Eye signs as a novel risk predictor in pulmonary arterial hypertension associated with systemic lupus erythematosus

doi:10.21203/rs.3.rs-3326326/v1

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Eye signs as a novel risk predictor in pulmonary arterial hypertension associated with systemic lupus erythematosus

https://doi.org/10.21203/rs.3.rs-3326326/v1

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Objective

To investigate the role of eye signs in predicting poor outcome of systemic lupus erythematosus (SLE) patients with pulmonary arterial hypertension (PAH).

Methods

This prospective observational study recruited the patients diagnosed with SLE-PAH from Jan. 2010 to Dec. 2010 at the first affiliated hospital of Nanchang University, while those with other potential causes of PAH were excluded. the evaluation of various parameters such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walking distance(6MWD), World Health Organization functional class (WHO-FC), echocardiography, and risk stratification based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines were conducted at intervals of every 1–3 months, and a 6-month follow-up period was observed. The primary outcome measure considered improvement if there was a decline in the risk stratification grade at the end point, and unimproved if there was no decline. Conjunctival microvasculation images were observed and recorded.

Results

A total of 29 SLE-PAH patients were enrolled, comprising 12 in the improved group and 17 in the non-improved group. ALL SLE-PAH show various manifestions in eye signs including vessel twisting, dilation, ischemic areas, hemorrhages, reticulum deformity, and wound spots. The non-improved group exhibited significantly lower vessel density (VD) and microvascular flow index (MFI) of conjuctival microvasculation images compared to the improved group. Correlation analysis revealed that VD displayed a negative correlation with the WHO-FC(r=-0.413, p = 0.026)and NT-proBNP (r=-0.472, p = 0.010), as well as a positive correlation with the 6MWD(r = 0.561, p = 0.002). Similarly, MFI exhibited a negative correlation with WHO-FC (r=-0.408, p = 0.028), and NT-proBNP (r=-0.472, p = 0.010), and a positive correlation with 6MWD (r = 0.157, p = 0.004). Multivariate logistic regression analysis indicated that VD (OR 10.11, 95% CI 1.95–52.36), MFI (OR 7.85, 95% CI 1.73–35.67), NT-proBNP, and 6MWD were influential factors in predicting the prognostic improvement of SLE-PAH patients. ROC curve analysis demonstrated that VD, MFI, 6MWD, and NT-proBNP (with respective ROC AUC values of 0.83, 0.83, 0.76, and 0.90) possessed a sensitivity and specificity of 75% and 100%, as well as 83% and 100%, respectively. Regarding prognostic prediction, VD and MFI exhibited higher sensitivity compared to 6MWD, whereas MFI displayed higher sensitivity and specificity compared to NT-proBNP.

Conclusion

SLE-PAH can lead to various conjuctival microvascular manifestions in which vascular density and microvascular flow index can be used to assess the cardiopulmonary function and predict therapeutic efficacy and prognosis in SLE-PAH patients.

systemic lupus erythematosus

pulmonary arterial hypertension

conjuctival vasculation

eye sign

vascular density

microvascular flow index

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems in the human body. Pulmonary arterial hypertension (PAH) is one of the most severe complications of SLE, associated with poor prognosis and high mortality rates. It is reported the 5-year survival rate of SLE-related PAH ranges from 50–62.9% [1, 2]. PAH can lead to systemic microcirculatory impairments[3]. Microcirculation refers to the circulation of blood between arterioles and venules, comprising the peripheral component of the circulatory system. It serves as a crucial site for substance exchange between blood and tissue cells. Common sites for assessing systemic microcirculation include the nail bed, tongue, and conjunctiva. Compared to other sites for evaluating systemic microcirculation, conjunctiva is minimally influenced by external temperature and offers closer insights into visceral microcirculatory alterations [4].

