The clinical significance of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 levels in patients with rheumatoid arthritis

Xin Li; Yuan Wang; Xiaoxia Jia; Jing Ke; Baoyu Zhang; Yan Wang

doi:10.4103/ed.ed_19_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 7 | Issue : 4 | Page : 89-95

The clinical significance of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 levels in patients with rheumatoid arthritis

Xin Li, Yuan Wang, Xiaoxia Jia, Jing Ke, Baoyu Zhang, Yan Wang
Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China

Date of Submission	20-Aug-2022
Date of Decision	03-Oct-2022
Date of Acceptance	17-Oct-2022
Date of Web Publication	27-Dec-2022

Correspondence Address:
Baoyu Zhang
MD, Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149
China
Yan Wang
PhD, Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ed.ed_19_22

Abstract

Objective: The objective of this study was to assess the expression of serum complement component 1q tumor necrosis factor-related protein 3 (CTRP3) and CTRP9 in rheumatoid arthritis (RA) patients, and further explore their correlation with disease activity and the predictive value of RA.
Methods: RA group (n = 60) and healthy group (n = 60) were enrolled in Beijing Luhe Hospital, Capital Medical University. We collected the clinical data, including the basic information, laboratory parameters as well as the Disease Activity Score using 28 joint counts (DAS28) scores, and measured the expression of serum CTRP3 and CTRP9 in two groups by enzyme-linked immunosorbent assay. To analyze the correlation between serum CTRP3 and CTRP9 and RA. We explored the predictive value of the serum CTRP3 and CTRP9 for RA.
Results: Compared to the healthy group, the expression of serum CTRP3 and CTRP9 was higher in the RA group (P < 0.05). Except rheumatoid factor (serum CTRP9: r = −0.310, P = 0.018), and immunoglobulin (serum CTRP9: r = 0.338, P = 0.010), platelet, erythrocyte sedimentation rate, C-reactive protein, DAS28, anti-cyclic citrullinated peptide antibody, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, etc., of RA patients were not related to the levels of serum CTRP3 and CTRP9. The best cutoff value of serum CTRP3 and CTRP9 was 31.66 and 34.39 ng/ml, respectively. In terms of sensitivity, negative predictive value, and accuracy, compared with single detection of serum CTRP3 or CTRP9, combined detection has more predictive value for RA.
Conclusion: CTRP3 and CTRP9 may become two candidate biomarkers for RA. The serum CTRP3 and CTRP9 may have certain predictive values for RA.

Keywords: Complement component 1q tumor necrosis factor-related protein 3, complement component 1q tumor necrosis factor-related protein 9, disease activity, predictive value, rheumatoid arthritis

How to cite this article:
Li X, Wang Y, Jia X, Ke J, Zhang B, Wang Y. The clinical significance of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 levels in patients with rheumatoid arthritis. Environ Dis 2022;7:89-95

How to cite this URL:
Li X, Wang Y, Jia X, Ke J, Zhang B, Wang Y. The clinical significance of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 levels in patients with rheumatoid arthritis. Environ Dis [serial online] 2022 [cited 2023 Mar 26];7:89-95. Available from: http://www.environmentmed.org/text.asp?2022/7/4/89/365625

Introduction

Rheumatoid arthritis (RA) is considered an autoimmune disease with synovitis as the main pathological manifestation, characterized by chronic symmetrical polyarthritis. RA has a high disability and mortality rate.^[1] Joint malformations, increased incidence of cardiovascular events, and systemic multi-organ involvement seriously affect the quality of life and physical and mental health of RA patients, and cause huge economic burden to society.^[2] Therefore, early diagnosis and treatment are extremely important. Biomarkers play an indispensable role in diagnosing, judging disease activity, and predicting the prognosis of RA. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), such as anti-cyclic citrullinated peptide (anti-CCP) antibody, anti-mutated citrullinated vimentin (MCV) antibody, antikeratin antibodies (AKAs), and anti-perinuclear factor (APF), detected in serum, are biomarkers for RA. Because of good diagnostic performance, RF and anti-CCP antibody were included in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA.^[3] RF, a serum biomarker closely related to RA, was detected in 70%–90% of RA patients and 1%–5% of healthy people. Anti-CCP antibody, which can be detected before the clinical manifestations of RA, is used for the early diagnosis of RA.^[4] Several studies have shown that the combined detection of RF and anti-CCP antibody can improve the probability of true positivity in the diagnosis of RA.^[5] Nevertheless, about 15%–25% of RA patients are negative for both RA and ACPA,^[6] which can make RA diagnosis more difficult. Therefore, it is of great significance to find new autoantibodies or new biomarkers that can identify RF- and ACPA-negative patients for early diagnosis and prognosis of RA.

