Evaluation of the Optic Nerve Head Using Optical Coherence Tomography Angiography in Systemic Sclerosis Patients Bewertung des Sehnervenkopfes mittels optischer Kohärenz-tomografie-Angiografie bei Patienten mit systemischer Sklerose

Purpose To quantify microvascular vessel density in the optic disc using optical coherence tomography angiography (OCTA) in patients with systemic sclerosis (SS); to determine whether there is a difference in values between patients and controls; and to correlate the OCTA measurements with disease activity, damage risk, and drug usage. Methods


Introduction
Systemic sclerosis (SS) is a chronic multisystem disorder associated with vasculitis.Immune activation, vasculopathy, and excessive fibrosis are seen in the joints and internal organs [1], anomalies that result in tissue hypoxia [2].The association between SS disease and endothelial cell dysfunction has been demonstrated, especially in the microvascular system [3] and, as a result of vascular damage, cutaneous manifestations, such as Raynaudʼs phenomenon, nailfold capillary changes, and digital ulcers, have been observed.Moreover, ischemic damage is present in other target organs, including the heart, lung, kidney, muscles, and gastrointestinal system [4].
Optical coherence tomography angiography (OCTA) enables imaging of the vascular plexus and segmentation of the inner retina, outer retina, and choriocapillaris using split-spectrum amplitude-decorrelation angiography (SSADA) [5].Previous studies have found that OCTA offers a high degree of repeatability at intra-and inter-visits [6].OCTA has also been employed for examining connective tissue diseases, e.g., systemic lupus erythematosus and vasculitis and Bechetʼs disease [7,8].
In light of these studies, we examined the optic disc microcirculation of the eye in patients with diffuse and limited SS.To our knowledge, no attempt has previously been made to evaluate the peripapillary retinal vasculature using OCTA in SS patients.Therefore, this study quantified the retinal microvascular vessel density in SS patients using OCTA and identified a difference in values between SS patients and healthy individuals, correlating any differences with disease activity, damage risk, and drug usage.

Subjects and Methods
Ethical Approval: This study was approved by the Bakirkoy Dr. Sadi Konuk Training and Research Hospital Ethics Committee (project number: 2018/3l6) and adhered to the tenets of the Declaration of Helsinki.Informed consent was obtained from all subjects.
Patients aged 20-76 who were followed up after a diagnosis of diffuse and limited SS in the hospitalʼs Rheumatology Department were included in this study.Patients were recruited between 1 June and 1 December 2019.The research protocols for this study were approved by the Ethics Committee of Bakirkoy Dr. Sadi Konuk Training and Research Hospital and conducted in accordance with the tenets of the Declaration of Helsinki.Written informed consent was obtained from each participant; the ethics committee approved the consent procedure.All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for the diagnosis of SS.Whether the patientsʼ conditions were active or in remission was determined by the Physician Global Assessment (PGA).SS was classified as diffuse, limited, morphea, or linear based on clinical examination.Patients who met the diffuse and limited SS criteria according to the ACR/EULAR criteria were included in the study.
The age-and gender-matched control group consisted of healthy individuals with no ocular or systemic disease history.All patients underwent comprehensive ophthalmologic tests, consisting of best-corrected visual acuity (decimal fraction), intraocular pressure (IOP), slit lamp examination of the anterior segment, and fundoscopic examination, all performed by the same clinician.After the examination, the retinal nerve fiber layer (RNFL) and OCTA measurements were made using the RT-XR Avanti instrument with AngioVue software (version: 2018.0.0.14) (Optovue, Inc., Fremont, CA, USA).Finally, based on the files in the rheumatology clinic, each patientʼs age, year of diagnosis, autoantibody profile [antinuclear antibody (ANA) titer, anti-centromere antibody, anti-C antibody, and anti-Scl-70 positivity], ocular symptoms, usage of systemic corticosteroid (CS), hydroxychloroquine (HCQ), calcium canal blocker, immunosuppressive agents, aminosalicylic acid, and anti-tumor necrosis factor were recorded.The subjects had visual acuity ≥ 20/40 and a spherical equivalent within ± 2.00 diopters.