In clinical practice, we have observed some distinct manifestations of conjunctival microcirculation in patients with hypercoagulability. These including vessel twisting, dilation, hemorrhages, ischemic areas, reticulum deformity, microangioma, and wound spots(Fig. 1), collectively refferred to as eye signs. In large-scale, multicenter study, eye signs were demonstrated to be an valuable diagnostic tool to assess systemic hypercoagulability and microcirculation disorders[5]. it is preliminarily discovered that eye signs were associated with cardiopulmonary function and can be used to assess the risk of mortality in systemic lupus erythematosus with pulmonary arterial hypertension [6]. To further investigate the role of eye signs in pulmonary arterial hypertension and explore the predictive value of eye signs in treatment response and prognosis of SLE-PAH, this prospective observational study observed conjuctival microvessel manifestations of eye signs and compared the differences on eye sign parameters between the improved and non-improved groups after a period of 6 months followed-up.

ischemic area(more than 3 capillary grid areas without vessels under a 40x microscope);reticulum deformity(the capillaries increase, the mesh decreases, and the dendrites become grid-like); microangioma (can be divided into local round, fusiform, cystic dilation, or isolated and scattered around the vessel); and wound spot(vascular blind end-shaped brown, purple, or dark blue material deposition) Bleeding is exudative (fuzzy vessel wall), and there are ruptures (wound spots, patches) around capillaries.

2.1 Subjects

This prospective observational study consecutively recruited patients diagnosed with SLE-PAH at the First Affiliated Hospital of Nanchang University from January 2021 to December 2021. All enrolled patients fulfilled the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus [7]. The diagnostic criteria for PAH included mean pulmonary arterial pressure (mPAP) > 20 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, pulmonary vascular resistance (PVR) > 2 Wood units, as determined by right heart catheterization (RHC), or systolic pulmonary arterial pressure (sPAP) ≥ 40 mmHg, as assessed through transthoracic echocardiography combined with clinical manifestations [8]. Patients with interstitial lung disease, congenital heart disease, chronic obstructive pulmonary disease, pulmonary thromboembolism, or human immunodeficiency virus infection were excluded from enrollment. This study adhered to the principles of the Helsinki Declaration and was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University. Written informed consent was obtained from all patients.

2.2 Study design

During the study, patients underwent regular visit every 1–3 months. the evaluation of various parameters such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walking distance(6MWD), World Health Organization functional class (WHO-FC), echocardiography, and risk stratification based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines were conducted at intervals of every 1–3 months, and a 6-month follow-up period was observed. The primary outcome of the study was the risk stratification of PAH, considering improvement if there was a decline in the risk stratification grade at the end point, and no improvement otherwise.

2.3 Conjunctival Microvasculation

An SLM-7E digital slit lamp was used to detect conjunctival microvasculation. Each subject rotated their eyeballs up, down, left, and right to fully expose the required observation range. Eight conjunctival microvasculation images were observed and recorded when the binoculars were in four different positions. The observations included the following: vessel twisting, dilation, hemorrhages, ischemic areas, reticulum deformity, microangioma, blood vessel lossand wound spots(Figure 1).For vessel density (VD) calculation method, the image under a 40x mirror was divided into 16 grids with three horizontal lines and three vertical lines, and the number of lines passing through the grid was calculated and averaged. For microvascular flow index (MFI), the image under a 100xmicroscope was divided into four directions, and the average was taken after integration. Normal flow was counted as 3 points, sluggish flow was 2 points, intermittent flow was 1 point, and no flow for at least 20 seconds was 0 points[10].

2.4 Statistical Analysis

SPSS version 26.0 (IBM, Armonk, NY, USA). Descriptive statistics were reported for continuous variables as the mean ± standard deviation for normally distributed data, or as the median (interquartile range) for non-normally distributed data. Categorical variables were represented as frequencies and percentages. The comparison between two groups was assessed using either the independent samples t-test or the Mann-Whitney U test for continuous variables, and the chi-square test or Fisher's exact test for categorical variables. Correlation analysis was conducted using Pearson's test or, if appropriate, Spearman's test. Logistic regression analysis was implemented to identify potential risk factors and generate a receiver operating characteristic (ROC) curve. The discriminatory performance of potential predictive factors for SLE-PAH was evaluated by calculating the area under the curve (AUC), sensitivity, and specificity. The cut-off point for identifying potential predictive factors was determined through ROC analysis. All statistical tests were two-tailed, and statistical significance was defined as p < 0.05.

