Cysteine-rich 61 (Cyr61): a biomarker reflecting disease activity in rheumatoid arthritis

Yong Fan, Xinlei Yang, Juan Zhao, Xiaoying Sun, Wenhui Xie, Yanrong Huang, Guangtao Li, Yanjie Hao, Zhuoli Zhang, Yong Fan, Xinlei Yang, Juan Zhao, Xiaoying Sun, Wenhui Xie, Yanrong Huang, Guangtao Li, Yanjie Hao, Zhuoli Zhang

Abstract

Background: Numerous preclinical studies have revealed a critical role of cysteine-rich 61 (Cyr61) in the pathogenesis of rheumatoid arthritis (RA). But there is little literature discussing the clinical value of circulation Cyr61 in RA patients. The aim of our study is to investigate the serum Cyr61 level and its association with disease activity in RA patients.

Methods: A training cohort was derived from consecutive RA patients who visited our clinic from Jun 2014 to Nov 2018. Serum samples were obtained at the enrollment time. To further confirm discovery, an independent validation cohort was set up based on a registered clinical trial. Paired serum samples of active RA patients were respectively collected at baseline and 12 weeks after uniformed treatment. Serum Cyr61 concentration was detected by enzyme-linked immunosorbent assay. The comparison of Cyr61 between RA patients and controls, the correlation between Cyr61 levels with disease activity, and the change of Cyr61 after treatment were analyzed by appropriate statistical analyses.

Results: A total of 177 definite RA patients and 50 age- and gender-matched healthy controls were enrolled in the training cohort. Significantly elevated serum Cyr61 concentration was found in RA patients, demonstrating excellent diagnostic ability to discriminate RA from healthy controls (area under the curve (AUC) = 0.98, P < 0.001). In addition, the Cyr61 level in active RA patients was significantly lower than that in patients in remission/low disease activity, and it was inversely correlated with composite disease activity scores and almost all of the components in statistic. Further study in the validation cohort (n = 77) showed a significant increase of the Cyr61 level at 12 weeks in ACR responders (ACR20/50/70), while no significant change of the Cyr61 level from baseline was observed in non-responders.

Conclusions: Serum Cyr61 levels were remarkably increased in RA patients compared with those in healthy controls. The Cyr61 concentration was inversely correlated with RA disease activity and upregulated in those therapeutic responders.

Trial registration: Combination Therapy Prevents the Relapse of RA, NCT02320630 . Registered 19 December 2014.

Keywords: Biomarker; Cysteine-rich protein 61; Disease activity; Rheumatoid arthritis; Treatment response.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Serum Cyr61 concentrations and diagnostic performance of Cyr61 in participants in the training cohort. a Levels of serum Cyr61 in healthy controls and RA patients (classified into inactive RA group and active RA group as evaluated by DAS28-ESR ≥ 3.2). b Receiver operating characteristic (ROC) curve to determine the best threshold for Cyr61 to discriminate RA and healthy controls. The red horizontal solid line represents a median value
Fig. 2
Fig. 2
Scatterplots showing correlations between Cyr61 levels with disease activity measures in RA patients in the training cohort. a Left to right: tender joint count (TJC), swollen joint count (SJC), patient global assessment (PGA), evaluator global assessment (EGA). b Left to right: DAS28-ESR, DAS28-CRP, simplified disease activity index (SDAI), clinical disease activity index (CDAI). R value represents Spearman’s correlation coefficient
Fig. 3
Fig. 3
Serum Cyr61 levels in RA patients in the validation cohort before and after treatment. a Left to right: scatter plots showing the levels of Cyr61 in ACR20 responders, ACR50 responders, ACR70 responders, and ACR non-responders before and after treatment. b Left to right: before-after plots showing the levels of Cyr61 in ACR20 responders, ACR50 responders, ACR70 responders, and ACR non-responders before and after treatment (in correspondence with a). The red horizontal solid line represents a median value

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