Klinische Studie
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The exclusion criteria included sine scleroderma (involvement of visceral organs in the absence of skin involvement), scleroderma overlap syndrome (SS associated with features of other connective tissue erythematosus), diabetes mellitus, severe hypertension, and retinal diseases, as well as diseases affecting the optic disc, e.g., glaucoma, optic neuropathy, previous intraocular surgery or trauma, and evidence that could confound OCT interpretation, such as intraocular pressure > 21 mmHg or oral CS use above 10 mm.Individuals with conditions that could cause media opacity, such as corneal opacity, fatal dry eye syndrome, grade 3-4 nuclear cataracts, and retinal microvascular abnormalities, were also excluded from the study.Only images with a signal strength index > 8/10 were used for the analysis of vessel density.
OCTA was carried out by the same technician using an RT-XR Avanti instrument in the morning (9 : 00-11 : 00 a. m.) to avoid possible diurnal variations.The volumetric scans were processed with the SSADA algorithm.Both eyes of each participant were examined and scanned during the same visit.The eye with the higher image quality in the OCTA measurement was included in the study.
All measurements were performed using the manufacturerʼs equipment and the analytical AngioVue software.Analyzing 4.5 × 4.5 mm OCTA scans centered on the optic nerve head (ONH) the radial peripapillary capillary (RPC) segment was assessed.The software automatically subdivided the retina into the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) for every scan.There were measurements conducted in five areas: inside disc vessel density results were obtained from the area within ONH, entire image vessel density was assessed from the total 4.5 × 4.5 mm image, and whole peripapillary vessel density results were obtained from the area of an elliptical annulus 750 µm wide extending from the ONH boundary.The peripapillary region was automatically separated into superior-and inferior-hemi-RPC by the OCTA instrument, and all quantitative findings were documented.▶ Fig. 1 depicts ONH and RPC images from a patient.

Statistical analysis
SPSS software was used to analyze the data (SPSS for Windows, v. 20.0; SPSS, Inc., Chicago, IL, USA).The Kolmogorov-Smirnov test was used to confirm the distributionʼs normality.For normally distributed variables, descriptive statistics included mean values with standard deviation and median values with a 95 % confidence interval for non-normally distributed variables.To compare the differences between the two groups, the Kruskal-Wallis test was used.Furthermore, a chi-squared test was used to analyze the gender frequency data.A Spearman correlation analysis was performed to determine the relationships between the peripapillary perfusion parameters and related factors, an independent t-test was used to compare the normally distributed independent variables, and the Mann-Whitney U test was used to analyze the independent variables.A statistically significant p value of 0.05 was used.

Discussion
In our study, we found no significant difference between SS patients and control groups in RNFL and RPC values.The vasculopathy of SS affects small arteries and capillaries.In particular, it reduces capillary density [9].Many reasons can be attributed to the perfusion of the optic disc.The leading cause is vasculopathy and immune activation, resulting in excessive fibrosis [10].In addition, ischemia can occur due to intimal fibroblastic proliferation and vasospastic episodes in SS [11].Endothelin-1 and angiotensin 2, which are potential vasoconstrictors, are increased in SS pa-tients and play a role in the vasospastic process [12].These structural changes and prolonged vasospasm are considered to be due to decreased blood flow [13].
Allanore et al. found that the incidence of the glaucomatous optic neuropathy rate was high, although IOP was normal in a prospective cohort study of patients with SS [14].Sahin-Atik and coworkers extended Allanore et al.ʼs study by examining the retinal nerve fiber and optic disc morphology using OCT in scleroderma patients who had not been diagnosed with glaucoma.They found that only those with a cup-to-disc ratio > 0.5 showed a statistically significant thinning in the inferior RNFL quadrant and suggested that there was a predisposition to ONH damage and glaucoma as a result of generalized vasospasm [15].The association between SS and non-glaucomatous optic neuropathy was demonstrated in one study [16], while the frequency of glaucoma in autoimmune diseases has been linked to vascular dysregulation and has been considered to be related to endothelin-1 [17].In our study, the lack of difference in both RNFL and RPC values in the patient group compared to the control group was attributed to the lack of change in the vessel density (VD) values in the early phase of the disease.Since we excluded glaucoma patients from the study, we also eliminated glaucoma-related RPC VD changes.