3.1 Patients' characteristics at baseline in improved and non-improved groups

According to Table 1, there are significant differences (p < 0.05) in the clinical parameters, including cardiac functional classification, NT-proBNP levels, 6MWD, conjunctival ischemic areas, Reticulum deformity, VD, and MFI, between the improved and non-improved groups of SLE-PAH patients. Both groups of SLE-PAH patients present with various conjunctival manifestations such as vessle twisting, dilation, ischemic areas, hemorrhages, reticulum deformity, and wound spots. Among these, conjunctival microangioma, vessel twisting, and wound spots are the most frequently observed changes.

Table.1 General characteristics and eye signs presentation of the two patient groups.

	Improved Group (n = 12)	Non-Improved Group (n = 17)	P
Gender (F/M)	12(100%)	16(94.1%)/ 1༈5.9%༉	0.393
Age(years)	41.42 ± 10.10	38.41 ± 12.19	0.565
Functional Level			0.006^**
Ⅰ	6(50%)	0
Ⅱ	4(33.33%)	2(11.76%)
Ⅲ~Ⅳ	2(16.67)	10(58.82%)
NTproBNP	297(135, 586)	1200(688, 2155)	0.000*
6MWD(m)	420(400, 470)	360(300, 410)	0.018*
Medication
Corticosteroids	12(100%)	17(100%)
Endothelin inhibitors	4(33.3%)	8(47.1%)	0.460
PDE5 Inhibitors	2(16.7%)	3(17.6%)	0.945
Combination therapy	6(50%)	6(35.3%)	0.428
eye signs
Ischemic areas, n (%)	6(50%)	8(47.1%)	0.876
Reticulum deformity, n (%)	4(33.3%)	6(35.3%)	0.913
Microangioma, n (%)	6(50%)	9(52.9%)	0.876
Twisting, n (%)	11(91.7%)	16(94.7%)	0.798
Dilation, n (%)	7(58.3%)	5(29.4%)	0.119
Wound spot, n (%)	5(41.7%)	13(76.5%)	0.057
Hemorrhage, n (%)	3(25%)	5(29.4%)	0.793
blood vessel loss, n (%)	2(16.7%)	5(29.4%)	0.430
VD(n/mm2)	1.83 ± 0.79	0.98 ± 0.42	0.001^**
MFI	2.4(2.0, 2.87)	1.2(1.0, 1.35)	0.002^**

6MWD, 6- minute walking distance; WHO FC, World Health Organization functional class; NT-proBNP, N-terminal prohormone of brain natriuretic peptide;VD: vessel density; MFI: microvascular flow index; ∗P < 0.05, ∗∗P < 0.01.

3.2 The correlation between eye signs indicators and cardiopulmonary function.

Spearman correlation analysis showed that VD and MFI were negatively correlated with NT-proBNP and WHO-FC (r < 0, P < 0.05), and positively correlated with 6MWD (r > 0, P < 0.05) (Table 2, Fig. 2).

Table 2

Correlation analysis of eye signs indicators with parameters of SLE-PAH
	6MWD		WHO-FC		NT-proBNP
	r	P	r	P	r	P
VD	0.561**	0.002	-0.413*	0.026	-0.472*	0.010
MFI	0.517**	0.004	-0.408*	0.028	-0.492**	0.007

6MWD, 6- minute walking distance; WHO FC, World Health Organization functional class; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; VD: vessel density; MFI: microvascular flow index;∗P < 0.05, ∗∗P < 0.01.

3.3 Comparison of various parameters in different PAH risk stratifications.

Based on the 2015 European guidelines, all patients were divided into low-risk, intermediate-risk, and high-risk groups using a multiparameter risk stratification scale, as shown in Table 3. NT-proBNP, 6-MWD, VD, and MFI showed significant differences among different risk groups, while pulmonary arterial pressure (PH) did not show statistical differences.

