual radiographic features of knee osteoarthritis in detail.
        Osteoarthritis Cartilage. 2008; 16: 234-243
        • Guermazi A.
        • Roemer F.W.
        • Burstein D.
        • Hayashi D.
        Why radiography should no longer be considered a surrogate outcome measure for longitudinal assessment of cartilage in knee osteoarthritis.
        Arthritis Res Ther. 2011; 13: 247
        • Schiphof D.
        • de Klerk B.M.
        • Kerkhof H.J.
        • et al.
        Impact of different descriptions of the Kellgren and Lawrence classification criteria on the diagnosis of knee osteoarthritis.
        Ann Rheum Dis. 2011; 70: 1422-1427
        • Nishida Y.
        • Hashimoto Y.
        • Orita K.
        • Nishino K.
        • Kinoshita T.
        • Nakamura H.
        Serum cartilage oligomeric matrix protein detects early osteoarthritis in patients with anterior cruciate ligament deficiency.
        Arthroscopy. 2022; 38: 873-878
        • Garnero P.
        • Ayral X.
        • Rousseau J.C.
        • et al.
        Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis.
        Arthritis Rheum. 2002; 46: 2613-2624
        • Lai Y.
        • Yu X.P.
        • Zhang Y.
        • et al.
        Enhanced COMP catabolism detected in serum of patients with arthritis and animal disease models through a novel capture ELISA.
        Osteoarthritis Cartilage. 2012; 20: 854-862
        • Streich N.A.
        • Zimmermann D.
        • Schmitt H.
        • Bode G.
        Biochemical markers in the diagnosis of chondral defects following anterior cruciate ligament insufficiency.
        Int Orthop. 2011; 35: 1633-1637
        • Zivanovic S.
        • Rackov L.P.
        • Zivanovic A.
        • Jevtic M.
        • Nikolic S.
        • Kocic S.
        Cartilage oligomeric matrix protein—Inflammation biomarker in knee osteoarthritis.
        Bosn J Basic Med Sci. 2011; 11: 27-32