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. 2017 Nov 22;19(1):257.
doi: 10.1186/s13075-017-1463-1.

Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis

Xinyu Yang  1 , Ke Lin  2 , Shanmin Ni  2 , Jianmin Wang  3 , Qingqing Tian  2 , Huaijun Chen  2 , Matthew A Brown  4   5 , Kaidi Zheng  2 , Weitao Zhai  6 , Li Sun  7 , Shengwei Jin  8 , Jianguang Wang  9
Affiliations

Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis

Xinyu Yang et al. Arthritis Res Ther. .

Abstract

Background: Our previous proteomic study indicated that connective tissue growth factor (CTGF) may be a potential biomarker for rheumatoid arthritis (RA) diagnosis. The aim was to assess the performance of CTGF as a biomarker of RA.

Method: Serum and synovial fluid CTGF was detected using a direct high sensitivity sandwich ELISA kit. Serum CTGF levels were tested for discriminatory capacity and optimal assay cutoffs determined in a training cohort of 98 cases of RA with 103 healthy controls. The assay performance was then validated in a further cohort of 572 patients (with RA (n = 217), ankylosing spondylitis (n = 92), gout (n = 74), osteoarthritis (n = 52), systemic lupus erythematosus (n = 72), or primary Sjögren's syndrome (pSS) (n = 65)).

Results: Significant elevation of synovial fluid CTGF concentration was found in RA patients, demonstrating excellent diagnostic ability to predict RA (area under the curve (AUC) = 0.97). Similar results were found in serum CTGF detection. At the optimal cutoff value 88.66 pg/mL, the sensitivity, specificity, and the AUC was 0.86, 0.92, and 0.92, respectively, in the training cohort. Similar performance was observed in the validation cohort, with sensitivity, specificity, positive likelihood, and negative likelihood of 0.82, 0.91, 5.74, and 0.12, respectively. Stronger discriminatory capacity was seen with the combination of CTGF and anti-citrullinated protein antibody (ACPA) (AUC = 0.96) than with either ACPA or rheumatoid factor (RF) alone (AUC = 0.80 or 0.79, respectively). The discriminatory performance of serum CTGF was consistent across all inflammatory conditions tested (AUC >0.92 in all cases), with the sole exception of pSS. Serum CTGF did not vary with symptom duration or disease activity.

Conclusions: Serum CTGF is a promising diagnostic biomarker for RA, with performance in the current study better than either ACPA or RF.

Keywords: ACPA; Biomarker; CTGF; Rheumatoid arthritis; Rheumatoid factor.

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Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the Clinical Research Ethics Committees of the First Affiliated Hospital of Wenzhou Medical University (No. 2016157), the Central Hospital of Jiamusi City (No. 2012010), and Shanghai Guanghua Hospital (No. 200903).

Consent for publication

All of the subjects provided written informed consent for publication.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Diagnostic performance of serum connective tissue growth factor (CTGF) and synovial fluid CTGF. a Serum CTGF in the training cohort. CTGF concentration was detected in serum samples from patients with rheumatoid arthritis (RA) (n = 98) and the control group (n = 103) using a CTGF ELISA kit. The black horizontal dotted line represents the cutoff value of 88.66 pg/mL and the asterisks represent statistical differences (p < 0.01). b Receiver operating characteristic (ROC) curve analysis of serum CTGF for diagnosis of RA. At the cutoff 88.66 pg/mL, the sensitivity and specificity of CTGF are 0.86 and 0.92, respectively. The AUC for CTGF is provided with its associated 95% confidence intervals. c Synovial fluid CTGF in the RA and control groups. Synovial fluid CTGF was detected using the CTGF ELISA kit, and the absorption rate was determined at an optical density of 450 nm. The black horizontal solid line represents the cutoff value of control at 104.2 pg/mL; asterisks represent statistical differences (p < 0.01). d ROC curve analysis of serum CTGF for diagnosis of RA. e Correlation between serum CTGF and synovial fluid CTGF. Linear correlation was analyzed, and a strong association was observed, with Pearson R of 0.81 (p < 0.01)
Fig. 2
Fig. 2
Serum concentration of connective tissue growth factor (CTGF) is not associated with rheumatoid arthritis (RA) symptom duration or the disease activity score in 28 joints (DAS28). a No significant association between symptom duration and serum CTGF concentration. All patients with RA (including patients with RA in the training and validation cohorts) were pooled in the final analysis, and the correlation between serum CTGF and symptom duration was tested. No significant correlation was observed, with R = 0.062 (p > 0.05). b No significant correlation between DAS28 and serum CTGF concentration. All patients with RA were pooled in the final analysis, and the correlation between serum CTGF and DAS28 was tested. No significant correlation was observed, with R = 0.10 (p > 0.05)
Fig. 3
Fig. 3
Serum indicators and combinations of serum indicators for diagnosis of rheumatoid arthritis (RA). a Receiver operating characteristic (ROC) analysis of connective tissue growth factor (CTGF), anti-citrullinated protein antibodies (ACPA), and their combination for diagnosing RA. Serum ACPA concentrations were tested in all participants recruited to the validation cohort. ROC analysis was carried out, and the area under the curve (AUC) for CTGF and ACPA was 0.93 and 0.80, respectively. The combination of CTGF and ACPA further improved the diagnostic ability for RA with an AUC of 0.96. b ROC analysis for CTGF, RF, and their combination for diagnosing RA. Serum rheumatoid factor (RF) concentrations were tested for all participants recruited to the training cohort. ROC analysis was carried out, and the AUC for CTGF and RF, and for their combination, was 0.93, 0.8, and 0.95, respectively. c. ROC analysis of the combinations of ACPA and RF, and CTGF, ACPA, and RF for diagnosing RA. We tested the diagnostic value of the currently recommended serum assay, and the AUC for the combination of ACPA and RF was 0.86, while the AUC for adding CTGF to the combined ACPA and RF was significantly increased to 0.97
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References

    1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358(9285):903–11. doi: 10.1016/S0140-6736(01)06075-5. - DOI - PubMed
    1. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. 1998;41(5):778–99. doi: 10.1002/1529-0131(199805)41:5<778::AID-ART4>3.0.CO;2-V. - DOI - PubMed
    1. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 3rd CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81. doi: 10.1002/art.27584. - DOI - PubMed
    1. Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797–808. doi: 10.7326/0003-4819-146-11-200706050-00008. - DOI - PubMed
    1. Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014;32(1):11–21. - PubMed

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