Adiponectin, a member of the adipokine group, is significantly increased in serum of RA patients.^[7] Studies have shown that adiponectin can be used as a biomarker to predict the degree of joint inflammation and bone erosion in RA patients.^[8] The complement component 1q tumor necrosis factor-related protein (CTRP) is highly homologous to adiponectin. It is also a class of adipokines and has a powerful biological function.^[9] The CTRP superfamily consists of 15 members from CTRP1 to CTRP15. CTRP proteins share a common structure: a signal peptide at the N terminus, a short variable region, a collagenous domain, and a C-terminal globular domain that is homologous to complement component 1q (C1q). At present, CTRPs are considered to have the dual functions of regulating metabolism and immunity, and are mostly studied in diabetes, obesity, cardiovascular and cerebrovascular diseases, fatty liver, immune-related diseases, and other diseases.^[10]

CTRP3 is the most intensively studied CTRP protein. Similar to adiponectin, CTRP3 is an adipokine that inhibits pro-inflammatory pathways.^[11] Several studies have found that CTRP3 could inhibit the production of Lipopolysaccharide (LPS)-induced inflammatory cytokines from human adipocytes, monocytes, and fibroblasts.^[12],[13] Furthermore, it was found that CTRP3 could play a protective role in cartilage by regulating fibroblast growth factor receptor-1 signaling, which was considered a potential anti-osteoarthritis (OA) drug.^[14] At present, there is little research on CTPR 3 in RA. Until now, only Murayama et al.^[15] have found that CTRP3 plays a vital role in the development of collagen-induced arthritis in mice.

CTRP9 is a new adipocyte factor discovered in recent years, which plays an important role in regulating metabolism, protecting myocardium, improving endothelial function, inhibiting platelet (PLT) activation, and reducing the expression of inflammatory factors.^[16],[17] CTRP9 has the highest homology with adiponectin, which can protect against inflammation-related diseases. About the study on OA, the results showed that CTRP9 can inhibit p38 mitogen-activated protein kinase and the nuclear factor-kappa B (NF-κB) signaling pathways to alleviate the inflammation of monosodium iodoacetate-induced OA rats.^[18] However, there is no research on CTRP9 and RA.

CTRP3 and CTRP9 have immunomodulatory effects. We suspect that they may also be closely related to RA. The main purpose of this study is to assess the expression of serum CTRP3 and CTRP9 in RA patients, and further explore their correlation with disease activity of RA and predictive value of RA.

Methods

Participants

The study was carried out on sixty RA patients (RA group) who were enrolled in the Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, during the period from March 2021 to August 2021. All RA patients were diagnosed according to the 2010 ACR/EULAR classification criteria for RA.^[3] Sixty healthy individuals (healthy group), who were matched for age and sex with the RA group, come from the physical examination center of Beijing Luhe Hospital, Capital Medical University. It is considered that some diseases are related to abnormal expression of CTRP3 and CTRP9, so all patients with the following conditions were excluded: pregnancy, infection, hypertension, diabetes, cardiovascular and cerebrovascular diseases, hyperlipidemia, other autoimmune diseases, as well as tumors. This study was approved by the Medical Ethics Committee of Beijing Luhe Hospital, Capital Medical University (Number 2021-LHKY-029). All participants gave informed consent to the study.

Clinical data collection

We collected and recorded the basic information (name, age, gender, disease duration, etc.) and laboratory parameters of all participants, including white blood cells (WBCs), PLTs, total cholesterol (TC), total triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and uric acid (UA) in serum. In addition, RA patients also needed to collect inflammatory biomarkers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), autoantibody antibodies (anti-CCP and RF), swollen joint counts (SJCs), tender joint counts (TJCs), and immunoglobulin (Ig) (IgA, IgM, and IgG).

