Serum C1q concentration is associated with disease activity in Chinese Takayasu arteritis patients: A case‐control study

Abstract Background C1q is a crucial component of the classical complement pathway. This study is the first to assess the association between disease activity and serum levels of C1q in Chinese Takayasu arteritis (TA) patients. Methods Serum C1q levels in 198 TA patients and 154 healthy controls were assessed, and the relationship between serum C1q levels and indices of TA disease activity was analyzed. Moreover, we examined the correlation between serum C1q levels and two traditional inflammatory biomarkers; erythrocyte sedimentation rate (ESR) and hypersensitive CRP (hs‐CRP). Results Serum C1q levels were increased in TA patients compared with healthy controls (P = .008). TA patients with active disease had higher levels of serum C1q than patients who had inactive disease (P < .0001). In addition, treatment‐naïve patients had higher serum C1q levels than those who had been treated with corticosteroids or at least one immunosuppressant (P = .001). Furthermore, a positive correlation between serum C1q levels and traditional inflammatory biomarkers in TA patients was found. The role of C1q in assessing disease activity was studied, and the area under the receiver operating characteristic curve (AUC) of C1q for predicting active disease was 0.752, and a serum cutoff value of 167.15 mg/L C1q maximized the ability of disease activity assessment, with a sensitivity/specificity of 77.80%/64.90%. When the three indicators (C1q, ESR, and hs‐CRP) were combined, the AUC increased to 0.845, and the sensitivity to 84.40%. Conclusions The serum C1q is associated with the disease activity of TA and the combination of three indicators (C1q, ESR, and hs‐CRP) increases the sensitivity of disease activity assessment.


| INTRODUCTION
Takayasu arteritis (TA) is an uncommon systemic vasculitis that is characterized by granulomatous inflammation of major blood vessels and primarily involves the aorta and its major branches. Vascular inflammation often leads to ischemia of organs and tissues supplied by the involved vessels and can result in potentially life-threatening organ ischemia as well as aortic regurgitation and pulselessness. 1 The active stage of TA is associated with the development of ischemic symptoms such as coronary artery disease, stroke, and vision loss. 2 Therefore, reliable disease activity assessment is important for preventing TA progression and end-organ ischemic injury. The erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) are the biomarkers most commonly used to monitor TA disease activity; however, as they may be influenced by several factors, they are neither sensitive nor specific. In clinical practice, some patients may undergo deterioration of vasculitis without elevation of CRP or ESR, and increases in CRP or ESR are found in only approximately half of patients with active TA. 3 Consequently, CRP and ESR do not always show a positive association with TA disease activity or severe vasculature impairment. 4 Complement 1q (C1q) is an important promoter in the classical complement pathway, which is related to the clearance of immune complexes (IC) and apoptotic cells. C1q initiates and activates the complement cascade by recognizing the complement-binding site of the antibody FC segment in the IgG or IgM immune complex to clear antigen-antibody complexes. 5 C1q, which accounts for approximately 70% of the C1 complex, can be deposited on the surface of apoptotic cells, facilitating phagocytosis by phagocytes and protecting the body from the inflammatory reactions. 6 Interestingly, historical studies demonstrated that C1q could also play a role in other immunoregulatory properties, containing restriction of monocytes differentiation into dendritic cells and the production of immune complex-induced interferon-α in plasmacytoid dendritic cells. 7 Previous studies have found immune complex (IC) in TA patient sera and on peripheral blood lymphocyte Fc receptors. 8 The pathogenesis of IC in TA is the strong affinity of antigen between aortic wall and complex. Alternatively, antigenic material may be present in the aortic wall. 9 Serum C1q levels have recently been evaluated in several autoimmune, such as lupus nephritis (LN), 10 pediatric systemic lupus erythematosus (PSLE), 11 juvenile idiopathic arthritis (JIA), 12 and idiopathic inflammatory myopathies (IIMs). 13 However, the serum C1q level and its association with disease activity have not been investigated in TA patients. This study is the first to examine serum C1q levels in Chinese TA patients and investigate their role in the assessment of TA disease activity.