Table 3.Comparison of various parameters among three groups in different PAH risk stratifications.

GROUP	Low Risk（n=8）	Moderate Risk（n=14）	High Risk（n=7）	P value
PH (mmHg)	44.38±3.89	47.86±9.49	54.71±23.91	0.336
NT- proBNP （pg/ml）	251.35±205.83	1059.49±643.79	1865.44±887.56	0.001**
6-MWD （m）	443.75±51.81	391.64±47.93	277.71±91.62	0.001**
VD (n/mm2)	2.1±0.42	1.08±0.65	0.96±0.52	0.001**
MFI	2.35±0.35	1.39±0.77	0.97±0.47	0.001**
Eye sign

6MWD, 6- minute walking distance; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; VD: vessel density; MFI: microvascular flow index;∗P < 0.05, ∗∗P < 0.01.

3.4 Assssment of risk parameters in predicting treatment response and prognosis of SLE-PAH

In univariable logistic analysis, variables such as VD, MFI, WHO-FC, 6-MWD, and NTproBNP demonstrated significant statistical significance in both improved and non-improved groups(p < 0.05). In the multivariable analysis, age was included as a confounding factor. In the adjusted model 1 for VD, it emerged as a significant predictor for SLE-PAH (HR 10.11, 95% CI 1.95–52.36, p = 0.006). Likewise, in the adjusted model 2 for MFI, it remained a significant predictor (HR 7.85, 95% CI 1.73–35.67, p = 0.008). Similarly, in the other adjusted models, WHO-FC (HR 0.12, 95% CI 0.02–0.75, p = 0.024), 6-MWD (HR 1.02, 95% CI 1.00-1.03, p = 0.039), and NTproBNP (HR 0.99, 95% CI 0.99-1.00, p = 0.010) were also identified as significant predictors (Table 4).

ROC curve analysis demonstrated that VD had a threshold of 1.75 (AUC 0.83, 95% CI 0.62-1.00, sensitivity 75%, specificity 100%), MFI had a threshold of 1.85 (AUC 0.83, 95% CI 0.62-1.00, sensitivity 83%, specificity 100%), 6-MWD had a threshold of 461.5 (AUC 0.76, 95% CI 0.58–0.94, sensitivity 25%, specificity 100%), and NTproBNP had a threshold of 664.25 (AUC 0.90, 95% CI 0.78-1.00, sensitivity 88%, specificity 83%). All these indicators effectively differentiated between SLE-PAH patients with improvement and those without improvement (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, respectively) (Table 4).

Table 4

Performance of potential predictive factors with cut-off points in adjusted univariate and multivariate logistic regression models for SLE-PAH.
	AUC	95%	Cut-off point	Sensitivity	Specificity
VD	0.83	0.62-1.00	1.75	75%	100%
MFI	0.83	0.62-1.00	1.85	83%	100%
6-MWD	0.76	0.58–0.94	461.5	25%	100%
NTproBNP	0.90	0.78-1.00	664.25	88%	83%
	Univariate		Multivariate
	OR(95CI)	P value	OR(95CI)	P value
VD	9.69(1.86–50.36)	0.007	10.11(1.95–52.36)	0.006**
MFI	7.74(1.74–34.52)	0.007	7.85(1.73–35.67)	0.008**
WHO-FC	0.16(0.04–0.69)	0.009	0.12(0.02–0.75)	0.024*
age	1.02(0.96–1.09)	0.475
6-MWD	1.02(1.00-1.03)	0.047	1.02(1.00-1.03)	0.039*
NTproBNP	0.99(0.99-1.00)	0.011	0.99(0.99-1.00)	0.010*

PAH is a severe and progressive pulmonary vascular disease characterized by elevated pulmonary artery pressure and increased pulmonary artery resistance, leading to right ventricular failure and mortality. The REVEAL registry study in the United States revealed that CTD-related PAH accounts for 25.3% of all PAH patients. SLE and systemic sclerosis (SSc) are the most common CTDs associated with PAH [11]. An analysis of the causes of death in SLE patients in China over the past 30 years found that SLE-PAH is the third leading cause of death in SLE patients [12]. The pathogenesis of CTD-PAH is complex, making treatment challenging, as even with novel targeted combination therapies, the three-year mortality rate in moderate to high-risk patients remains as high as 56% [13].