We assessed the disease activity in RA patients by the Disease Activity Score using 28 joint counts (DAS28).^[19] The DAS28 was calculated by SJC28 (range: 0–28), TJC28 (range: 0–28), CRP (mg/L), as well as the Visual Analog Scale (range: 0–100) of RA patients.

Complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 in the serum were measured by enzyme-linked immunosorbent assay

At room temperature, we collected the 4 ml peripheral venous blood of all participants, which was placed for 30 min and centrifuged for 20 min (1,000 × g). The serum samples of the participants were removed and stored at −80°C. When we need to further analysis, the serum samples were thawed on ice. The level of serum CTRP3 and CTRP9 expression was measured by commercial enzyme-linked immunosorbent assay kits (Mlbio, Shanghai, China) in accordance with the manufacturer's instructions.

Statistical analysis

The data were analyzed using SPSS22.0 (IBM, Inc., Armonk, NY, USA) software. Quantitative data, including normal distribution variables and abnormal distribution variables, were respectively presented as mean ± standard deviation or median (P25, P75). Qualitative data were presented as number. The differences between the two groups were analyzed by the Student's t-test (two-tailed), nonparametric test (Mann–Whitney test), or Chi-square test. The correlation analysis was performed by Spearman correlation analysis. The predictive value of CTRP3 and CTRP9 in the serum was determined by constructing receiver operator characteristic (ROC) curve and calculating area under the curve (AUC). In addition, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CTRP3 and CTRP9 as well as the combination of CTRP3 and CTRP9 were calculated. P < 0.05 was considered to be statistically significant.

Results

The expression of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 in rheumatoid arthritis patients and healthy individuals

First of all, we explored the distribution of the basic information (age and gender) and laboratory parameters (WBC, PLT, TC, TG, etc.) between the RA group and the healthy group [Supplementary Table 1]. There was no significant difference in age and gender between the two groups (P > 0.05). However, compared with the healthy group, the expression of PLT (228.27 ± 62.27) (P < 0.05), TC (4.27 ± 0.91) (P < 0.001), LDL (2.62 ± 0.74) (P < 0.05), HDL (1.31 ± 0.40) (P < 0.05), and UA (255.85 ± 86.25) (P < 0.05) in the RA group was lower. In addition, we found that the expression of serum CTRP3 and CTRP9 in the RA group was higher than that in the healthy group [P < 0.05, [Table 1] and [Figure 1]].

Figure 1: The expression of serum CTRP3 and CTRP9 in the RA group and the healthy group. (a) The expression of serum CTRP3; (b) The expression of serum CTRP9. CTRP: The complement C1q tumor necrosis factor-related protein. *P < 0.05; **P < 0.01. CTRP3: Complement component 1q tumor necrosis factor-related protein 3, CTRP9: Complement component 1q tumor necrosis factor-related protein 9, RA: Rheumatoid arthritis

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Table 1: The expression of component 1q tumor necrosis factor-related protein 3 and component 1q tumor necrosis factor-related protein 9 in serum

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Correlation between the expression levels of complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 in serum and rheumatoid arthritis

We analyzed the correlation between the basic information of RA patients and the expression levels of CTRP3 and CTRP9 in serum. Age was positively correlated with the level of CTRP3 (r = 0.300, P = 0.021). Disease duration of RA has no correlation with the expression of CTRP3 and CTRP9. We further explored the predictive effect of CTRP3 and CTRP9 expression levels in serum on disease activity of RA. PLT, ESR, CRP, SJC, TJC, and DAS28 of RA patients were not related to the expression levels of CTRP3 and CTRP9. Additionally, IgA (r = 0.338, P = 0.010) was positively correlated with the level of serum CTRP9. RF (r = −0.310, P = 0.018) was negatively correlated with the expression of serum CTRP9. However, the level of anti-CCP antibody was unrelated to the expression of serum CTRP3 and CTRP9 [P > 0.05, [Table 2]].

