CRTAC1 Biomarker Linked to Increased Osteoarthritis Risk, Joint Replacements

The level of cartilage acidic protein-1 (CRTAC1) in plasma is a biomarker of osteoarthritis (OA), and predicted OA risk and progression to joint replacements, according to a study published in Arthritis & Rheumatology.¹ Adding aggrecan core protein (ACAN) and neurocan core protein (NCAN) to this protein may improve the prediction of OA.

“The lack of a biomarker of OA has hindered development of effective therapies for this common disease,” investigators explained. “No measures are presently available for early diagnosis of OA, before destructive changes are observable on radiographs, and there are no disease-modifying drugs marketed for OA. A biomarker that is associated with disease occurrence and/or progression would help to identify cases earlier and monitor the disease course.”

In total, 1462 plasma proteins were analyzed among 54,265 patients from the UK Biobank, a large-scale prospective study, via 4 Olink Explore 384-plex panels. Three main studies evaluated plasma proteins regarding prevalent OA, incident OA, and progression to joint replacement. The specificity of OA was determined through comparison of association of previous joint replacement and inflammatory joint diseases. Analyses were adjusted for age, sex, and body mass ratio (BMI) when deemed significant. Ninety-two non-specific proteins linked to other inflammatory joint diseases, or a history of joint replacements were excluded.

Patients diagnosed with knee OA (n = 1482), hip OA (n = 698), and hand OA (n = 104) were compared at the time of plasma sampling with participants without an OA diagnosis to determine any association of protein levels in plasma for those with prevalent disease. The CRTAC1 protein had the strongest link to prevalent knee OA (odds ratio [OR] 1.34 [CI 1.27–1.41]) and was also associated with hip OA (OR 1.19 [CI 1.11–1.28]). Further, it was able to predict incident diagnosis of OA in both the knee and hip (hazard ratio [HR] 1.40 [CI 1.35-1.46]; HR 1.25 [CI 1.19-1.31], respectively) and progression to joint replacement (HR for knee: 1.20 [CI 1.08-1.33]; HR for hip: 1.22 [CI 1.08- 1.38]). However, inflammatory joint diseases were not associated with the CRTAC1 protein.

Patients with the highest quintile of risk based on factors such as plasma CRTAC1 levels, BMI, age, and sex, had a 9.8 times increased risk of developing knee OA and were 9.7 times more likely to develop knee OA within 5 years when compared with those in the lowest quintile. The addition of ACAN and NCAN to the model improved OA predictions, but not joint replacements.

The possibility of misclassification hinders the study, due to the registry nature of the data collected and limited information about disease severity, hand OA, and health-related information about the patients. Analyses of the progression of OA to joint replacements and the association with prior joint replacement was restricted due to missing data on joint replacements. Further, generalizability may be limited as patients were predominantly of European descent.

“We show here in a hypothesis-free proteomic analysis that CRTAC1 levels in plasma of UK Biobank participants associate with prevalent OA, OA risk, and progression to joint replacement, and it is independent from established risk factors,” investigators concluded. “This confirms and extends our previous findings in Iceland, using a different protein assay. Therefore, CRTAC1 is validated as a biomarker for OA, and carries with it a promise to facilitate an earlier diagnosis of OA, that is currently captured only when destruction is evident.”

Reference:

Styrkarsdottir U, Lund SH, Thorleifsson G, et al. The CRTAC1 protein in plasma associates with prevalent osteoarthritis and predicts future risk as well as progression to joint replacements - Results from the UK Biobank resource [published online ahead of print, 2022 Oct 14]. Arthritis Rheumatol. 2022;10.1002/art.42376. doi:10.1002/art.42376