BOSTON — Disease progression in early osteoarthritis is associated with combined increases in biochemical markers for the synthesis and degradation of type II collagen, and these changes can be identified before radiologic evidence of the disease is apparent, a study has shown.
The findings suggest that measuring these biomarkers may help identify patients with early knee osteoarthritis who are at high risk for rapid progression, Dr. Patrick Garnero said at the 10th World Congress on Osteoarthritis.
“Currently, the only validated methodology for assessing progression in osteoarthritis is the measurement of joint space width by radiography, which has limited sensitivity,” said Dr. Garnero of the Institut National de la Santé et de la Recherche Médicale in Lyon, France. “When there is radiologic evidence of osteoarthritis, significant joint damage has already occurred,” he said at the congress, which was sponsored by the Osteoarthritis Research Society International. Previous short-term studies in advanced osteoarthritis have shown that baseline levels of serum concentration of the N-propeptide of collagen type IIA (PIIANP) and the urinary excretion of cross-linked C-telopeptide (CTX-II) are associated with disease progression.
Dr. Garnero and his associates at the University of Bristol in England followed 84 patients with early osteoarthritis in one or both knees for 5 years. All of the patients, mean age 62 years, had experienced persistent pain in one or both knees for more than 3 months, and 39% presented with a Kellgren-Lawrence score of less than 2. Using specific ELISA assays, the investigators measured each patient's PIIANP and CTX-II levels and obtained knee radiographs at baseline and at 2, 3, and 5 years. The radiographs were read by two independent readers. “Of interest,” Dr. Garnero said, independent readings showed that “about 60% of the patients had Kellgren-Lawrence scores lower than 2 and about 42% had scores below 0, suggesting a large proportion of this cohort had very early disease.”
“We defined disease progression as either a reduction in the tibiofemoral joint space by at least 2 mm or total replacement of either knee during the 5-year follow up,” Dr. Garnero said. Based on these criteria, 24 had progressive disease and 60 did not.
In the overall cohort there was a “slight but significant” mean PIIANP increase of 1.6% per year and no increase in urinary CTX-II levels during the 5-year follow up. When patients with and without progressive disease were considered independently, however, there were substantial differences. “Both measures were significantly higher throughout the study in the 24 patients with progressive disease compared with the remaining 60 patients,” Dr. Garnero said. Even so, “we could not differentiate the two groups according to x-ray measurements,” suggesting that detectable biomarker changes precede radiologic progression.
When classified by quartile of mean 5-year levels for both PIIANP and CTX-II measures, patients in the highest quartile of PIIANP and in the two highest quartiles for CTX-II were associated with increased risk for progression. The odds ratio for increased progression risk for the highest quartile PIIANP measures alone and the two highest quartiles for CTX-II measures alone were 3.2 and 3.4, respectively, compared with 11.8 for the combination of both markers.
The sensitivity and specificity of the PIIANP top quartile alone were 42% and 82%, respectively, compared with 71% and 58% for the CTX-II top two quartiles. “Combined, the sensitivity and specificity for both markers was 92% and 52%, respectively,” Dr. Garnero said. Because progression of joint damage likely results primarily from an imbalance between degradation and reparative processes, “combining these two markers is more effective in predicting progression than the measurement of a single marker.”
Predicting progression in osteoarthritis is notoriously difficult “because the outcomes vary substantially from patient to patient even if other considerations are the same,” he said.
The findings need to be validated in a larger study, he noted.