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Coşkun et al. [18] found a statistically significant difference in choroidal thickness in SS patients, which they attributed to the choroidal hypoperfusion shown in patientsʼ fundus fluorescein angiography (FFA).Another study reported some changes, especially in pigment epitheliopathy and retinal arterioles, and persistent hyperfluorescence in the temporal venules in the FFA [19].Some choroidal changes with endothelial damage were found by Farkas et al. [20]; these changes were considered to be similar alterations to effects noted in the skin and renal system, and they could be related to the flow in the optic nerve.Although the exact cause of RPE atrophy in primary SS has not been determined, it is considered to be associated with choroidal flow and choroidal disorder secondary to hypertensive retinopathy.Ushiyama et al. [21] reported that retinopathy findings were higher in normotensive SS patients than in a control group.Grennan and Forrester [22] found choroidal hypoperfusion areas in the FFA; no one had hypertension, except for one patient.In our study, we also excluded patients diagnosed with severe hypertension so that hypertensive retinopathy did not affect the RPC VD values.
In the current study, the inverse correlation between the values of the RNFL measurements and the disease duration suggests that these parameters are altered due to the disease itself as its duration increases.The decrease in these values with the duration of the disease made us think the inflammatory process accumulates in the vessel wall over time.Nevertheless, as the significances of the correlations are not substantial, this assertion needs to be verified in future studies.
Although ANA levels and ANA positivity are not helpful in monitoring the diseaseʼs activity, studies have pointed out that ANA subsets can be useful in anticipating long-term outcomes [23].In our study, the increase in the ANA titers and the decrease in RNFLsuperior and RPCwhole, peripapillary, inferior, and temporal values suggest that vascular values are affected.The decrease in the RPC inside value in anti-Scl-70-positive patients also supports this finding.We attributed this relationship to the autoimmune inflammatory process that occurs with different ANA titers.
Calcium channel blockers are widely used agents for reducing the frequency and severity of ischemic attacks in Reynaudʼs phenomenon, especially in SS patients [24].Esen  cium channel blocker users [25] In the present study, the RPCinside value was higher in patients using calcium channel blockers.
In addition, the higher RPC values in those who use HCQ, immunosuppressive drugs, and corticosteroids suggest that these drugs are protective against vascular density and inflammation in SS disease.Besides, due to the decrease in optic disc RPC VD values with certain drugs, high RPC VD values can be investigated on disease prognosis.
To the best of our knowledge, there has been no research on OCTA that examines the optic disc RPC parameters.Kılınç Hekimsoy et al. [26] conducted OCTA measurements in the macular region in patients with SS and found that the superficial capillary plexus vessel density and the deep capillary plexus vessel density of the fovea were significantly lower than those in healthy control subjects.Rommel et al. [27] confirmed their findings and investigated choroidal substructures.They thought that these findings might be related to disease duration.Carnevali et al.
[28] also studied choroidal and retinal VD changes of the poste-rior pole in SS patients and suggested that their results may represent a hypothesis-generating basis for exploring the potential role of OCTA in diagnosis, monitoring, and prognosis stratification in SS.Considering the recent studies and our study, we can say that the retinal vessels in the macula are thinner than those in the optic disc, suggesting that the vascular changes in the SS occur at the first posterior pole.
This study is limited by cross-sectional design, and the inclusion of SS patients with a relatively short follow-up period, i.e., a median of 6 years.Therefore, this condition limits the use of these values as biomarkers because the optic disc RPC VD values did not change in early disease.Future research may investigate whether the presence of concomitant vascular diseases alters OCTA levels in SS patients.

Conclusion
Noninvasive tests like OCTA are required to identify early vasculopathy in SS due to the well-known characteristics of SS patients with choroidal and retinal abnormalities.This is the first study to examine the microvascularization of the optic disc in SS patients using an OCTA device.In our analysis, peripapillary VD did not differ between SS patients and controls, which means OCTA evaluation of early vasculopathy did not reveal any additional benefits.However, further research into OCTA and other parameters is required to comprehend VD alterations.

CONCLUSION BOX
Already known: ▪ SS is a systemic disease with vasculopathy.According to prior research, although it affects various layers of the eye, the retina and choroid are primarily altered.

▶ Fig. 1
Optical coherence tomography angiography (OCTA) imaging (4.5 × 4.5 mm) of the radial peripapillary capillaries (RPC) of the right eye of a patient with systemic sclerosis (SS).The diagram on the right side of the figure shows the quantitative vessel density results.Image downloaded from OCT device (RTVue-XR OCT; Optovue Inc., Fremont, CA, USA).
Newly described: ▪ There was no change in radial peripapillary capillary vessel density values measured by OCTA in SS disease.ANA titer, anti-scl-70 positivity, and the use of CS, HCQ, and calcium channel blockers in scleroderma patients affect RPC VD values.

Table 1
Demographic and clinical characteristics of subjects by groups.

Table 2
et al. found no difference in choroid thickness and central macular thickness in cal-Optic disc morphologic parameters, RNFL thickness PRC measurements of the SS patients and control subjects.
b SS systemic sclerosis; SD: standard deviation; RNFL: retinal nerve fiber layer; c/d: cup/disc ratio; RPC: radial peripapillary capillary plexus; wVD: whole vessel density; iVD: inside vessel density; *normally distributed values; **values that do not show normal distribution; a Mann-Whitney U test; b independent sample t-test ▶ Fig. 2 The correlation and regression line between nasal RNFL and time from diagnosis.Designed with SPSS Graphs function (SPSS for Windows, v. 20.0; SPSS, Inc., Chicago, IL, USA).