- Email: [email protected]
Unique changes in the retinal microvasculature reveal subclinical retinal impairment in patients with systemic lupus erythematosus
Journal Pre-proof Unique changes in the retinal microvasculature reveal subclinical retinal impairment in patients with systemic lupus erythematosus
Lulu Bao, Rong Zhou, Yufei Wu, Jianhua Wang, Meixiao Shen, Fan Lu, Hong Wang, Qi Chen PII:
S0026-2862(19)30220-1
DOI:
https://doi.org/10.1016/j.mvr.2019.103957
Reference:
YMVRE 103957
To appear in:
Microvascular Research
Received date:
22 August 2019
Revised date:
11 November 2019
Accepted date:
12 November 2019
Please cite this article as: L. Bao, R. Zhou, Y. Wu, et al., Unique changes in the retinal microvasculature reveal subclinical retinal impairment in patients with systemic lupus erythematosus, Microvascular Research(2019), https://doi.org/10.1016/ j.mvr.2019.103957
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof Title: Unique changes in the retinal microvasculature reveals subclinical retinal impairment in patients with systemic lupus erythematosus Short title: Retinal microvasculature in SLE patients Word count: 3372 words Tables and figures: 4 figures and 4 tables Key words: Systemic lupus erythematosus; optical coherence tomography; retinal microvascular; retinal thickness
of
Author names, degrees and affiliations: Lulu Bao, MD1*, Rong Zhou, MD1*, Yufei Wu, MD1, , Jianhua Wang, MD, PhD2, 3, Meixiao Shen, PhD1, Fan Lu, MD, OD1, Hong Wang, MD4, Qi Chen, MD, PhD1 1
ro
School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China 2
lP
re
-p
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA 3 Electrical and Computer Engineering, University of Miami, Miami, FL, USA 4 The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China * Authors have the equal contributions to the project.
Jo ur
na
Corresponding Authors: Hong Wang, MD & Qi Chen, MD, PhD Mailing address: School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang, China, 325027 Tel: (086) 577-88824116; Fax: (086) 577-88824115 Email: [email protected] (to Wang); [email protected] (to Chen) Funding/Support: This study was supported by research grants from the Nature Science Foundation of Zhejiang Province (LY19H120003), the National Nature Science Foundation of China (81570880), the Public Service Program of Wenzhou Science and Technology Bureau of China (Y20160151). Proprietary interests: The authors have no proprietary interest in any materials or methods described within this article.
Journal Pre-proof Abstract Purpose: To determine the changes of the microvasculature and microstructure in the inner intra-retinal layers in systemic lupus erythematosus (SLE) patients without lupus retinopathy (LR). Methods: Thirty-two SLE patients (58 eyes) without LR (NLR), 14 patients (22 eyes) with LR and 50 healthy subjects (50 eyes) were enrolled. Spectral domain optical coherence tomography equipped with Angiovue was used to obtain three-dimensional retinal thickness maps and microvascular images of the superficial and deep retinal capillary plexuses (SRCP/DRCP) around
of
the macula. Quantitative analyses were performed using a custom automated algorithm. Disease
ro
activity of patients was assessed using the SLE disease activity index (SLEDAI).
-p
Results: Retinal capillary skeleton density of the SRCP in SLE patients without LR was significantly lower than the controls in almost all regions, which further decreased in the LR group
re
(P < 0.05). No significant changes were evident in DRCP of the NLR group (P > 0.05). The inner
lP
retina in the LR group were significantly thinner than the controls in most regions, though there were only a few regions were different between the NLR and the control groups (P < 0.05). There
na
were significant differences of the SLEDAI scores between the two SLE groups. Conclusion: Significantly lower density in SRCP and regional thinning in inner retina were
Jo ur
observed in the SLE patients without clinical fundus changes. OCT equipped with Angiovue might be useful in evaluating the microvascular and microstructural disorders of the inner retinal layers in SLE patients, which may contribute a quantitative approach to the early diagnosis and progression of LR.
Journal Pre-proof
Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with undefined etiology and remarkably heterogeneous clinical features (Dammacco, 2018). Ocular
of
manifestations affecting multiple ocular structures can occur in up to one-third of SLE patients
ro
(Silpa-archa S et al., 2016). Retinal involvement in SLE, termed lupus retinopathy (LR), is the second most common ocular manifestation after dry eye disease with an incidence of 7–29%, and
-p
it is most frequently associated with visual loss (Palejwala NV et al., 2012). The major
re
pathological changes in LR are attributed to microangiopathy caused by the deposition of immune
lP
complexes in the basement membrane of endothelial cells of the fundus blood vessels (Sivaraj RR
na
et al., 2007). The most frequent clinical signs in the fundus color photograph include cotton wool spots, retinal hemorrhages, and vascular tortuosity. In addition, retinal hard exudates, retinal
Jo ur
vasculitis, retinal artery and/or vein occlusion, arteriolar narrowing, arteriovenous crossing changes, macular pigmentary mottling, retinal scarring, and macular infarction have also been reported (Lanham JG et al., 1982; Shein J et al., 2008; Ushiyama O et al., 2000). LR is suggestive of elevated disease activity of SLE and correlates with central nervous system and kidney involvement which are represented by neuropsychiatric systemic lupus erythematosus (NPSLE) and lupus nephropathy(LN) with progression of SLE (Kharel SR et al., 2016; Stafford-Brady FJ et al., 1988). It is also considered as a marker of poor prognosis for survival (Kharel SR et al., 2016; Stafford-Brady FJ et al., 1988). Therefore, an early diagnosis and the adoption of suitable therapeutic measures are indispensable and might help to prevent sight-threatening consequences
Journal Pre-proof
and poor disease prognosis. It is well known that there is a multilayered complex of capillaries parallel to the cellular layers in the inner retina. As a complication of SLE characterized by microangiopathy, the earliest clinical findings in LR are small intra-retinal hemorrhages and cotton wool spots (Ushiyama O et al., 2000). With advanced developments of optical coherence tomography (OCT), the nerve fiber
of
layer (NFL), ganglion cell layer and the inner plexiform layer (GCL+IPL) as well as the inner
ro
nuclear layer (INL) around the macula have also been found to be significantly thinner in SLE patients compared to normal subjects (Liu GY et al., 2015). In addition, according to an
-p
immunopathologic study, the retinal impairment in SLE has been considered to be associated with
re
vasculitis caused by deposition of IgG immune complexes in the walls of retinal vessels (Karpik
lP
AG et al., 1985). However, no clinically quantitative parameters are available to describe the
na
impairment of the retinal microvascular network and structure in the early stages of SLE to identify patients at risk of developing SLE associated retinopathy.
Jo ur
OCT angiography (OCT-A) is a novel imaging modality that non-invasively and quickly obtains high resolution images of the in vivo retinal microvasculature, allowing in-depth visualization of the retinal microvascular network in the different retinal layers (Chen Q et al., 2017; Chen Q et al., 2018; Savastano MC, 2015). Spectral domain OCT (SD-OCT) provides high resolution images that enable detailed detection of intra-retinal structures that were previously available only by histopathology (Staurenghi, 2014). The goal of the current study is to investigate the changes of the microvasculature and structure in the inner intra-retinal layers in SLE patients without clinically diagnosed LR using the OCT-A and SD-OCT devices. This might allow earlier diagnosis and timely implementation of treatment, as well as predictions for other complications
Journal Pre-proof
of SLE.
Methods Patients Patients with a history of SLE were identified by a rheumatologist (HW) following the American College of Rheumatology (ACR) classification criteria (Tan EM et al., 1982), and the
of
systemic lupus erythematosus disease activity index (SLEDAI) of each patient was also evaluate.
ro
Patients with a diagnosis of LR were determined by an ophthalmologist (RZ) according to the presence of (1) cotton–wool spots, perivascular hard exudates, retinal hemorrhages, (2) focal or
-p
generalized arteriolar constriction and venous tortuosity, (3) and/or vaso-occlusive retinopathy
re
(Dammacco, 2018; Gao N et al., 2017; Kharel Sitaula et al., 2016). Patients recruited from the
lP
Second Affiliated Hospital & Yuying Children’s Hospital, China from May 2018 to September
na
2018 were carried out in the Eye Hospital of Wenzhou Medical University. Inclusion criteria were: (1) age ≥18 and ≤75 years, (2) best-corrected visual acuity (BCVA) better than 0.1 LogMAR, and
Jo ur
(3) spherical equivalent (SE) refractive error between −3.00 and +0.50 diopters. Exclusion criteria were: (1) established primary ocular diseases including a history of any retinal or optic nerve disease, (2) presence of any drusen-like deposits, focal atrophy, or retinal pigment epithelium detachment, and alterations associated to Chloroquine (CQ)/Hydroxychloroquine (HCQ) toxicity on indirect ophthalmology or SD-OCT examination; (3) ocular trauma or surgery, (4) lens opacities, and (5) systemic disorders with ocular involvement such as diabetes and hypertension (current and past medical history). All study procedures were explained to the participating subjects and informed written consent was obtained before inclusion of participants. The study was performed in accordance
Journal Pre-proof
with the tenets of the Declaration of Helsinki and also adhered to the requirements of the ethics committee of the Eye Hospital of Wenzhou Medical University and the Second Affiliated Hospital & Yuying Children’s Hospital, China. Age- and sex-matched control subjects were recruited from workers or the members accompanying the patients at the Eye Hospital. Evaluations and Measurements
of
Clinical Examinations
ro
All subjects underwent comprehensive clinical examinations, including refraction and BCVA,
-p
slit-lamp biomicroscopy, axial length (AL) measurement (IOL Master: Carl Zeiss Meditec, Jena, Germany), intraocular pressure (IOP) measurement (Kowa applanation tonometer HA-2; Kowa
re
Company Ltd. Tokyo, Japan), visual field test (Humphrey Field Analyzer; 24-2 Swedish
lP
interactive threshold algorithm; Carl-Zeiss Meditec, Inc.), and ophthalmoscopy. In addition, the
na
fundus photography was performed with a 45-degree digital retinal camera (Canon EOS 10D SLR
Jo ur
backing; Canon, Inc., Tokyo, Japan).
