Ocular Involvement in Systemic Sclerosis: Updated Review and New Insights on Microvascular Impairment

ABSTRACT

Systemic sclerosis (SSc) is a chronic multisystemic disease characterized by immunological activation, diffuse vasculopathy, and generalized fibrosis exhibiting a variety of symptoms. A recognized precursor of SSc is Raynaud’s phenomenon, which is part of the very early disease of systemic sclerosis (VEDOSS) in combination with nailfold videocapillaroscopy (NVC) impairment. The pathophysiology of ocular involvement, alterations in internal organs, and body integumentary system involvement in SSc patients are complicated and poorly understood, with multiple mechanisms presumptively working together. The most prevalent ocular symptoms of SSc are abnormalities of the eyelids and conjunctiva as well as dry eye syndrome, due to fibroblasts’ dysfunction and inflammation of the ocular surface. In particular, lagophthalmos, blepharophimosis limitation of eyelid motion, eyelid telangiectasia, and rigidity or tightening of the lids may affect up to two-third of the patients. In addition, reduction in central corneal thickness, iris defects and higher rates of glaucoma were reported. In the first reports based on retinography or fluorescein angiography, about 50% of SSc patients showed signs of vascular disease: peripheral artery occlusion, thinning of retinal pigment epithelium and choroidal capillaries, ischemic areas surrounded by intraretinal extravasation and microaneurysms, and peripheral capillary non-perfusion. Successively, thanks to the advent of optical coherence tomography angiography (OCTA), several studies highlighted significant impairment of either the choriocapillaris and retinal vascular plexuses, also correlating with NVC involvement and skin disease, even in VEDOSS disease. Given the sensitivity of this technique, ocular micro-vasculopathy may act as a tool for early SSc identification and discriminate between disease stages.

KEYWORDS:

• Dry eye disease
• eyelid alterations
• micro-vasculopathy
• optical coherence tomography angiography
• systemic sclerosis

Systemic sclerosis (SSc) is a chronic multisystemic disease characterized by immunological activation, diffuse vasculopathy, and generalized fibrosis exhibiting a variety of symptoms.^1,2 The hallmark of SSc is substantial vascular involvement, which is seen not only in the skin’s peripheral microcirculation but also in the heart, lungs, kidneys, gastrointestinal system, and eyes. There are two types of the disease: limited cutaneous systemic sclerosis (lcSSc), in which the development of internal organ fibrosis is far outweighed by the occurrence of skin lesions, and diffuse cutaneous systemic sclerosis (dcSSc), in which internal organ involvement occurs soon after the emergence of skin lesions. Both types of the illness have different skin lesions, which are distinguished by the presence of additional autoantibodies.^3,4 Systemic sclerosis sans scleroderma is a rare form of SSc that is defined by the onset of organ lesions without the early onset or late expression of skin lesions.⁵ There are SSc overlap syndromes as well, most often with polymyositis (scleromyositis) and other systemic connective tissue disorders.

Raynaud’s phenomenon (RP), which occurs due to vasculopathy, is generally the first symptom and might be a precursor for the development of SSc.⁶ The idea of very early disease of systemic sclerosis (VEDOSS), or a very early image of SSc, has evolved based on this clinical picture.⁷ A multicenter expert consensus categorized puffy fingers (PFs), antinuclear antibody (ANA) positivity, and RP as “red flags” or level 1 markers of VEDOSS. Apart from the “red flag” requirements, VEDOSS was identified as the existence of SSc-specific antibodies, such centromere or Scl-70, and/or aberrant nailfold video-capillaroscopy (NVC) results in the level 2 evaluation.^7,8 The complete clinical manifestation of the illness is anticipated to occur in 65–80% of individuals with very early systemic sclerosis within a period of 5 years.⁹

Although bigger arteries may also be affected, vascular injury predominantly affects microcirculation, as shown by the early onset of capillaroscopically visible lesions. Microvascular involvement may lead to pathological alterations such as endothelium rupture, mononuclear cell infiltration of the vessel wall, and obliterative lesions, consequently determining progressive organ failure. These structural vascular alterations and protracted vasospasm may lead to insufficient blood flow, tissue injury, atrophy, and even capillary infarction.^10,11

Numerous visual symptoms affecting both the anterior and posterior segments of the eye, have been reported, including optic neuropathy, primary retinopathy, choroidopathy, keratoconjunctivitis sicca, anterior uveitis, and normal tension glaucoma.^12–14 Furthermore, secondary Sjögren’s syndrome – dryness syndrome, may coexist with SSc in a variable percentage of 14–23% of cases, according to literature.^9,15