Assessing the risk of pulmonary arterial hypertension (PAH) is crucial in guiding standardized treatment and reducing mortality rates in PAH patients. Therefore, PAH risk assessment methods were introduced in the 2012 REVEAL study, the 2015 European PAH guidelines, and the 2018 6th World Symposium on Pulmonary Hypertension (WSPH) [9, 14, 15]. Evaluation indicators include clinical manifestations, the level of cardiac function, plasma brain natriuretic peptide (BNP) level, cardiac echocardiography and hemodynamic levels. However, in these risk stratification, some risk parameters require high measurement conditions, such as cardiac index(CI), mixed venous oxygen saturation(SvO2) derived by right heart catheterization, limiting their practicality. Research has been conducted to identify more simple risk assessment indicators for dialy clinical practice, such as age, right atrial area, pulmonary arteriole diameter, serum iron, red cell distribution width, and blood uric acid levels [16–18]. However, the predictive value of these indicators in CTD-PAH remains controversial. Currently, there are no specific risk assessment indicators or models for pulmonary arterial hypertension in CTD patients.

Although various microvascular changes in eye signs were observed in SLE-PAH patients, which encompass decreased vessel number(ischemic areas), increased vessel number(reticulum deformity), changes in vascular morphology( twisting, dialated, microangioma) and vascular vall injury ( hemorrhage and wound spots). It is demonstrated decreased VD and MFI were associated with poor cardiopulmonary function. Compared to conventional risk assessment indicators for pulmonary hypertension, such as WHO functional class (HR 0.12, 95% CI 0.02–0.75, p = 0.024), 6MWD (HR 1.02, 95% CI 1.00-1.03, p = 0.039), and NT-proBNP (HR 0.99, p = 0.010), VD (HR 10.11, p = 0.006) and MFI (HR 7.85, p = 0.008) appeared to be more effective in predicting inadequate therapeutic response and poor prognosis in SLE-PAH.

Vessel density (VD) and microvascular flow index (MFI) are essential parameters in microcirculation [19]. VD refers to the number of blood vessels in a unit area. The level of vascular density reflects the distribution of microvessels and the degree of blood supply. The formation and regulation of vascular density involve multiple mechanisms, including angiogenesis, proinflammatory cytokines release, and vascular constriction and dilation. For instance, angiogenic factors such as VEGF stimulate the formation of new blood vessels. The release of cytokines and chemical mediators may induce vascular constriction or dilation, thereby regulating vascular density. MFI assesses the hemodynamic characteristics of microcirculation by measuring the average flow velocity and density of red blood cells in the microvessels. It reflects the blood flow velocity and volume in the microcirculation. Clinically, changes in MFI effectively indicate alterations in blood perfusion. Higher MFI values indicate faster blood flow velocity and larger vascular blood volume [6].

VD and MFI have gained increasing attention as crucial assessments for hemodynamic changes and systemic microcirculation disorder in critically ill patients. Research on microcirculation evaluation in sepsis and critical care monitoring has shown that VD and MFI can determine the fluid resuscitation needs of ICU patients [20, 21]. There is currently a lack of relevant research on VD and MFI for assessing SLE-PAH. Previous cross-sectional study has shown VD and MFI in conjunctival microvasculation were associated with risk levels of mortality in SLE-PAH [6]. Further investigation into the measurement of VD and MFI in SLE-PAH were contribute to evaluating the systemic hemodynamic changes caused PAH and a better understanding of the pathophysiological mechanisms of SLE-PAH.