Image Acquisition Protocol and Analysis
All the subjects were imaged by a commercial SD-OCT device (Optovue RTVue XR Avanti; Optovue, Inc., Fremont, CA, USA) which was equipped with Angiovue for OCT-A. The bimodal system was operated in the radial scan mode (8-mm diameter; 18 lines) to generate three-dimensional thickness maps. A good set of scans with a signal strength index of >6 for each eye was selected for further analysis. The segmentation of intra-retinal layers was achieved by a dedicated software program based on the gradient information and shortest path search that was developed in Matlab (The MathWorks, Inc., Natick, MA, USA) for automated image analysis. The thickness of each intra-retinal layer was calculated by subtracting the boundary positions of
Journal Pre-proof
each of the adjacent layers, obtained by automated segmentation along the depth. The intra-retinal layers included the (1) NFL, (2) GCL+IPL, (3) INL, (4) outer plexiform layer (OPL), (5) Henle fiber layer and outer nuclear layer (HFL+ONL), (6) the myoid and ellipsoid zone (MEZ), (7) photoreceptor outer segments (OS), (8) interdigitation zone + retinal pigment epithelium (IZ+RPE), and (9)choroid (Fig. 1). The algorithm that identifies the different layers automatically
of
and analyzes layer thicknesses have been demonstrated in our previous papers (Chen Q et al.,
ro
2018; Chen et al., 2017; Kwapong WR et al., 2018). In the current study, only the NFL between the first and second boundaries and the GCL+IPL between the second and third boundaries were
-p
investigated.
re
To match the areas of retinal structure and microvasculature, a 2.5-mm diameter 3D thickness
lP
map of the NFL and GCL+IPL in each eye was generated based on the segmented layers around
na
the macula (Fig. 1). For analysis, the macular thickness map was divided into a 0.6-mm diameter circle centered over the fovea and a total annular zone (TAZ) surrounded by a concentric ring 0.3 -
Jo ur
1.25 mm from the fovea. The areas of the central circle and the TAZ were then divided into five regions including the central and the superior, temporal, inferior, and nasal regions. The mean thicknesses for the NFL and GCL+IPL in each region were calculated.
In addition, the OCT-A model (3×3-mm area) was operated to obtain microvascular images of the superficial and deep retinal capillary plexuses (SRCP and DRCP) around the fovea. The SRCP and DRCP were detected and separated automatically by the OCT instrument as seen in Fig. 1. The SRCP extends from 3 μm below the internal limiting membrane to 15 μm below the IPL. The DRCP extends from 15 to 70 μm below the IPL (Shen C et al., 2018). A custom automated algorithm was performed on the en face OCT-A projection images to quantify the SRCP and
Journal Pre-proof
DRCP, which have been described in detail in our previous studies (Chen Q et al., 2017; Yang Y et al., 2016). Briefly, the grayscale of each two-dimensional OCT-A images were extended by bicubic interpolation to 1024×1024 pixels to enhance the image details. Then, the image was segmented to obtain the microvascular network after excluding the foveal avascular zone (FAZ), which was detected by a two-way combined method consisting of a canny edge detector algorithm
of
and a level set algorithm. At last, based on the final binary image containing only the small vessels,
ro
which was obtained by subtracting the binary image containing only the large blood vessels from another containing both large and small vessels, a skeletonized image was created by identifying
-p
the central axis of the binary, white-pixelated vasculature, and remaining one pixel along the
re
central axis. In the current study, the retinal capillary density was calculated as the percentage of
lP
pixels with skeletonized microvessels by an automated algorithm to extract the skeletonized
na
images of the retinal capillary network in the OCTA images, which was called retinal capillary skeleton density (RCSD). The RCSD of the SRCP and DRCP were automatically calculated in the
Jo ur
parafoveal regions, i.e., superior, temporal, inferior, and nasal regions of the 2.5-mm diameter circular zone after excluding the FAZ based on skeletonized images (Fig. 1). The methods above were implemented using MATLAB v7.10 (Mathworks, Inc., Natick, MA, USA). Statistical Analysis All data were calculated as means ± standard deviations and analyzed with SPSS software (version 22.0; SPSS, Inc., Chicago, IL, USA). The SE of refraction error was calculated as the spherical dioptric power plus one-half of the cylindrical dioptric power. Differences of gender among the groups were determined by the x2 test. One-way analysis of variance (ANOVA) was used to compare the differences among the groups, and post hoc procedures were used to compare
Journal Pre-proof
differences between the two groups. The durations of disease in the subgroups of SLE patients were compared using Student’s t-test. Pearson’s correlation coefficients (2-sided) were calculated to analyze correlations between the microstructural thickness of the inner retina and the density of the macular retinal microvascular layers. P values of < 0.05 were considered statistically
of
significant.
ro
Results
-p
In total, 32 SLE patients (58 eyes) with no LR (NLR), 14 patients (22 eyes) with LR and 50
re
healthy subjects (50 eyes) were enrolled in the current study. There were no significant differences
lP
in the age, gender, body mass index (BMI), SE, AL, IOP, and mean arterial blood pressure (MABP) among the three groups (P = 0.090 ~ 0.910), except for the BCVA (P < 0.001, Table 1). Moreover,
na
there were no differences in the disease duration between the two SLE groups (P = 0.950). Fundus
Jo ur
photographs and raw OCT/OCT-A images in the Control, NLR and LR eyes were presented in Figure 2. In eyes with LR, the presence of an abnormal retinal vasculature was evident as a decrease in capillary complexity and density.
Compared to the controls, the RCSDs of the SRCP were significantly decreased in both NLR (P values: 0.004 ~ 0.018) and LR (P values: all < 0.001) groups in almost all regions except for the nasal region when comparing the NLR and the control groups (P = 0.076, Table 2). Moreover, the RCSDs of the SRCP in the LR group were further decreased compared to the NLR group (P values: 0.010 ~ 0.043, Table 2). For the DRCP, the RCSDs of the LR group were significantly lower than the NLR (P values: 0.011 ~ 0.047) and control (P values: 0.002 ~ 0.028) groups in all
Journal Pre-proof
the regions except for the temporal region between the two SLE groups (P = 0.115, Table 2). However, there were no significant differences between the control and NLR groups (P > 0.05, Table 2).
The NFL thicknesses of the NLR group in superior (P = 0.045) and nasal (P = 0.040) regions and the LR group in the superior (P = 0.002), inferior (P = 0.020) and nasal (P = 0.020) regions
of
were decreased, compared to the controls (Table 3). Meanwhile, compared to the controls, the
ro
GCL+IPL thicknesses of the NLR group in the temporal (P = 0.006) region and the LR group in
-p
the central (P = 0.039), superior (P = 0.012), temporal (P < 0.001) and inferior (P = 0.015) regions were also decreased (Table 3). Moreover, the GCL+IPL thicknesses in the LR group were further
re
decreased compared to the NLR in the temporal (P = 0.029) and inferior (P = 0.044) regions
lP
(Table 3). The total retinal thickness of the NLR group in the temporal (P = 0.001) region and the
na
LR group in the superior (P = 0.002), temporal (P < 0.001), inferior (P = 0.009) and nasal (P = 0.036) regions were also decreased (Table 3). In addition, the thicknesses of NFL in the TAZ
Jo ur
region is significantly associated with the RCDs of SRCP (r = 0.38, P = 0.001), meanwhile the thicknesses of GCL+IPL in the TAZ region were significantly associated with the RCSDs of SRCP (r = 0.51, P < 0.001) and DRCP (r = 0.43, P < 0.001) in patients with SLE (Fig. 3).
In Figure 4, the SLE patients with LR presented a higher SLEDAI score than those patients without LR (13.8 6.5 vs 7.7 8.1, P = 0.020). As for the complications of SLE, the percentages of NPSLE and LN, which represent the involvement of the central nervous system and kidney respectively within the LR group were also larger than NLR group (14% vs 9% for NPSLE, 50% vs 38% for LN; Table 4).
Journal Pre-proof
Discussion The present study investigated the microvascular features around the macula in the SLE patients with and without clinically diagnosed LR using OCT-A technology. In addition, instead of the non-skeletonized density that is susceptible to threshold setting, we used the skeletonized density to quantify the retinal microvasculature which was considered to be more sensitive to
of
vessel width (Kim et al., 2016; Pedinielli et al., 2017) (Ashimatey et al., 2019). We found that the
ro
retinal microvascular density, especially in the superficial layer, has a decreased gradient among
-p
the controls, SLE patients without and with LR, consistent with the characteristics of the SLE as a microvascular disease. We also found that the thicknesses of the inner retinal layers were
re
decreased in both SLE groups at the fovea and various regions of the parafovea. In addition, the
lP
activity score of the disease, and the percentages of the LN and NPSLE, were significantly
na
different between the two SLE groups.
As we know, the published reports mostly focused on the obviously vascular lesion in eyes
Jo ur
with LR using fundus photography or fluorescence angiography (FA) (Bhojwani et al., 2014; Gao N et al., 2017; Kharel SR et al., 2016; Seth G et al., 2018; Tolba DA et al., 2017). In the current study, using the OCT-A, we found that the retinal microvascular density in both SRCP and DRCP were decreased in the SLE patients with clinically diagnosed LR, compared to the controls. Furthermore, we also found that the retinal microvascular density in the SRCP had a significant decline in the NLR group, however, this phenomenon did not exist in the DRCP. The retinal lesions of SLE patients are mainly caused by the abnormalities in the retinal microvasculature supplying oxygen and nutrition to the NFL, which was supported in an animal experiment (Nakamura A et al., 1998). It was also confirmed in previous studies that the progress of LR was
Journal Pre-proof
based on microangiopathy and vaso-occlusions (Dammacco, 2018; Nag TC and Wadhwa S, 2006). Moreover, the so-called severe vaso-occlusive retinopathy is characterized by small arterial occlusions and diffuse capillary non-perfusion (Jabs DA et al., 1986; Read, 2004). It was reported that the characteristics of the SRCP tends to be arterial, but on the contrary, the DRCP consists of veins (Bonnin S et al., 2015). This may possibly explain the different performances of the SRCP
of
and DRCP in the early stage of LR. We speculate that the impairment in the SRCP may occur
ro
before the DRCP in patients with SLE, which still needs to be verified by a future longitudinal study.