Visual loss directly associated with the illness is uncommon, and posterior region involvement is often asymptomatic. Nevertheless, reports claim that 34–55% of individuals with SSc have retinal vascular disease and that modest retinal injury can manifest well in advance of systemic (or even cutaneous) manifestations.^16,17 Detecting early changes in the ocular microcirculation may therefore facilitate early diagnosis: evaluation of the choroidal and retinal vasculature would be optimal for identifying arteriole and capillary pathology in SSc in this context, given that choroidal vessels have the highest blood flow in the human body and retinal tissue has the maximum oxygen extraction per blood volume.¹⁸

The aim of this article is to review the most recent scientific literature, analyzing the occurrence of ocular symptoms in SSc patients as well as their relationship to the disease’s stage. We’ll indeed focus on new insights on microvascular impairment outlined thanks to novel technologies, such as optical coherence tomography angiography (OCTA).

Pathogenesis of microvascular involvement in systemic sclerosis

The pathophysiology of ocular involvement, alterations in internal organs, and body integumentary system involvement in SSc patients are complicated and poorly understood, with multiple mechanisms presumptively working together: immune system imbalance, vascular abnormalities, and finally fibrosis.¹⁹ It is often believed that the fibrosis process is an advanced stage of the illness and that vascular alterations, altered immune-inflammatory processes, and excessive formation of extracellular connective tissue are the common denominators of fibroblast activation.

Early SSc pathophysiology involves altered innate and adaptive immune response, including increased inflammatory cells and products in target tissues like skin and lungs, marked by a type I interferon (IFN) signature. SSc risk increases with interferon-regulatory factor polymorphisms, and IFN excess is seen in many SSc patients’ blood and skin.²⁰ Interestingly, SSc expresses more type 2 T helper (TH2) cells, which produce IL-4 and IL-13, than TH1 cells, which largely release anti-fibrotic IFNγ (38). Over the last decade, researchers have explored the involvement of T-regulatory (Treg) cells, which make about 5–15% of the CD4+ T cell population, in the development of SSc. Recent research suggests that Treg cells may contribute to SSc development by transforming into pathogenic effector T cells.²¹ Additionally, SSc has been shown to convert circulating Treg to Th17 cells and skin-resident Treg to Th2 cells, which produce inflammatory and profibrotic cytokines.^22,23

On the other side, B cell activation leads to autoantibodies (AAb), detected in over 95% of patients at diagnosis, targeting various nuclear, cytoplasmatic, and extracellular autoantigens. Some AAbs are particularly SSc-specific. In dcSSc, anti-topoisomerase AAbs (ATA), previously known as anti-Scl70 AAbs, are more common, whereas anticentromere AAbs (ACA) are more common in restricted cutaneous SSc.^24,25 Moreover, AAbs against angiotensin II type 1 receptor (AT1R) and endothelin type A receptor (ETAR) were found in nearly all SSc patients and high levels are associated with severe SSc manifestations such as digital ulcers and pulmonary arterial hypertension, predicting cardiovascular complications. Finally, anti-endothelial cell Abs (AECA) are identified in 25–85% of SSc patients and linked to severe vascular involvement.²⁶

The abnormal function of the endothelium in SSc patients results in an imbalance of vasoactive factors, including overproduction of the vasoconstrictor endothelin-1 (ET-1) in skin, lung tissue, and serum, and underproduction of the vasodilator nitric oxide (NO) and prostacyclin.^27–31 The frequent and sustained ET1-induced alteration of the microvascular tone triggers the endothelial barrier, leading to opening of endothelial junctions, further inflammatory cell homing, increased microvessel permeability, and continuous vascular leak. Progressive microvascular leak causes microhemorrhages and local edema. Platelet activation is demonstrated in SSc, leading to the release of thromboxane, a potent vasoconstrictor.³²

As ultimate step of the microvascular activation cascade, the endothelial-to-mesenchymal transition (EndoMT) process causes the endothelial cells to trans-differentiate and lose the ability to express their phenotype markers and morphology, acquiring mesenchymal/myofibroblast features. The EndoMT process seems to be mediated by vasoconstrictor molecules and growth factors, including ET-1 and transforming growth factor-beta (TGFβ).^33,34