Table 2: Correlation between levels of component 1q tumor necrosis factor-related protein 3 and component 1q tumor necrosis factor-related protein 9 in serum and clinical and laboratory data in patients with rheumatoid arthritis

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Predictive value of serum complement component 1q tumor necrosis factor-related protein 3 and complement component 1q tumor necrosis factor-related protein 9 for rheumatoid arthritis

ROC curve was used to show the accuracy of serum CTRP3 and CTRP9 in predicting RA. When the best cutoff value of serum CTRP3 was selected as 31.66 ng/ml, the AUC was 0.635 (P < 0.05), with 95% confidence interval (CI) (0.535–0.735), sensitivity of 60.3%, and specificity of 61.7%. When the best cutoff value was 34.39 ng/ml, serum CTRP9 for RA had higher specificity (95%), with the AUC (0.611, P < 0.05), 95% CI (0.51–0.713). In addition, combined serum CTRP3 and CTRP9 detection could greatly increase sensitivity (72.4%), NPV (70.2%), and accuracy (68.7%) to RA, with a higher AUC (0.706, P < 0.001, 95% CI: 0.613–0.9) [Figure 2] and [Table 3].

Figure 2: ROC curve of serum CTRP3, CTRP9, and CTRP3 + CTRP9 for discrimination between the RA group and the healthy group. (a) Predictive value of detecting serum CTRP3 and CTRP9 separately in RA. (b) Predictive value of combined detection of serum CTRP3 and CTRP9 in RA. ROC: Receiver operator characteristic, CTRP3: Complement component 1q tumor necrosis factor-related protein 3, CTRP9: CTRP9: Complement component 1q tumor necrosis factor-related protein 9, RA: Rheumatoid arthritis

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Table 3: Predictive value of serum component 1q tumor necrosis factor-related protein 3 and component 1q tumor necrosis factor-related protein 9 for rheumatoid arthritis

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Discussion

RA is a kind of autoimmune disease, featured with multi-joint bone destruction and multiple organs involved. People's low awareness, poor compliance, delayed diagnosis, improper treatment, and other reasons lead to a high disability and mortality rate of RA.^[1] The physical disability and serious complications often make the patients of RA suffer from physical and mental torture, which imposes a heavy burden on patients, families, and society.^[2] With the age-standardized prevalence and incidence rates increasing, RA has become a global public health challenge.^[20] Therefore, early diagnosis, finding effective treatment, and preventing and reducing complications have become the goal of rheumatologists. Finding candidate biomarkers are particularly important for diagnosing, judging disease activity, and predicting the prognosis of RA.

RF and ACPAs, including anti-CCP antibody, anti-MCV antibody, AKA, and APF, have been known in the diagnosis and prognosis of RA. However, ACPA and RF are not positive in all RA patients.^[6],[21] Therefore, it is of great significance to find new candidate biomarkers for RA, especially for RA patients with negative RF and ACPA antibodies. In 2004, Wong et al.^[22] first introduced the term CTRPs, which were described as a new family of proteins homologous to adiponectin, composed of 15 members (CTRP1 to CTRP15). Studies have shown that CTRP3 and CTRP9 have anti-inflammatory, metabolic regulation, and cardiovascular protection effects.^{[16],[17],[23],[24]} At present, there is no research on CTRP3 and CTRP9 in patients with RA. We firstly explored the clinical significance of serum CTRP3 and CTRP9 expression in RA patients.

At the beginning of the study, compared with the healthy group, we found that the expression levels of TC, LDL, and HDL in RA patients were lower, which was consistent with the published results.^[25] It is known that TC, TG, LDL, and HDL can regulate the level of lipid metabolism. CTRP3 and CTRP9 are found to be closely related to TC, TG, LDL, and HDL in type 2 diabetes, cardiovascular disease and other diseases.^[26],[27] However, in our study, we did not find that TC, TG, HDL, and LDL were related to the expression levels of serum CTRP3 and CTRP9. We suspected that it may be related to the exclusion of metabolic diseases, such as hyperlipidemia, diabetes, and cardiovascular and cerebrovascular diseases, or CTRP3 and CTRP9 were not involved in the lipid metabolism process of RA. Those aspects still need to be explored in the future.