-p
In the current study, we also evaluated the inner retinal layers and the total retina among the
re
three groups. We found that the thicknesses of NFL, GCL+IPL as well as the total retina in the
lP
SLE patients with LR were significantly thinner in most regions of the macula, which was
na
consistent with the results of Liu et al (Liu GY et al., 2015). However, in those patients without LR, the thicknesses did not change in almost any of the regions compared to the controls, which
Jo ur
indicated that the microstructure involvement was not as evident as the microvasculature in the early stage of LR. Therefore, we considered that the retinal microvasculature is an initial and primary element in the process of LR, which might be caused by the deposition of immune complexes in the basement membrane of endothelial cells of the blood vessels (Cao X et al., 2009; Herrmann M et al., 2000). In the development of LR, the impairment of the retinal microvasculature would therefore fail to supply the enough oxygen and nutrition to the inner retina, and thus compromises and produces the abnormalities in the retinal structure and even visual function which then lead to the development the LR. Further longitudinal studies are needed to verify such a hypothesis.
Journal Pre-proof
Previous studies indicated that the existence of LR is closely associated with the severity and prognosis of the disease in SLE patients (Gao N et al., 2017; Seth G et al., 2018; Ushiyama O et al., 2000). The pathological process in the retinal microvasculature is also considered as a mirror of microangiopathy in various organs of the body due to the systemic immune complex response in patients with SLE (Giorgi D et al., 1999; Ushiyama O et al., 2000). It is supported by previous
of
studies where the patients with LR have a higher percentage of NPSLE and LN (Asherson RA et
ro
al., 1989; Stafford-Brady FJ et al., 1988), which is consistent with our study. In addition, the scholars also indicated that the presence of LR is an important clue to disease activity as it
-p
provides direct visualization of vascular changes (Kharel SR et al., 2016) (Md Noh UK et al.,
lP
the LR patients than the NLR patients.
re
2012), which has been confirmed in our study as the SLEDAI scores were found much higher in
na
In the current study, there are still some limitations. Firstly, we did not describe the duration of HCQ use in patients with SLE, however, we have excluded those with the diagnosis of HCQ
Jo ur
retinopathy. The use of HCQ was reported to mainly be associated with choroidal thinning and outer retinal degeneration, but not affecting the inner retinal layers (Ahn SJ et al., 2017). Moreover, a maximal daily dosage of 6.5 mg/kg and a less than 5 years usage was considered to be safe (Mavrikakis L et al., 2003; Ronald BM and Marmor MF, 2014). Secondly, we used a small field (2.5×2.5 mm) to analyze the retinal microvasculature in this study. It is likely that significant information that could have been found by using larger fields around the macula was present but not detected. Future studies may focus on a larger imaging field. Lastly, a longitudinal study with a larger sample size is needed to confirm retinal microvascular and microstructural changes from NLR to LR disease states.
Journal Pre-proof
In conclusion, the retinal microvascular density in patients without clinically diagnosed LR was evidently decreased in the SRCP, however, the thinning of inner retinal thicknesses has not been evident yet. It indicated that impaired microvasculature might promote changes in the retinal microstructure, resulting in a risk of progression into fully developed LR, which will be demonstrated in a future longitudinal study. Macular microstructure and microvasculature
of
evaluated by OCT/OCT-A might be valuable in detecting the disorders of the inner retinal layer in
Jo ur
na
lP
re
-p
ro
SLE patients.
Journal Pre-proof
ACKNOWLEDGEMENT A. Funding / Support This study was supported by research grants from the Nature Science Foundation of Zhejiang Province (LY19H120003), the National Nature Science Foundation of China
of
(81570880), the Public Service Program of Wenzhou Science and Technology Bureau of China (Y20160151).
ro
B. Financial Disclosures
this article.
lP
C. Contributions of each author
re
-p
The authors have no proprietary interest in any materials or methods described within
na
Design of the study (QC, HW, MS); Conduct of the study, data collection, analysis
JW).
Jo ur
and interpretation (LB, RZ, YW, MS); Manuscript preparation and review (QC, FL,
D: Statement about conformity
The ethics committee of the Eye Hospital of Wenzhou Medical University and the Second Affiliated Hospital & Yuying Children’s Hospital approved this study.
Journal Pre-proof
References Ahn SJ, et al., 2017. Choroidal Thinning Associated With Hydroxychloroquine Retinopathy. Am J Ophthalmol. 183, 56-64. Asherson RA, et al., 1989. Antiphospholipid antibodies a risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the 'primary' antiphospholipid syndrome. Ann. Rheum. Dis. 48(5), 358-361. Ashimatey, B. S., et al., 2019. Impaired Retinal Vascular Reactivity in Diabetic Retinopathy as Assessed by Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 60,
of
2468-2473. Bhojwani, D., et al., 2014. Systemic lupus erythematosus retinopathy in a 32-year-old female: report of
ro
a case. Indian J Ophthalmol. 62, 951-2.
Bonnin S, et al., 2015. NEW INSIGHT INTO THE MACULAR DEEP VASCULAR PLEXUS
-p
IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 35, 2347-2352. Open Ophthalmol J. 3, 20-25.
re
Cao X, et al., 2009. Autoimmune Retinopathy in Systemic Lupus Erythematosus Histopathologic. Chen Q, et al., 2017. Macular Vascular Fractal Dimension in the Deep Capillary Layer as an Early
lP
Indicator of Microvascular Loss for Retinopathy in Type 2 Diabetic Patients. Invest. Ophthalmol. Vis. Sci. 58(9), 3785-3794.
Chen Q, et al., 2018. Characteristics of Retinal Structural and Microvascular Alterations in Early Type
na
2 Diabetic Patients. Invest. Ophthalmol. Vis. Sci. 59, 2110-2118. Chen, Q., et al., 2017. Ultra-high resolution profiles of macular intra-retinal layer thicknesses and associations with visual field defects in primary open angle glaucoma. Sci Rep. 7, 41100.
Jo ur
Dammacco, R., 2018. Systemic lupus erythematosus and ocular involvement: an overview. Clin Exp Med. 18, 135-149.
Gao N, et al., 2017. Retinal vasculopathy in patients with systemic lupus erythematosus. Lupus. 26(11), 1-8.
Giorgi D, et al., 1999. Retinopathy in Systemic Lupus Erythematosus Pathogenesis and Approach to Therapy. Human Immunology. 60, 688–696. Herrmann M, et al., 2000. Etiopathogenesis of Systemic Lupus Erythematosus. Int Arch Allergy Immunol. 123, 28–35. Jabs DA, et al., 1986. Severe Retinal Vaso-Occlusive Disease in Systemic Lupus Erythematosus. Arch Ophthalmol. 104, 558-563. Karpik AG, et al., 1985. Ocular immune reactants in patients dying with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 35(3), 295-312. Kharel Sitaula, R., et al., 2016. Role of lupus retinopathy in systemic lupus erythematosus. J Ophthalmic Inflamm Infect. 6, 15. Kharel SR, et al., 2016. Role of lupus retinopathy in systemic lupus erythematosus. J Ophthalmic Inflamm Infect. 6, 15. Kim, A. Y., et al., 2016. Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography. Invest Ophthalmol Vis
Journal Pre-proof Sci. 57, OCT362-70. Kwapong WR, et al., 2018. Altered Macular Microvasculature in Neuromyelitis Optica Spectrum Disorders. Am J Ophthalmol. 192, 47-55. Lanham JG, et al., 1982. SLE retinopathy evaluation by fluorescein angiography. Ann. Rheum. Dis. 41(5), 473-478. Liu GY, et al., 2015. Retinal nerve fiber layer and macular thinning in systemic lupus erythematosus: an optical coherence tomography study comparing SLE and neuropsychiatric SLE. Lupus. 24, 1169-1176. Mavrikakis L, et al., 2003. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine. Ophthalmology. 110, 1321-1326. Md Noh UK, et al., 2012. Retinal vasculitis in systemic lupus erythematosus: an indication of active disease. Clin Pract. 2, e54.
of
Nag TC, Wadhwa S, 2006. Vascular Changes of the Retina and Choroid in Systemic Lupus Erythematosus Pathology and Pathogenesis. Curr Neurovasc Res. 3(2), 159 -168.
ro
Nakamura A, et al., 1998. Ocular Fundus Lesions in Systemic Lupus Erythematosus Model Mice. Jpn. J. Ophthalmol. 42, 345-351.
-p
Palejwala NV, et al., 2012. Ocular manifestations of systemic lupus erythematosus: a review of the literature. Autoimmune Dis. 2012, 290898.
re
Pedinielli, A., et al., 2017. Three Different Optical Coherence Tomography Angiography Measurement Methods for Assessing Capillary Density Changes in Diabetic Retinopathy. Ophthalmic Surg Lasers Imaging Retina. 48, 378-384.
lP
Read, R. W., 2004. Clinical mini-review: systemic lupus erythematosus and the eye. Ocular Immunology and Inflammation. 12, 87-99.
Ronald BM, Marmor MF, 2014. The risk of toxic retinopathy in patients on long-term
na
hydroxychloroquine therapy. JAMA Ophthalmol. 132, 1453-1460. Savastano MC, L. B., Rispoli M., 2015. IN VIVO CHARACTERIZATION OF RETINAL
Jo ur
VASCULARIZATION MORPHOLOGY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. RETINA. 35, 2196-2203. Seth G, et al., 2018. Lupus retinopathy: a marker of active systemic lupus erythematosus. Rheumatol Int. 38, 1495-1501.
Shein J, et al., 2008. Macular infarction as a presenting sign of systemic lupus erythematosus. Retin Cases Brief Rep. 2(1), 55-60.
