By Wayne Kuznar
San Diego, CA—Biomarkers for osteoarthritis (OA) hold great promise, but they need further refinement before they can be effectively used in clinical research and daily practice, said Erwin W.E. van Spil, MD, PhD, of the Rheumatology and Immunology Clinic, University Medical Center Utrecht, the Netherlands, at the 2013 American College of Rheumatology meeting.
OA is the most prevalent rheumatic disease, affecting an estimated 27 million Americans in 2005, but treatments have been lagging.
Biomarkers for managing OA have the potential to assist in the early diagnosis of OA, which could allow for the treatment of OA before structural changes can occur.
“Ultimately, they [biomarkers] can help identify therapeutic targets for disease-modifying OA drugs,” said Dr van Spil. “Altogether, effective biomarkers would aid in identifying preclinical or early-stage OA, and create an opportunity for disease-modifying treatment at this stage.”
The Search for OA Biomarkers
Selected biomarkers should have sufficient molecular validity, and the markers must relate to the process of interest, “so they should be able to discriminate between healthy and OA subjects or between different OA categories,” Dr van Spil noted.
The C-terminal telopeptide of type II collagen (CTX-II) is a collagen type II cartilage degradation product that is currently considered the most successful OA biomarker. It may be a reflection of bone metabolism, however, because CTX-II has been shown to cluster with bone markers rather than with other cartilage markers in patients with OA, Dr van Spil pointed out.
Synovial levels of potential OA biomarkers do not always correlate with serum or urine levels, and in the case of collagenase-generated cleavage neoepitope of type II collagen, an inverse association exists, calling into question the validity of these potential biomarkers.
“We cannot be sure that things we are measuring in serum or urine represent local joint conditions in synovial fluid, which makes things quite complicated,” said Dr van Spil. “In line with this point, we need to relate systemic levels to 1 or a few joints of interest.”
A recent study (Kraus VB, et al. PLoS One. 2010;5:e9739) showed that as the number of radiographically affected OA joints increases, the levels of hyaluronic acid and CTX-II also increase, but the levels of cartilage oligomeric matrix protein (COMP), a cartilage degradation marker, decrease. The interpretation of biomarker levels may be complicated by various molecular mechanisms, as well as by the complex biology represented by the biomarker, Kraus and colleagues concluded.
Between-subject variability and the natural diurnal rhythm of biomarker levels also need to be considered. The use of COMP as a marker in knee OA may be limited in individual patients, said Dr van Spil. A recent meta-analysis showed that the overall effect of COMP levels was only moderate in patients with radiographically diagnosed knee OA (Hoch JM, et al. Osteoarthritis Cartilage. 2011;19:1396-1404).
Although high levels of CTX-II and urinary glucosyl-galactosyl-pyridinoline are associated with the progression of joint erosion in OA, substantial overlap is seen in the levels of these markers in patients with varying OA severity as assessed radiographically, limiting their clinical utility. The same is true of COMP, Dr van Spil said.
CTX-II performs better when combined with type IIA procollagen amino terminal propeptide, a collagen synthesis marker. “Especially when levels of cartilage degradation are high and levels of cartilage synthesis are low, the chances of showing knee progression in the future increase,” Dr van Spil pointed out, which suggests that combining biomarkers may be more efficient than individual markers.
“We’re all waiting for a more sensitive marker showing efficacy of intervention, so that trials can be shortened and cheaper,” he said.
CTX-II has shown mixed results, with some clinical trials showing decreases in CTX-II levels after intraarticular injections of hyaluronic acid in patients with knee OA, and other trials showing increases in CTX-II.