According to difference in length and glycosylation, CTRP3, which is also called CORS-26, cartducin, and cartonectin, is divided into two subtypes: CTRP3A (40 kDa) and CTRP3B (32 kDa) in humans.^[28] Some studies have demonstrated that CTRP3, as a potential anti-inflammatory mediator, could stimulate endothelial cell proliferation and migration, could regulate inflammatory response, and is negatively correlated with pro-inflammatory cytokines, such as tumor necrosis factor, interleukin-6, and transforming growth factor-β.^{[29],[30],[31]} Meanwhile, some studies have found that serum CTRP3 is negatively correlated with osteoporosis and knee OA in postmenopausal women.^[32],[33] CTRP3 can inhibit the activation of NF of activated T cells 1 (NFATc1) through AMP-activated protein kinase (AMPK) signaling pathway and play a negative regulatory role in receptor activator of NF-κB ligand-mediated osteoclast differentiation.^[34] Since synovitis and bone destruction exist in the pathogenesis of RA, the researchers hypothesize that CTRP3 might be associated with RA.

Murayama et al.^[15] first explored the pathogenic role of C1qtnf3, which encodes CTRP3, in collagen-induced arthritis. Compared with wild-type mice, the expression C1qtnf3 was higher in the joints of RA models and the joint severity and pro-inflammatory cytokine mRNAs were higher in C1qtnf3 (-/-) mice. Compared with the healthy group, we found that the level of serum CTRP3, like adiponectin, was higher in RA patients, suggesting that CTRP3 may be a candidate biomarker for RA.^{[7],[35],[36]} We suspected that CTRP3, like adiponectin, may have both anti-inflammatory and pro-inflammatory effects on RA patients. The mechanism will be further studied.

Interestingly, like adiponectin, we also found that age was positively correlated with the level of CTRP3.^[37] At present, it was considered that serum CTRP3 was closely related to Type 2 diabetes, obesity, cardiovascular diseases, etc.^[10] With the increase of age, the risk of these diseases also increases, which may be the reason for the age-related CTRP3. Meanwhile, in our studies, we did not find a correlation between serum CTRP3 expression and DAS28, ESR, CRP, SJC, and TJC, suggesting that serum CTRP3 may not be associated with RA disease activity. Similarly, adiponectin has previously been found not to be associated with RA disease activity.^[35] At present, there is little research on CTRP3 and RA, and whether CTRP3 participates in the pathogenesis of RA still needs further study.

CTRP9, another novel adipokine, is closest to adiponectin in CTRP family and has a similar metabolic regulation function with adiponectin. In addition to regulating metabolism, protecting myocardium and endothelium, CTRP9 also plays an important role in inhibiting the inflammatory response.^[16],[17] Nevertheless, there are a few studies on CTRP9 in autoimmune diseases. Yang et al.^[38] findings suggest that CTRP9 may be a potential biomarker in SSc-associated interstitial lung disease. Interestingly, for the first time, we found that CTRP9 was highly expressed in serum of RA patients. Similar to our results, some studies also have found that the circulating levels of serum CTRP9 is upregulated in Type 2 diabetes mellitus and coronary artery disease. We hypothesized that the elevated CTRP9 levels may be a compensatory response to RA. The serum CTRP9 may be another candidate biomarker for RA. In the future, more studies are needed to confirm this. Moreover, the same as CTRP3, the expression of serum CTRP9 was not found to be related to disease activity in RA patients. To our surprise, our study also found a negative correlation between serum CTRP9 levels and RF. Similar results were obtained in the study of adiponectin in RA.^[39]

Up to now, no relevant research on the predictive value of serum CTRP3 and CTRP9 for RA has been reported. In this study, the sensitivity, specificity, PPV, NPV, and accuracy of CTRP3 and CTRP9 in RA patients were not ideal, which may be related to the insufficient sample size. However, we found that testing serum CTRP9 alone has high specificity for RA and combined detection of serum CTRP3 and CTRP9 could greatly improve the sensitivity, NPV, and accuracy of RA. These data suggested that the serum CTRP3 and CTRP9 may have certain predictive values for RA.

Conclusion

Our results demonstrate that CTRP3 and CTRP9 may become two candidate biomarkers for RA. The combined detection of serum CTRP3 and CTRP9 levels may be more significant in RA patients. However, the study of CTRP3 and CTRP9 in RA is still in its primary stage, and its mechanism is still unclear, which needs further study.

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Financial support and sponsorship

The work was supported by the Youth Scientific Research Incubation Program of Beijing Luhe Hospital, Capital Medical University in 2019 (Grant number: LHYY2019-LC05).

Conflicts of interest

There are no conflicts of interest.

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