Shen C , et al., 2018. Assessment of capillary dropout in the superficial retinal capillary plexus by optical coherence tomography angiography in the early stage of diabetic retinopathy. BMC Ophthalmol. 18, 113. Silpa-archa S, et al., 2016. Ocular manifestations in systemic lupus erythematosus. Br J Ophthalmol. 100, 135-41. Sivaraj RR, et al., 2007. Ocular manifestations of systemic lupus erythematosus. Rheumatology (Oxford). 46, 1757-62. Stafford-Brady FJ, et al., 1988. Lupus retinopathy. Patterns, associations, and prognosis. Arthritis Rheum. 31(9), 1105-1110. Staurenghi, G., Sadda, S, Chakravarthy, U, Spaide, R. F, 2014. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN*OCT consensus. Ophthalmology. 121, 1572-8.
Journal Pre-proof Tan EM, et al., 1982. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25(11), 1271-1277. Tolba DA, et al., 2017. Fluorescein Angiographic Findings in Patients with Active Systemic Lupus Erythematosus. Ocul Immunol Inflamm. 25, 884-890. Ushiyama O, et al., 2000. Retinal disease in patients with systemic lupus erythematosus. Ann Rheum Dis. 59(9), 705-708. Yang Y, et al., 2016. Retinal Microvasculature Alteration in High Myopia. Invest Ophthalmol Vis Sci.
Jo ur
na
lP
re
-p
ro
of
57, 6020-6030.
Journal Pre-proof
Figure Legends Fig. 1 Optical coherence tomography (OCT) / OCT-angiography (OCT-A) imaging, fundus photography, and analysis of the intra-retinal layers. The five regions around the macula in this 3×3-mm OCT image included a central region (C), superior (S), temporal (T), inferior (I), and nasal (N) region in fundus photography (A). Nine layers of the Intra-retinal and choroid structures in horizontal scan RTVue OCT images: NFL, GCL+IPL, INL, OPL, HFL+ONL, MEZ, OS,
of
IZ+RPE/Bruch complex, and choroid (B). Superficial and deep retinal capillary plexus
ro
(SRCP/DRCP) analyses were performed on the OCT-A images in the parafoveal four quadrant
-p
regions—S, T, I, and N—of a circular zone with a diameter of 2.50 mm after excluding the FAZ (C, D).
re
Fig. 2 Representative fundus photographs, OCT B-scan images of choroidal and
lP
intra-retinal microstructure, and OCT-A images of the superficial, and deep retinal capillary plexus (SRCP/DRCP) of a Control eye, a NLR eye, and a LR eye. In the fundus
retinal hemorrhages.
na
photograph of the LR patient, Black arrows mark cotton wool spots, black arrowheads mark
Jo ur
Fig. 3 Correlations between the inner retina thickness and microvascular density in SLE patients. (A) Correlation between the NFL thickness and SRCP RCSD in the TAZ region (r = 0.38, P = 0.001). (B) Correlation between the GCL+IPL thickness and SRCP RCSD in the TAZ region (r = 0.51, P < 0.001). (C) Correlation between the NFL thickness and DRCP RCSD in the TAZ region (r = 0.10, P = 0.383). (D) Correlation between the GCL+IPL thickness and DRCP RCSD in the TAZ region (r = 0.43, P < 0.001). SLE, systemic lupus erythematosus; NFL, nerve fiber layer; GCL+ IPL, ganglion cell layer and inner plexiform layer; RCSD, retinal capillary skeleton density; SRCP, superficial retinal capillary plexus; DRCP, deep retinal capillary plexus; TAZ, total annular zone. Fig. 4 Systemic lupus erythematosus disease activity index (SLEDAI) scores in the patients with (LR) and without (NLR) retinopathy. There were significant differences between the two groups (P = 0.020). The SLEDAI score for each patient was shown.
Journal Pre-proof
Table 1. Basic characteristics of the subjects NLR
LR
P Value
50 (50)
32 (58)
14 (22)
-
41:9
30:2
14:0
0.090
Age, years
34.4 ± 10.1
34.9± 11.8
35.8 ± 9.3
0.910
BMI (kg/m2)
22.1 ± 2.5
21.6 ± 2.5
21.4 ± 2.1
0.550
SE, diopters
-1.1 ± 1.5
-1.7 ± 1.7
-1.6 ± 1.8
0.150
-0.04 ± 0.06
-0.01 ± 0.04
0.01 ± 0.03
< 0.001
AL, mm
23.7 ± 1.2
23.5 ± 0.8
23.3 ± 1.0
0.210
IOP, mmHg
13.3 ± 2.6
13.6 ± 2.6
12.6 ± 3.5
0.420
MABP, mmHg
89.9 ± 10.7
91.9 ± 12.4
90.0 ± 8.0
0.680
Duration of disease, years
NA
3.8± 3.0
3.9 ± 4.1
0.950
re
BCVA, LogMAR
ro
Gender (F:M)
-p
N (Eyes)
of
Control
lP
NLR, non-lupus retinopathy; LR, lupus retinopathy; F, female; M, male; BMI, body mass index; SE, spherical equivalent; BCVA, best corrected visual acuity; AL, axial length; IOP, intraocular pressure; MABP, mean arterial blood pressure; ; –, not performed; NA, not applicable.
na
P values for differences among the three groups were determined by one-way ANOVA (except for sex and duration of disease, where the P value were determined by 2 and Student’s t-test respectively).
Jo ur
Bold P-value represents < 0.05.
Journal Pre-proof
Table 2. The retinal capillary skeleton density (%) among the three groups Layers SRCP
DRCP
Regions TAZ S T I N TAZ S T I N
Control 5.8 ± 0.5 5.9 ± 0.4 5.9 ± 0.5 5.8 ± 0.5 5.7 ± 0.5 7.4 ± 0.7 7.4 ± 0.7 7.3 ± 0.7 7.4 ± 0.8 7.3 ± 0.7
NLR 5.6 ± 0.4 5.6 ± 0.5 5.6 ± 0.5 5.5 ± 0.5 5.5 ± 0.5 7.3 ± 0.5 7.3 ± 0.6 7.2 ± 0.5 7.3 ± 0.6 7.2 ± 0.5
LR 5.3 ± 0.5 5.3 ± 0.7 5.3 ± 0.5 5.2 ± 0.5 5.2 ± 0.5 7.0 ± 0.6 7.0 ± 0.7 7.0 ± 0.6 7.0 ± 0.6 6.8 ± 0.6
n r u
l a
P* 0.007 0.018 0.004 0.006 0.076 0.377 0.489 0.383 0.306 0.440
f o
o r p
e
r P
P+ <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.007 0.028 0.007 0.002
P# 0.010 0.017 0.043 0.017 0.015 0.028 0.024 0.115 0.047 0.011
P <0.001 <0.001 <0.001 <0.001 0.001 0.018 0.022 0.090 0.026 0.008
NLR, non-lupus retinopathy; LR, lupus retinopathy; SRCP, superficial retinal capillary plexus; DRCP, deep retinal capillary plexus; TAZ, total annular zone; S, superior region; T, temporal region; I, inferior region; N, nasal region. P*, control versus NLR; P+, control versus LR; P#, NLR versus LR; P, the differences among the three groups. Bold P-value represents < 0.05.
o J
Journal Pre-proof
Table 3. The thickness (μm) of total and inner retinal layers among the three groups Layers
Regions
Control
NLR
LR
P*
P+
P#
P
NFL
C S T I N C S T I N C S T I N
8.9 ± 1.3
8.8 ± 1.4
8.5 ± 1.5
0.854
0.305
0.365
0.572
23.1 ± 2.7
22.1 ± 2.7
20.9 ± 2.7
0.045
0.002
0.084
0.005
16.0 ± 1.7
16.3 ± 1.7
15.9 ± 2.2
0.422
0.855
0.420
0.620
23.7 ± 2.6
23.2 ± 2.6
22.2 ± 2.2
0.213
0.020
0.149
0.062
20.0 ± 2.7
18.9 ± 2.6
18.3 ± 3.3
0.040
0.020
0.415
0.032
22.6 ± 5.9
21.1 ± 5.6
19.4 ± 6.6
0.197
0.039
0.262
0.105
86.8 ± 6.9
85.0 ± 7.8
81.2 ± 13.0
0.278
0.012
0.078
0.041
83.0 ± 7.1
78.8 ± 7.3
74.5 ± 10.2
<0.001
0.029
<0.001
86.0 ± 7.1
85.0 ± 7.0
81.2 ± 9.8
0.524
0.015
0.044
0.047
81.3 ± 7.2
80.0 ± 11.9
77.0 ± 12.4
0.496
0.109
0.263
0.274
236.8 ± 18.5
233.1 ± 18.3
230.5 ± 19.5
0.299
0.188
0.584
0.360
328.6 ± 14.8
323.0 ± 13.5
r P
0.006
316.1 ± 18.8
0.057
0.002
0.070
0.005
318.2 ± 14.8
309.2 ± 12.2
GCL + IPL
Total retina
rn
l a
f o
o r p
e
303.3 ± 16.0
0.001
<0.001
0.090
<0.001
323.9 ± 14.7
319.8 ± 15.0
314.3 ± 15.2
0.137
0.009
0.118
0.029
321.6 ± 16.3
319.6 ± 15.0
312.7 ± 19.8
0.540
0.036
0.094
0.107
J
u o
NLR, non-lupus retinopathy; LR, lupus retinopathy; NFL, nerve fiber layer; GCL + IPL, ganglion cell layer and inner plexiform layer; C, central region; S, superior region; T, temporal region; I, inferior region; N, nasal region. P*, control versus NLR; P+, control versus LR; P#, NLR versus LR; P, the differences among the three groups. Bold P-value represents < 0.05.
Journal Pre-proof
Table 4. The complications in SLE patients with and without lupus retinopathy NPSLE 3 (9%) 2 (14%)
NLR (n=32) LR (n=14)
LN 12 (38%) 7 (50%)
NLR, non-lupus retinopathy; LR, lupus retinopathy; NPSLE, neuropsychiatric systemic lupus
Jo ur
na
lP
re
-p
ro
of
erythematosus; LN, lupus nephropathy.
Journal Pre-proof
Jo ur
na
lP
re
-p
ro
of
Highlights General superficial retinal capillary plexuses density decreasing and regional inner-retinal thinning were detected in the systemic lupus erythematosus patients without clinically diagnosed lupus retinopathy, using spectral domain optical coherence tomography equipped with Angiovue.