The conjunctival microcirculation, as a crucial window into systemic microcirculation, indirectly reflects the overall state of microcirculation through the observation and measurement of conjunctival vascular density, vessel diameter, blood flow velocity, vascular branching pattern, endothelial wall, vascular reactivity and perfusion status. In comparison with other common methods for sublingual microcirculation and nailfold microcirculation, conjunctival microcirculation offers advantages such as being unaffected by external temperature and having a stronger correlation with visceral blood vessels [23, 24]. However, it also has certain limitations, including difficulties in cooperation during testing, complexity in examination procedures, and higher requirements for equipment and personnel expertise. In order to solve complex operational problems, eye signs were proceeded through clinical observational studies involving a large sample size. Focusing on the distinct manifestations of conjunctival microcirculation changes in patients with hypercoagulable state, a conjuctival vascular panel was defined including vessel twisting, dilation, hemorrhages, ischemic areas, reticulum deformity, microangioma, and wound spots (Fig. 1). This set of distinctive features is referred to as "eye signs." Copared to conjunctival microcirlation examination, the detection of the eye signs is more simple, as they can be observed using a conventional slit lamp or even with the naked eye. Clinical validation of eye signs demonstrates their high accuracy in assessing thrombosis or hypercoagulability, exhibiting a strong correspondence with nailfold capillary microcirculation [25].

In SLE patients with pulmonary arterial hypertension, eye signs suggested two hemodynamic states(figure 3): hyperinflammatory state (dilation and reticulum deformity) and hypoinfusion state ( ischemic areas, decreased VD and MFI). Patients in hyperinflammtory state were respond well to treatment and has better outcome compared to hypoinfusion state .

Hypoinfusion state means reduced blood volume, decline in oxygenation function and impaired cardiac performance which caused by severe condition of pulmonary hypertension and extremly elevated vascular resistance[26]. Therefore, patients in hypoinfusion state had poor prognosis and needed intensive monitor and progressive treatment. To the best of our knowledge, this is the first report on eye signs in predicting theraputic response and outcome in SLE patients with PAH. The study discovered a novel simple tool for predicting the prognosis of SLE-PAH by observing conjunctival vascular changes, and proposes hypothesis of two states which is important for guiding clinical practice for SLE-PAH.

This study was conducted in a single center with a relatively small sample size, and further research with larger sample sizes is needed to confirm the clinical significance of VD and MFI in PAH. While further clinical trials and applications are needed to address parameter calculations and standardization issues, it is undeniable that conjunctival microcirculation assessment provides a convenient and feasible option, deserving of further clinical promotion and application.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgments

The researcher would like to thank all participants involved in this study.

Contributors: JLi, BXiong, and CLiu: conceptualization, data curation, formal analysis, investigation, methodology, resources, software, writing-original draft, writing-review and editing. LPeng and SCai: conceptualization, supervision, formal analysis, writing-review and editing. XFang, JYu, and JZhao: conceptualization, supervision, writing-review and editing. RWu: conceptualization, data curation, formal analysis, investigation, methodology, resources, software, supervision, validation, visualization, writing-original draft, writing-review and editing.

Funding

Not applicable

Data availability

Primary data are available upon the corresponding author request.

Ethics approval and consent to participate

This study was approved by our Ethics Committee.

Consent for publication

The patient provided consent for publication of the images.

Competing interests

Not applicable.

Consent for publication

Not applicable

Author details

All authors are affiliated with the Department of Rheumatology and Immunology, the First Affiliated Hospital of Nanchang University, Jiangxi, China.

ORCID

Rui Wu iD https://orcid.org/0000-0003-0110-4912

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Eye signs as a novel risk predictor in pulmonary arterial hypertension associated with systemic lupus erythematosus

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Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1 Introduction

2 Materials and methods

2.1 Subjects

2.2 Study design

2.3 Conjunctival Microvasculation

2.4 Statistical Analysis

3 Results

3.1 Patients' characteristics at baseline in improved and non-improved groups

3.2 The correlation between eye signs indicators and cardiopulmonary function.

3.3 Comparison of various parameters in different PAH risk stratifications.

3.4 Assssment of risk parameters in predicting treatment response and prognosis of SLE-PAH

4 Discussion

Declarations

References

Status:

Version 1