No biomarkers have so far been established as accepted tools for characterizing the status of OA
. This is particularly due to the fact that there are no biomarkers in OA that can characterize the disease state in an individual patient
[3, 13]. In addition, the burden of disease markers can be used only for clinical studies because individual values obtained in groups of patients with different degrees of OA burden overlap considerably
. A reexamination of the approach for reporting biomarker results was proposed to overcome this problem
, and this study was conducted to determine whether sHA levels could be employed as a burden of disease marker for individual patients by estimating the reference intervals of sHA levels corresponding to the radiographic severity of knee OA. The results revealed that the reference intervals of sHA in patients with severe knee OA (K/L grade 4) can be estimated without overlap, while those of the patients with primary to moderate OA (K/L grade 1 to 3) overlapped, considerably. These findings indicate that sHA can be available as a burden of disease marker for severe (K/L grade 4) knee OA patients and cannot for primary to moderate (K/L grade 1, 2, and 3) knee OA patients.
A measured or observed laboratory test, such as biomarker, are established when a person (usually a patient) is compared with a reference interval for the purpose of making a medical diagnosis, therapeutic management decision, or other physiological assessment. The interpretation of clinical laboratory data is, therefore, a comparative decision-making process. This decision making process requires reliable reference intervals for the biomarkers
. Therefore, the establishment of the reference intervals for sHA may be useful to predict the prognosis of the disease in an individual patient, because sHA has been reported to be a biomarker that can predict the prognosis of the disease
[15, 16], although further study is necessary.
The burden of disease biomarkers indicates the extent or severity of disease, and therefore such biomarkers can be considered to be useful tools for the staging of the disease
. The sHA level has been reported to be a biomarker of radiographic knee OA
. In general, the severity of OA increases with age, and the sHA level was increased with age in our study (Figure
1). It is impossible to exclude the possibility that an overlap of the reference intervals for the sHA levels corresponding to the patients with K/L grade 1, 2 and 3 may be due to the influence of the extent of the disease in other joints
. However, even though the level in patients with K/L grade 4 must be affected by the extent of the disease in other joints, no overlap was shown for the reference interval of the sHA level corresponding to the patients with K/L grade 4. The sHA level has been reported to be a biomarker not only of the burden of disease, but also as a marker of disease progression
. Therefore, the result of this study could be meaningful, as we were able to identify the patients with progressive OA using the sHA level, in addition to examining the radiographic severity of OA because we cannot distinguish the patients with progressive OA from those without using solely radiography
[3, 5]. For example, the sHA, in addition to the radiography, may be helpful to identify patients with progressive OA for inclusion into future clinical trials of DMORDs.
This current study had some limitations. The study included only Japanese female patients in the analyses. Therefore, the findings cannot be generalized to other ethnic groups and male patients. Although sHA levels were affected by total body burden of disease
, there was no detailed phenotyping of other joints in this study, as mentioned above. Thus, the contribution of other joints to the systemic levels of biomarkers cannot be addressed.