Figure 1
Figure 2
Figure 3
Figure 4
Lulu Bao, Rong Zhou, Yufei Wu, Jianhua Wang, Meixiao Shen, Fan Lu, Hong Wang, Qi Chen PII:
S0026-2862(19)30220-1
DOI:
https://doi.org/10.1016/j.mvr.2019.103957
Reference:
YMVRE 103957
To appear in:
Microvascular Research
Received date:
22 August 2019
Revised date:
11 November 2019
Accepted date:
12 November 2019
Please cite this article as: L. Bao, R. Zhou, Y. Wu, et al., Unique changes in the retinal microvasculature reveal subclinical retinal impairment in patients with systemic lupus erythematosus, Microvascular Research(2019), https://doi.org/10.1016/ j.mvr.2019.103957
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof Title: Unique changes in the retinal microvasculature reveals subclinical retinal impairment in patients with systemic lupus erythematosus Short title: Retinal microvasculature in SLE patients Word count: 3372 words Tables and figures: 4 figures and 4 tables Key words: Systemic lupus erythematosus; optical coherence tomography; retinal microvascular; retinal thickness
of
Author names, degrees and affiliations: Lulu Bao, MD1*, Rong Zhou, MD1*, Yufei Wu, MD1, , Jianhua Wang, MD, PhD2, 3, Meixiao Shen, PhD1, Fan Lu, MD, OD1, Hong Wang, MD4, Qi Chen, MD, PhD1 1
ro
School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China 2
lP
re
-p
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA 3 Electrical and Computer Engineering, University of Miami, Miami, FL, USA 4 The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China * Authors have the equal contributions to the project.
Jo ur
na
Corresponding Authors: Hong Wang, MD & Qi Chen, MD, PhD Mailing address: School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang, China, 325027 Tel: (086) 577-88824116; Fax: (086) 577-88824115 Email: [email protected] (to Wang); [email protected] (to Chen) Funding/Support: This study was supported by research grants from the Nature Science Foundation of Zhejiang Province (LY19H120003), the National Nature Science Foundation of China (81570880), the Public Service Program of Wenzhou Science and Technology Bureau of China (Y20160151). Proprietary interests: The authors have no proprietary interest in any materials or methods described within this article.
Journal Pre-proof Abstract Purpose: To determine the changes of the microvasculature and microstructure in the inner intra-retinal layers in systemic lupus erythematosus (SLE) patients without lupus retinopathy (LR). Methods: Thirty-two SLE patients (58 eyes) without LR (NLR), 14 patients (22 eyes) with LR and 50 healthy subjects (50 eyes) were enrolled. Spectral domain optical coherence tomography equipped with Angiovue was used to obtain three-dimensional retinal thickness maps and microvascular images of the superficial and deep retinal capillary plexuses (SRCP/DRCP) around
of
the macula. Quantitative analyses were performed using a custom automated algorithm. Disease
ro
activity of patients was assessed using the SLE disease activity index (SLEDAI).
-p
Results: Retinal capillary skeleton density of the SRCP in SLE patients without LR was significantly lower than the controls in almost all regions, which further decreased in the LR group
re
(P < 0.05). No significant changes were evident in DRCP of the NLR group (P > 0.05). The inner
lP
retina in the LR group were significantly thinner than the controls in most regions, though there were only a few regions were different between the NLR and the control groups (P < 0.05). There
na
were significant differences of the SLEDAI scores between the two SLE groups. Conclusion: Significantly lower density in SRCP and regional thinning in inner retina were
Jo ur
observed in the SLE patients without clinical fundus changes. OCT equipped with Angiovue might be useful in evaluating the microvascular and microstructural disorders of the inner retinal layers in SLE patients, which may contribute a quantitative approach to the early diagnosis and progression of LR.
Journal Pre-proof
Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with undefined etiology and remarkably heterogeneous clinical features (Dammacco, 2018). Ocular
of
manifestations affecting multiple ocular structures can occur in up to one-third of SLE patients
ro
(Silpa-archa S et al., 2016). Retinal involvement in SLE, termed lupus retinopathy (LR), is the second most common ocular manifestation after dry eye disease with an incidence of 7–29%, and
-p
it is most frequently associated with visual loss (Palejwala NV et al., 2012). The major
re
pathological changes in LR are attributed to microangiopathy caused by the deposition of immune
lP
complexes in the basement membrane of endothelial cells of the fundus blood vessels (Sivaraj RR
na
et al., 2007). The most frequent clinical signs in the fundus color photograph include cotton wool spots, retinal hemorrhages, and vascular tortuosity. In addition, retinal hard exudates, retinal
Jo ur
vasculitis, retinal artery and/or vein occlusion, arteriolar narrowing, arteriovenous crossing changes, macular pigmentary mottling, retinal scarring, and macular infarction have also been reported (Lanham JG et al., 1982; Shein J et al., 2008; Ushiyama O et al., 2000). LR is suggestive of elevated disease activity of SLE and correlates with central nervous system and kidney involvement which are represented by neuropsychiatric systemic lupus erythematosus (NPSLE) and lupus nephropathy(LN) with progression of SLE (Kharel SR et al., 2016; Stafford-Brady FJ et al., 1988). It is also considered as a marker of poor prognosis for survival (Kharel SR et al., 2016; Stafford-Brady FJ et al., 1988). Therefore, an early diagnosis and the adoption of suitable therapeutic measures are indispensable and might help to prevent sight-threatening consequences
Journal Pre-proof
and poor disease prognosis. It is well known that there is a multilayered complex of capillaries parallel to the cellular layers in the inner retina. As a complication of SLE characterized by microangiopathy, the earliest clinical findings in LR are small intra-retinal hemorrhages and cotton wool spots (Ushiyama O et al., 2000). With advanced developments of optical coherence tomography (OCT), the nerve fiber
of
layer (NFL), ganglion cell layer and the inner plexiform layer (GCL+IPL) as well as the inner
ro
nuclear layer (INL) around the macula have also been found to be significantly thinner in SLE patients compared to normal subjects (Liu GY et al., 2015). In addition, according to an
-p
immunopathologic study, the retinal impairment in SLE has been considered to be associated with
re
vasculitis caused by deposition of IgG immune complexes in the walls of retinal vessels (Karpik
lP
AG et al., 1985). However, no clinically quantitative parameters are available to describe the
na
impairment of the retinal microvascular network and structure in the early stages of SLE to identify patients at risk of developing SLE associated retinopathy.
Jo ur
OCT angiography (OCT-A) is a novel imaging modality that non-invasively and quickly obtains high resolution images of the in vivo retinal microvasculature, allowing in-depth visualization of the retinal microvascular network in the different retinal layers (Chen Q et al., 2017; Chen Q et al., 2018; Savastano MC, 2015). Spectral domain OCT (SD-OCT) provides high resolution images that enable detailed detection of intra-retinal structures that were previously available only by histopathology (Staurenghi, 2014). The goal of the current study is to investigate the changes of the microvasculature and structure in the inner intra-retinal layers in SLE patients without clinically diagnosed LR using the OCT-A and SD-OCT devices. This might allow earlier diagnosis and timely implementation of treatment, as well as predictions for other complications
Journal Pre-proof
of SLE.
Methods Patients Patients with a history of SLE were identified by a rheumatologist (HW) following the American College of Rheumatology (ACR) classification criteria (Tan EM et al., 1982), and the
of
systemic lupus erythematosus disease activity index (SLEDAI) of each patient was also evaluate.
ro
Patients with a diagnosis of LR were determined by an ophthalmologist (RZ) according to the presence of (1) cotton–wool spots, perivascular hard exudates, retinal hemorrhages, (2) focal or
-p
generalized arteriolar constriction and venous tortuosity, (3) and/or vaso-occlusive retinopathy
re
(Dammacco, 2018; Gao N et al., 2017; Kharel Sitaula et al., 2016). Patients recruited from the
lP
Second Affiliated Hospital & Yuying Children’s Hospital, China from May 2018 to September
na
2018 were carried out in the Eye Hospital of Wenzhou Medical University. Inclusion criteria were: (1) age ≥18 and ≤75 years, (2) best-corrected visual acuity (BCVA) better than 0.1 LogMAR, and
Jo ur
(3) spherical equivalent (SE) refractive error between −3.00 and +0.50 diopters. Exclusion criteria were: (1) established primary ocular diseases including a history of any retinal or optic nerve disease, (2) presence of any drusen-like deposits, focal atrophy, or retinal pigment epithelium detachment, and alterations associated to Chloroquine (CQ)/Hydroxychloroquine (HCQ) toxicity on indirect ophthalmology or SD-OCT examination; (3) ocular trauma or surgery, (4) lens opacities, and (5) systemic disorders with ocular involvement such as diabetes and hypertension (current and past medical history). All study procedures were explained to the participating subjects and informed written consent was obtained before inclusion of participants. The study was performed in accordance
Journal Pre-proof
with the tenets of the Declaration of Helsinki and also adhered to the requirements of the ethics committee of the Eye Hospital of Wenzhou Medical University and the Second Affiliated Hospital & Yuying Children’s Hospital, China. Age- and sex-matched control subjects were recruited from workers or the members accompanying the patients at the Eye Hospital. Evaluations and Measurements
of
Clinical Examinations
ro
All subjects underwent comprehensive clinical examinations, including refraction and BCVA,
-p
slit-lamp biomicroscopy, axial length (AL) measurement (IOL Master: Carl Zeiss Meditec, Jena, Germany), intraocular pressure (IOP) measurement (Kowa applanation tonometer HA-2; Kowa
re
Company Ltd. Tokyo, Japan), visual field test (Humphrey Field Analyzer; 24-2 Swedish
lP
interactive threshold algorithm; Carl-Zeiss Meditec, Inc.), and ophthalmoscopy. In addition, the
na
fundus photography was performed with a 45-degree digital retinal camera (Canon EOS 10D SLR
Jo ur
backing; Canon, Inc., Tokyo, Japan).