| Study population
We designed a retrospective study recruiting 198 subjects with TA diagnosed according to the criteria of the American College of Rheumatology (ACR). 14 All TA patients were screened in Beijing Anzhen Hospital between September 2015 and August 2019. Patients who had other autoimmune diseases were excluded. A total of 154 healthy unrelated age-and sex-matched controls without any history of chronic disease were recruited during their physical examinations.
Disease activity was assessed in patients with TA based on the National Institutes of Health (NIH) criteria proposed by Kerr et al. 15 Clinical classification of TA (I, IIa, IIb, III, IV, and V) patients was according to the Numano criteria by catheterography or computed tomography angiography (CTA). 16

| Statistical analysis
All statistical analyses were conducted with SPSS version 23.0 (SPSS Inc., Chicago, Illinois) software. Numerical data were compared with an independent sample t test or the Mann-Whitney-Wilcoxon test.
Categorical data were compared with the Chi-square test or Fisher's exact test. Spearman's nonparametric correlation test was applied to examine the associations between serum C1q levels and Kerr's score/ ESR/hs-CRP. We selected the cutoff values for serum C1q, ESR, hs-CRP, and the combination of three indicators (C1q, ESR, and hs-CRP) using receiver operating characteristic (ROC) curves with MedCalc software (v.15.2) to compare the accuracies of these markers with disease activity identification. The cutoff points of these markers were the values with the highest Youden's Index (sensitivity + specificity − 1) score. A P-value less than .05 was considered to be statistically significant.

| RESULTS
Of the 198 TA patients, 178 were female, and 47 patients had active disease based on the NIH criteria (Table 1). In addition, 29 of the TA patients in our study were naïve to corticosteroid or immunosuppressant treatment. Malaise (68.2%), headache (46.0%), and chest distress (26.3%) were the three most common constitutional symptoms, and Numano subtype V was common among the TA patients. The prevalence of claudication differed between the TA patients with active and stable disease (P = .013). Furthermore, the prevalence of hypertension was notable between untreated TA patients and treated patients (P = .002).
Compared with the healthy controls, patients with TA had higher ESR and C1q levels ( Table 1 and Figure 1). However, the level of hs-CRP was similar between the TA patients and healthy controls. Compared with patients who had the inactive disease, those with active disease had higher levels of serum C1q and hs-CRP as well as ESR (Table 1 and Figure 1). Similarly, treatment-naïve patients had higher T A B L E 1 Demographic, clinical characteristics, and laboratory findings between TA patients and healthy controls Treated (Mean ± SEM/ n)/Median (25%, 75%Q)  F I G U R E 1 A, Serum C1q levels were significantly higher in TA patients than in healthy controls (P = .008); B, Serum C1q levels were significantly higher in TA patients with active disease than inpatients who had inactive disease (P < .0001); C, Serum C1q levels were significantly higher in treatment-naïve patients than in those who had always been treated with corticosteroids or at least one immunosuppressant (P = .001). TA, Takayasu arteritis C1q was lower than that of both ESR and hs-CRP. In addition, when the three indicators (C1q, ESR, and hs-CRP) were combined, the sensitivity increased. Therefore, hs-CRP has the highest specificity, and the sensitivity of combining three indicators (C1q, ESR, and hs-CRP) was the highest. Based on the above, we conclude that the concentration of serum C1qisa potential inflammatory marker for TA and that the combination of the above three indicators increases the sensitivity of disease activity assessment.
There are several limitations to our study. We did not detect C1q deposited in vascular tissue. In addition, using the Kerr criteria to assess disease activity might have missed some TA patients with angiographic activity. As a result, well-designed prospective studies should be performed to clarify the exact clinical molecular mechanisms of C1q in TA patients and the association with TA disease activity. Also, the clinical application of C1q in TA needs to be expanded.

| CONCLUSION
The present study is the first to assess serum C1q levels in TA patients and evaluate their relationship with disease activity. We found that serum C1q levels were increased in TA patients compared to healthy controls and that TA patients with active disease had higher levels of serum C1q than patients who had inactive disease. In addition, there were positive correlations between serum C1q levels and traditional inflammatory biomarkers in TA patients. Therefore, our findings show that the serum C1q concentration is associated with the disease activity of TA and that the combination of three indicators (C1q, ESR, and hs-CRP) increases the sensitivity of disease activity assessment, but the exact mechanism of C1q remains unclear.

CONFLICT OF INTEREST
The authors declare no conflicts of interest. Hui Yuan had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article supplementary materials.