Image Acquisition Protocol and Analysis
All the subjects were imaged by a commercial SD-OCT device (Optovue RTVue XR Avanti; Optovue, Inc., Fremont, CA, USA) which was equipped with Angiovue for OCT-A. The bimodal system was operated in the radial scan mode (8-mm diameter; 18 lines) to generate three-dimensional thickness maps. A good set of scans with a signal strength index of >6 for each eye was selected for further analysis. The segmentation of intra-retinal layers was achieved by a dedicated software program based on the gradient information and shortest path search that was developed in Matlab (The MathWorks, Inc., Natick, MA, USA) for automated image analysis. The thickness of each intra-retinal layer was calculated by subtracting the boundary positions of
Journal Pre-proof
each of the adjacent layers, obtained by automated segmentation along the depth. The intra-retinal layers included the (1) NFL, (2) GCL+IPL, (3) INL, (4) outer plexiform layer (OPL), (5) Henle fiber layer and outer nuclear layer (HFL+ONL), (6) the myoid and ellipsoid zone (MEZ), (7) photoreceptor outer segments (OS), (8) interdigitation zone + retinal pigment epithelium (IZ+RPE), and (9)choroid (Fig. 1). The algorithm that identifies the different layers automatically
of
and analyzes layer thicknesses have been demonstrated in our previous papers (Chen Q et al.,
ro
2018; Chen et al., 2017; Kwapong WR et al., 2018). In the current study, only the NFL between the first and second boundaries and the GCL+IPL between the second and third boundaries were
-p
investigated.
re
To match the areas of retinal structure and microvasculature, a 2.5-mm diameter 3D thickness
lP
map of the NFL and GCL+IPL in each eye was generated based on the segmented layers around
na
the macula (Fig. 1). For analysis, the macular thickness map was divided into a 0.6-mm diameter circle centered over the fovea and a total annular zone (TAZ) surrounded by a concentric ring 0.3 -
Jo ur
1.25 mm from the fovea. The areas of the central circle and the TAZ were then divided into five regions including the central and the superior, temporal, inferior, and nasal regions. The mean thicknesses for the NFL and GCL+IPL in each region were calculated.
In addition, the OCT-A model (3×3-mm area) was operated to obtain microvascular images of the superficial and deep retinal capillary plexuses (SRCP and DRCP) around the fovea. The SRCP and DRCP were detected and separated automatically by the OCT instrument as seen in Fig. 1. The SRCP extends from 3 μm below the internal limiting membrane to 15 μm below the IPL. The DRCP extends from 15 to 70 μm below the IPL (Shen C et al., 2018). A custom automated algorithm was performed on the en face OCT-A projection images to quantify the SRCP and
Journal Pre-proof
DRCP, which have been described in detail in our previous studies (Chen Q et al., 2017; Yang Y et al., 2016). Briefly, the grayscale of each two-dimensional OCT-A images were extended by bicubic interpolation to 1024×1024 pixels to enhance the image details. Then, the image was segmented to obtain the microvascular network after excluding the foveal avascular zone (FAZ), which was detected by a two-way combined method consisting of a canny edge detector algorithm
of
and a level set algorithm. At last, based on the final binary image containing only the small vessels,
ro
which was obtained by subtracting the binary image containing only the large blood vessels from another containing both large and small vessels, a skeletonized image was created by identifying
-p
the central axis of the binary, white-pixelated vasculature, and remaining one pixel along the
re
central axis. In the current study, the retinal capillary density was calculated as the percentage of
lP
pixels with skeletonized microvessels by an automated algorithm to extract the skeletonized
na
images of the retinal capillary network in the OCTA images, which was called retinal capillary skeleton density (RCSD). The RCSD of the SRCP and DRCP were automatically calculated in the
Jo ur
parafoveal regions, i.e., superior, temporal, inferior, and nasal regions of the 2.5-mm diameter circular zone after excluding the FAZ based on skeletonized images (Fig. 1). The methods above were implemented using MATLAB v7.10 (Mathworks, Inc., Natick, MA, USA). Statistical Analysis All data were calculated as means ± standard deviations and analyzed with SPSS software (version 22.0; SPSS, Inc., Chicago, IL, USA). The SE of refraction error was calculated as the spherical dioptric power plus one-half of the cylindrical dioptric power. Differences of gender among the groups were determined by the x2 test. One-way analysis of variance (ANOVA) was used to compare the differences among the groups, and post hoc procedures were used to compare
Journal Pre-proof
differences between the two groups. The durations of disease in the subgroups of SLE patients were compared using Student’s t-test. Pearson’s correlation coefficients (2-sided) were calculated to analyze correlations between the microstructural thickness of the inner retina and the density of the macular retinal microvascular layers. P values of < 0.05 were considered statistically
of
significant.
ro
Results
-p
In total, 32 SLE patients (58 eyes) with no LR (NLR), 14 patients (22 eyes) with LR and 50
re
healthy subjects (50 eyes) were enrolled in the current study. There were no significant differences
lP
in the age, gender, body mass index (BMI), SE, AL, IOP, and mean arterial blood pressure (MABP) among the three groups (P = 0.090 ~ 0.910), except for the BCVA (P < 0.001, Table 1). Moreover,
na
there were no differences in the disease duration between the two SLE groups (P = 0.950). Fundus
Jo ur
photographs and raw OCT/OCT-A images in the Control, NLR and LR eyes were presented in Figure 2. In eyes with LR, the presence of an abnormal retinal vasculature was evident as a decrease in capillary complexity and density.
Compared to the controls, the RCSDs of the SRCP were significantly decreased in both NLR (P values: 0.004 ~ 0.018) and LR (P values: all < 0.001) groups in almost all regions except for the nasal region when comparing the NLR and the control groups (P = 0.076, Table 2). Moreover, the RCSDs of the SRCP in the LR group were further decreased compared to the NLR group (P values: 0.010 ~ 0.043, Table 2). For the DRCP, the RCSDs of the LR group were significantly lower than the NLR (P values: 0.011 ~ 0.047) and control (P values: 0.002 ~ 0.028) groups in all
Journal Pre-proof
the regions except for the temporal region between the two SLE groups (P = 0.115, Table 2). However, there were no significant differences between the control and NLR groups (P > 0.05, Table 2).
The NFL thicknesses of the NLR group in superior (P = 0.045) and nasal (P = 0.040) regions and the LR group in the superior (P = 0.002), inferior (P = 0.020) and nasal (P = 0.020) regions
of
were decreased, compared to the controls (Table 3). Meanwhile, compared to the controls, the
ro
GCL+IPL thicknesses of the NLR group in the temporal (P = 0.006) region and the LR group in
-p
the central (P = 0.039), superior (P = 0.012), temporal (P < 0.001) and inferior (P = 0.015) regions were also decreased (Table 3). Moreover, the GCL+IPL thicknesses in the LR group were further
re
decreased compared to the NLR in the temporal (P = 0.029) and inferior (P = 0.044) regions
lP
(Table 3). The total retinal thickness of the NLR group in the temporal (P = 0.001) region and the
na
LR group in the superior (P = 0.002), temporal (P < 0.001), inferior (P = 0.009) and nasal (P = 0.036) regions were also decreased (Table 3). In addition, the thicknesses of NFL in the TAZ
Jo ur
region is significantly associated with the RCDs of SRCP (r = 0.38, P = 0.001), meanwhile the thicknesses of GCL+IPL in the TAZ region were significantly associated with the RCSDs of SRCP (r = 0.51, P < 0.001) and DRCP (r = 0.43, P < 0.001) in patients with SLE (Fig. 3).
In Figure 4, the SLE patients with LR presented a higher SLEDAI score than those patients without LR (13.8 6.5 vs 7.7 8.1, P = 0.020). As for the complications of SLE, the percentages of NPSLE and LN, which represent the involvement of the central nervous system and kidney respectively within the LR group were also larger than NLR group (14% vs 9% for NPSLE, 50% vs 38% for LN; Table 4).
Journal Pre-proof
Discussion The present study investigated the microvascular features around the macula in the SLE patients with and without clinically diagnosed LR using OCT-A technology. In addition, instead of the non-skeletonized density that is susceptible to threshold setting, we used the skeletonized density to quantify the retinal microvasculature which was considered to be more sensitive to
of
vessel width (Kim et al., 2016; Pedinielli et al., 2017) (Ashimatey et al., 2019). We found that the
ro
retinal microvascular density, especially in the superficial layer, has a decreased gradient among
-p
the controls, SLE patients without and with LR, consistent with the characteristics of the SLE as a microvascular disease. We also found that the thicknesses of the inner retinal layers were
re
decreased in both SLE groups at the fovea and various regions of the parafovea. In addition, the
lP
activity score of the disease, and the percentages of the LN and NPSLE, were significantly
na
different between the two SLE groups.
As we know, the published reports mostly focused on the obviously vascular lesion in eyes
Jo ur
with LR using fundus photography or fluorescence angiography (FA) (Bhojwani et al., 2014; Gao N et al., 2017; Kharel SR et al., 2016; Seth G et al., 2018; Tolba DA et al., 2017). In the current study, using the OCT-A, we found that the retinal microvascular density in both SRCP and DRCP were decreased in the SLE patients with clinically diagnosed LR, compared to the controls. Furthermore, we also found that the retinal microvascular density in the SRCP had a significant decline in the NLR group, however, this phenomenon did not exist in the DRCP. The retinal lesions of SLE patients are mainly caused by the abnormalities in the retinal microvasculature supplying oxygen and nutrition to the NFL, which was supported in an animal experiment (Nakamura A et al., 1998). It was also confirmed in previous studies that the progress of LR was
Journal Pre-proof
based on microangiopathy and vaso-occlusions (Dammacco, 2018; Nag TC and Wadhwa S, 2006). Moreover, the so-called severe vaso-occlusive retinopathy is characterized by small arterial occlusions and diffuse capillary non-perfusion (Jabs DA et al., 1986; Read, 2004). It was reported that the characteristics of the SRCP tends to be arterial, but on the contrary, the DRCP consists of veins (Bonnin S et al., 2015). This may possibly explain the different performances of the SRCP
of
and DRCP in the early stage of LR. We speculate that the impairment in the SRCP may occur
ro
before the DRCP in patients with SLE, which still needs to be verified by a future longitudinal study.
-p
In the current study, we also evaluated the inner retinal layers and the total retina among the
re
three groups. We found that the thicknesses of NFL, GCL+IPL as well as the total retina in the
lP
SLE patients with LR were significantly thinner in most regions of the macula, which was
na
consistent with the results of Liu et al (Liu GY et al., 2015). However, in those patients without LR, the thicknesses did not change in almost any of the regions compared to the controls, which
Jo ur
indicated that the microstructure involvement was not as evident as the microvasculature in the early stage of LR. Therefore, we considered that the retinal microvasculature is an initial and primary element in the process of LR, which might be caused by the deposition of immune complexes in the basement membrane of endothelial cells of the blood vessels (Cao X et al., 2009; Herrmann M et al., 2000). In the development of LR, the impairment of the retinal microvasculature would therefore fail to supply the enough oxygen and nutrition to the inner retina, and thus compromises and produces the abnormalities in the retinal structure and even visual function which then lead to the development the LR. Further longitudinal studies are needed to verify such a hypothesis.
Journal Pre-proof
Previous studies indicated that the existence of LR is closely associated with the severity and prognosis of the disease in SLE patients (Gao N et al., 2017; Seth G et al., 2018; Ushiyama O et al., 2000). The pathological process in the retinal microvasculature is also considered as a mirror of microangiopathy in various organs of the body due to the systemic immune complex response in patients with SLE (Giorgi D et al., 1999; Ushiyama O et al., 2000). It is supported by previous
of
studies where the patients with LR have a higher percentage of NPSLE and LN (Asherson RA et
ro
al., 1989; Stafford-Brady FJ et al., 1988), which is consistent with our study. In addition, the scholars also indicated that the presence of LR is an important clue to disease activity as it
-p
provides direct visualization of vascular changes (Kharel SR et al., 2016) (Md Noh UK et al.,
lP
the LR patients than the NLR patients.
re
2012), which has been confirmed in our study as the SLEDAI scores were found much higher in
na
In the current study, there are still some limitations. Firstly, we did not describe the duration of HCQ use in patients with SLE, however, we have excluded those with the diagnosis of HCQ
Jo ur
retinopathy. The use of HCQ was reported to mainly be associated with choroidal thinning and outer retinal degeneration, but not affecting the inner retinal layers (Ahn SJ et al., 2017). Moreover, a maximal daily dosage of 6.5 mg/kg and a less than 5 years usage was considered to be safe (Mavrikakis L et al., 2003; Ronald BM and Marmor MF, 2014). Secondly, we used a small field (2.5×2.5 mm) to analyze the retinal microvasculature in this study. It is likely that significant information that could have been found by using larger fields around the macula was present but not detected. Future studies may focus on a larger imaging field. Lastly, a longitudinal study with a larger sample size is needed to confirm retinal microvascular and microstructural changes from NLR to LR disease states.
Journal Pre-proof
In conclusion, the retinal microvascular density in patients without clinically diagnosed LR was evidently decreased in the SRCP, however, the thinning of inner retinal thicknesses has not been evident yet. It indicated that impaired microvasculature might promote changes in the retinal microstructure, resulting in a risk of progression into fully developed LR, which will be demonstrated in a future longitudinal study. Macular microstructure and microvasculature
of
evaluated by OCT/OCT-A might be valuable in detecting the disorders of the inner retinal layer in
Jo ur
na
lP
re
-p
ro
SLE patients.
Journal Pre-proof
ACKNOWLEDGEMENT A. Funding / Support This study was supported by research grants from the Nature Science Foundation of Zhejiang Province (LY19H120003), the National Nature Science Foundation of China
of
(81570880), the Public Service Program of Wenzhou Science and Technology Bureau of China (Y20160151).
ro
B. Financial Disclosures
this article.
lP
C. Contributions of each author
re
-p
The authors have no proprietary interest in any materials or methods described within
na
Design of the study (QC, HW, MS); Conduct of the study, data collection, analysis
JW).
Jo ur
and interpretation (LB, RZ, YW, MS); Manuscript preparation and review (QC, FL,
D: Statement about conformity
The ethics committee of the Eye Hospital of Wenzhou Medical University and the Second Affiliated Hospital & Yuying Children’s Hospital approved this study.
Journal Pre-proof
References Ahn SJ, et al., 2017. Choroidal Thinning Associated With Hydroxychloroquine Retinopathy. Am J Ophthalmol. 183, 56-64. Asherson RA, et al., 1989. Antiphospholipid antibodies a risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the 'primary' antiphospholipid syndrome. Ann. Rheum. Dis. 48(5), 358-361. Ashimatey, B. S., et al., 2019. Impaired Retinal Vascular Reactivity in Diabetic Retinopathy as Assessed by Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 60,
of
2468-2473. Bhojwani, D., et al., 2014. Systemic lupus erythematosus retinopathy in a 32-year-old female: report of
ro
a case. Indian J Ophthalmol. 62, 951-2.
Bonnin S, et al., 2015. NEW INSIGHT INTO THE MACULAR DEEP VASCULAR PLEXUS
-p
IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina. 35, 2347-2352. Open Ophthalmol J. 3, 20-25.
re
Cao X, et al., 2009. Autoimmune Retinopathy in Systemic Lupus Erythematosus Histopathologic. Chen Q, et al., 2017. Macular Vascular Fractal Dimension in the Deep Capillary Layer as an Early
lP
Indicator of Microvascular Loss for Retinopathy in Type 2 Diabetic Patients. Invest. Ophthalmol. Vis. Sci. 58(9), 3785-3794.
Chen Q, et al., 2018. Characteristics of Retinal Structural and Microvascular Alterations in Early Type
na
2 Diabetic Patients. Invest. Ophthalmol. Vis. Sci. 59, 2110-2118. Chen, Q., et al., 2017. Ultra-high resolution profiles of macular intra-retinal layer thicknesses and associations with visual field defects in primary open angle glaucoma. Sci Rep. 7, 41100.
Jo ur
Dammacco, R., 2018. Systemic lupus erythematosus and ocular involvement: an overview. Clin Exp Med. 18, 135-149.
Gao N, et al., 2017. Retinal vasculopathy in patients with systemic lupus erythematosus. Lupus. 26(11), 1-8.
Giorgi D, et al., 1999. Retinopathy in Systemic Lupus Erythematosus Pathogenesis and Approach to Therapy. Human Immunology. 60, 688–696. Herrmann M, et al., 2000. Etiopathogenesis of Systemic Lupus Erythematosus. Int Arch Allergy Immunol. 123, 28–35. Jabs DA, et al., 1986. Severe Retinal Vaso-Occlusive Disease in Systemic Lupus Erythematosus. Arch Ophthalmol. 104, 558-563. Karpik AG, et al., 1985. Ocular immune reactants in patients dying with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 35(3), 295-312. Kharel Sitaula, R., et al., 2016. Role of lupus retinopathy in systemic lupus erythematosus. J Ophthalmic Inflamm Infect. 6, 15. Kharel SR, et al., 2016. Role of lupus retinopathy in systemic lupus erythematosus. J Ophthalmic Inflamm Infect. 6, 15. Kim, A. Y., et al., 2016. Quantifying Microvascular Density and Morphology in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography Angiography. Invest Ophthalmol Vis
Journal Pre-proof Sci. 57, OCT362-70. Kwapong WR, et al., 2018. Altered Macular Microvasculature in Neuromyelitis Optica Spectrum Disorders. Am J Ophthalmol. 192, 47-55. Lanham JG, et al., 1982. SLE retinopathy evaluation by fluorescein angiography. Ann. Rheum. Dis. 41(5), 473-478. Liu GY, et al., 2015. Retinal nerve fiber layer and macular thinning in systemic lupus erythematosus: an optical coherence tomography study comparing SLE and neuropsychiatric SLE. Lupus. 24, 1169-1176. Mavrikakis L, et al., 2003. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine. Ophthalmology. 110, 1321-1326. Md Noh UK, et al., 2012. Retinal vasculitis in systemic lupus erythematosus: an indication of active disease. Clin Pract. 2, e54.
of
Nag TC, Wadhwa S, 2006. Vascular Changes of the Retina and Choroid in Systemic Lupus Erythematosus Pathology and Pathogenesis. Curr Neurovasc Res. 3(2), 159 -168.
ro
Nakamura A, et al., 1998. Ocular Fundus Lesions in Systemic Lupus Erythematosus Model Mice. Jpn. J. Ophthalmol. 42, 345-351.
-p
Palejwala NV, et al., 2012. Ocular manifestations of systemic lupus erythematosus: a review of the literature. Autoimmune Dis. 2012, 290898.
re
Pedinielli, A., et al., 2017. Three Different Optical Coherence Tomography Angiography Measurement Methods for Assessing Capillary Density Changes in Diabetic Retinopathy. Ophthalmic Surg Lasers Imaging Retina. 48, 378-384.
lP
Read, R. W., 2004. Clinical mini-review: systemic lupus erythematosus and the eye. Ocular Immunology and Inflammation. 12, 87-99.
Ronald BM, Marmor MF, 2014. The risk of toxic retinopathy in patients on long-term
na
hydroxychloroquine therapy. JAMA Ophthalmol. 132, 1453-1460. Savastano MC, L. B., Rispoli M., 2015. IN VIVO CHARACTERIZATION OF RETINAL
Jo ur
VASCULARIZATION MORPHOLOGY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. RETINA. 35, 2196-2203. Seth G, et al., 2018. Lupus retinopathy: a marker of active systemic lupus erythematosus. Rheumatol Int. 38, 1495-1501.
Shein J, et al., 2008. Macular infarction as a presenting sign of systemic lupus erythematosus. Retin Cases Brief Rep. 2(1), 55-60.
Shen C , et al., 2018. Assessment of capillary dropout in the superficial retinal capillary plexus by optical coherence tomography angiography in the early stage of diabetic retinopathy. BMC Ophthalmol. 18, 113. Silpa-archa S, et al., 2016. Ocular manifestations in systemic lupus erythematosus. Br J Ophthalmol. 100, 135-41. Sivaraj RR, et al., 2007. Ocular manifestations of systemic lupus erythematosus. Rheumatology (Oxford). 46, 1757-62. Stafford-Brady FJ, et al., 1988. Lupus retinopathy. Patterns, associations, and prognosis. Arthritis Rheum. 31(9), 1105-1110. Staurenghi, G., Sadda, S, Chakravarthy, U, Spaide, R. F, 2014. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN*OCT consensus. Ophthalmology. 121, 1572-8.
Journal Pre-proof Tan EM, et al., 1982. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25(11), 1271-1277. Tolba DA, et al., 2017. Fluorescein Angiographic Findings in Patients with Active Systemic Lupus Erythematosus. Ocul Immunol Inflamm. 25, 884-890. Ushiyama O, et al., 2000. Retinal disease in patients with systemic lupus erythematosus. Ann Rheum Dis. 59(9), 705-708. Yang Y, et al., 2016. Retinal Microvasculature Alteration in High Myopia. Invest Ophthalmol Vis Sci.
Jo ur
na
lP
re
-p
ro
of
57, 6020-6030.
Journal Pre-proof
Figure Legends Fig. 1 Optical coherence tomography (OCT) / OCT-angiography (OCT-A) imaging, fundus photography, and analysis of the intra-retinal layers. The five regions around the macula in this 3×3-mm OCT image included a central region (C), superior (S), temporal (T), inferior (I), and nasal (N) region in fundus photography (A). Nine layers of the Intra-retinal and choroid structures in horizontal scan RTVue OCT images: NFL, GCL+IPL, INL, OPL, HFL+ONL, MEZ, OS,
of
IZ+RPE/Bruch complex, and choroid (B). Superficial and deep retinal capillary plexus
ro
(SRCP/DRCP) analyses were performed on the OCT-A images in the parafoveal four quadrant
-p
regions—S, T, I, and N—of a circular zone with a diameter of 2.50 mm after excluding the FAZ (C, D).
re
Fig. 2 Representative fundus photographs, OCT B-scan images of choroidal and
lP
intra-retinal microstructure, and OCT-A images of the superficial, and deep retinal capillary plexus (SRCP/DRCP) of a Control eye, a NLR eye, and a LR eye. In the fundus
retinal hemorrhages.
na
photograph of the LR patient, Black arrows mark cotton wool spots, black arrowheads mark
Jo ur
Fig. 3 Correlations between the inner retina thickness and microvascular density in SLE patients. (A) Correlation between the NFL thickness and SRCP RCSD in the TAZ region (r = 0.38, P = 0.001). (B) Correlation between the GCL+IPL thickness and SRCP RCSD in the TAZ region (r = 0.51, P < 0.001). (C) Correlation between the NFL thickness and DRCP RCSD in the TAZ region (r = 0.10, P = 0.383). (D) Correlation between the GCL+IPL thickness and DRCP RCSD in the TAZ region (r = 0.43, P < 0.001). SLE, systemic lupus erythematosus; NFL, nerve fiber layer; GCL+ IPL, ganglion cell layer and inner plexiform layer; RCSD, retinal capillary skeleton density; SRCP, superficial retinal capillary plexus; DRCP, deep retinal capillary plexus; TAZ, total annular zone. Fig. 4 Systemic lupus erythematosus disease activity index (SLEDAI) scores in the patients with (LR) and without (NLR) retinopathy. There were significant differences between the two groups (P = 0.020). The SLEDAI score for each patient was shown.
Journal Pre-proof
Table 1. Basic characteristics of the subjects NLR
LR
P Value
50 (50)
32 (58)
14 (22)
-
41:9
30:2
14:0
0.090
Age, years
34.4 ± 10.1
34.9± 11.8
35.8 ± 9.3
0.910
BMI (kg/m2)
22.1 ± 2.5
21.6 ± 2.5
21.4 ± 2.1
0.550
SE, diopters
-1.1 ± 1.5
-1.7 ± 1.7
-1.6 ± 1.8
0.150
-0.04 ± 0.06
-0.01 ± 0.04
0.01 ± 0.03
< 0.001
AL, mm
23.7 ± 1.2
23.5 ± 0.8
23.3 ± 1.0
0.210
IOP, mmHg
13.3 ± 2.6
13.6 ± 2.6
12.6 ± 3.5
0.420
MABP, mmHg
89.9 ± 10.7
91.9 ± 12.4
90.0 ± 8.0
0.680
Duration of disease, years
NA
3.8± 3.0
3.9 ± 4.1
0.950
re
BCVA, LogMAR
ro
Gender (F:M)
-p
N (Eyes)
of
Control
lP
NLR, non-lupus retinopathy; LR, lupus retinopathy; F, female; M, male; BMI, body mass index; SE, spherical equivalent; BCVA, best corrected visual acuity; AL, axial length; IOP, intraocular pressure; MABP, mean arterial blood pressure; ; –, not performed; NA, not applicable.
na
P values for differences among the three groups were determined by one-way ANOVA (except for sex and duration of disease, where the P value were determined by 2 and Student’s t-test respectively).
Jo ur
Bold P-value represents < 0.05.
Journal Pre-proof
Table 2. The retinal capillary skeleton density (%) among the three groups Layers SRCP
DRCP
Regions TAZ S T I N TAZ S T I N
Control 5.8 ± 0.5 5.9 ± 0.4 5.9 ± 0.5 5.8 ± 0.5 5.7 ± 0.5 7.4 ± 0.7 7.4 ± 0.7 7.3 ± 0.7 7.4 ± 0.8 7.3 ± 0.7
NLR 5.6 ± 0.4 5.6 ± 0.5 5.6 ± 0.5 5.5 ± 0.5 5.5 ± 0.5 7.3 ± 0.5 7.3 ± 0.6 7.2 ± 0.5 7.3 ± 0.6 7.2 ± 0.5
LR 5.3 ± 0.5 5.3 ± 0.7 5.3 ± 0.5 5.2 ± 0.5 5.2 ± 0.5 7.0 ± 0.6 7.0 ± 0.7 7.0 ± 0.6 7.0 ± 0.6 6.8 ± 0.6
n r u
l a
P* 0.007 0.018 0.004 0.006 0.076 0.377 0.489 0.383 0.306 0.440
f o
o r p
e
r P
P+ <0.001 <0.001 <0.001 <0.001 <0.001 0.005 0.007 0.028 0.007 0.002
P# 0.010 0.017 0.043 0.017 0.015 0.028 0.024 0.115 0.047 0.011
P <0.001 <0.001 <0.001 <0.001 0.001 0.018 0.022 0.090 0.026 0.008
NLR, non-lupus retinopathy; LR, lupus retinopathy; SRCP, superficial retinal capillary plexus; DRCP, deep retinal capillary plexus; TAZ, total annular zone; S, superior region; T, temporal region; I, inferior region; N, nasal region. P*, control versus NLR; P+, control versus LR; P#, NLR versus LR; P, the differences among the three groups. Bold P-value represents < 0.05.
o J
Journal Pre-proof
Table 3. The thickness (μm) of total and inner retinal layers among the three groups Layers
Regions
Control
NLR
LR
P*
P+
P#
P
NFL
C S T I N C S T I N C S T I N
8.9 ± 1.3
8.8 ± 1.4
8.5 ± 1.5
0.854
0.305
0.365
0.572
23.1 ± 2.7
22.1 ± 2.7
20.9 ± 2.7
0.045
0.002
0.084
0.005
16.0 ± 1.7
16.3 ± 1.7
15.9 ± 2.2
0.422
0.855
0.420
0.620
23.7 ± 2.6
23.2 ± 2.6
22.2 ± 2.2
0.213
0.020
0.149
0.062
20.0 ± 2.7
18.9 ± 2.6
18.3 ± 3.3
0.040
0.020
0.415
0.032
22.6 ± 5.9
21.1 ± 5.6
19.4 ± 6.6
0.197
0.039
0.262
0.105
86.8 ± 6.9
85.0 ± 7.8
81.2 ± 13.0
0.278
0.012
0.078
0.041
83.0 ± 7.1
78.8 ± 7.3
74.5 ± 10.2
<0.001
0.029
<0.001
86.0 ± 7.1
85.0 ± 7.0
81.2 ± 9.8
0.524
0.015
0.044
0.047
81.3 ± 7.2
80.0 ± 11.9
77.0 ± 12.4
0.496
0.109
0.263
0.274
236.8 ± 18.5
233.1 ± 18.3
230.5 ± 19.5
0.299
0.188
0.584
0.360
328.6 ± 14.8
323.0 ± 13.5
r P
0.006
316.1 ± 18.8
0.057
0.002
0.070
0.005
318.2 ± 14.8
309.2 ± 12.2
GCL + IPL
Total retina
rn
l a
f o
o r p
e
303.3 ± 16.0
0.001
<0.001
0.090
<0.001
323.9 ± 14.7
319.8 ± 15.0
314.3 ± 15.2
0.137
0.009
0.118
0.029
321.6 ± 16.3
319.6 ± 15.0
312.7 ± 19.8
0.540
0.036
0.094
0.107
J
u o
NLR, non-lupus retinopathy; LR, lupus retinopathy; NFL, nerve fiber layer; GCL + IPL, ganglion cell layer and inner plexiform layer; C, central region; S, superior region; T, temporal region; I, inferior region; N, nasal region. P*, control versus NLR; P+, control versus LR; P#, NLR versus LR; P, the differences among the three groups. Bold P-value represents < 0.05.
Journal Pre-proof
Table 4. The complications in SLE patients with and without lupus retinopathy NPSLE 3 (9%) 2 (14%)
NLR (n=32) LR (n=14)
LN 12 (38%) 7 (50%)
NLR, non-lupus retinopathy; LR, lupus retinopathy; NPSLE, neuropsychiatric systemic lupus
Jo ur
na
lP
re
-p
ro
of
erythematosus; LN, lupus nephropathy.
Journal Pre-proof
Jo ur
na
lP
re
-p
ro
of
Highlights General superficial retinal capillary plexuses density decreasing and regional inner-retinal thinning were detected in the systemic lupus erythematosus patients without clinically diagnosed lupus retinopathy, using spectral domain optical coherence tomography equipped with Angiovue.
Figure 1
Figure 2
Figure 3
Figure 4