Meantime, monocyte-derived circulating mesenchymal progenitor cells move into tissues containing T cells and macrophage precursors, forming a perivascular infiltration with a distinct phenotype. After differentiating from monocytes, macrophages may differentiate into conventionally activated (M1) or alternatively activated (M2) phenotypes based on surface markers.³⁵ M1 macrophages primarily generate proinflammatory cytokines like TNF-alpha, IL-6, and IL-1, whereas M2-polarized macrophages create anti-inflammatory cytokines like IL-4, IL-13, and IL-10.³⁶

In SSc, M2 macrophages cause tissue fibrosis during wound healing or the apex of the profibrotic late immune response. Thus, M2 macrophages polarize, limit M1 responses, contribute to the expansion of the myofibroblasts, increase ECM protein synthesis, release profibrotic cytokines, and enhance anti-inflammatory response by promoting Th2 effector activities. As a result, the persistent release of cytokines and growth factors, particularly from Th2 cells and M2 macrophages, leads to progressive fibrosis in tissues and organs.³⁷

All of these described mechanisms, including vascular, autoimmune, inflammatory, and excessive connective tissue component deposition, may be seen in ocular manifestations of this disease.

Types of ocular involvement in SSc

Systemic sclerosis may cause variable ocular manifestations, schematically divided into compartments in the following section (Table 1).

Table 1. Prevalence of ocular findings among SSc patients in different researches.

Ocular findings	Percent (%)
Eyelid (stiffness, tightness, telangiectasia)	51.1–77.0
Conjunctiva (neovascularization, teleangiectasia, varicose vein dilatation)	15.7–63.0
Dry eye disease	48.9–64.7
Iris (transilumination, vascular deformation)	8.9–13.7
Cataract	42.2–51.0
Retina (hard exudates, tortuosity of vessels)	10.0–34.0
Choroid (perfusion abnormalities)	33.0–55.0
Glaucoma	11.1–21.6

Eyelids

The most well-documented ocular symptom in SSc patients is eyelid skin involvement, caused by collagen deposition in the dermis. A variety of clinical manifestations may ensue from fibrosis of the skin of the eyelids, including lagophthalmos, blepharophimosis, limitation of eyelid motion, eyelid telangiectasia, and rigidity or tightening of the lids.^38,39 In their investigation, Szucs et al. discovered eyelid alterations in 57% of SSc patients, which raised to 77% of cases in a research by Ratilglia et al.^39,40 According to Gomes et al., eyelid abnormalities are more frequent in patients with dcSSc and in those whose underlying illness was diagnosed earlier in life – on average, 35.9 years vs. 44.6 years in those who don’t have eyelid involvement.¹³

Furthermore, eyelid skin changes may affect anterior segment parameters of the eye. Atik et al. recently showed that anterior chamber depth (ACD) measurements of SSc patients with moderate/severe eyelid skin thickening were significantly lower than the control group, suggesting that tight eyelids transfer mechanical forces on the anterior segment of the eye.⁴¹ The rigidity of the eyelid skin, which limits their movement, also showed a substantial influence on the inhomogeneous tear film distribution across the anterior surface of the eye. Lagophthalmos therefore increases the evaporation process, which results in an excessive loss of tear film and increases the risk of developing chronic dry eye disease (DED).³⁹

Dry eye syndrome and conjunctiva

Dry eye syndrome (DES) is a complex condition impacting on tear production and ocular surface, leading to irritation, visual impairment, instability of the tear film, and possible ocular surface injury.⁴² A number of connective tissue disorders are correlated with DES, and it has also been documented as a clinical presentation during SSc.⁴³ Undoubtedly, a disruption in the immunoregulatory mechanisms or an excessive stimulation of the ocular immune system results in an imbalance between the innate and adaptive phases. As a consequence, an atypical generation of autoantibodies and a cell-mediated autoimmunity response ensue, culminating in dysfunction of fibroblasts and inflammation of the ocular surface.⁴⁴

Particularly, physiopathologic mechanism of SSc is characterized by fibrosis of the tear ducts, which inhibits the formation of an aqueous layer in the tears. Consequently, a reduction in the quantity of goblet cells within the conjunctival epithelium results in a downregulation of tear film mucin layer secretion. Reports showed that the velocity of tear secretion is as much as 67% lower in patients with SSc when compared to the control group.⁴⁵ The aforementioned modifications lead to increased tear evaporation from the ocular surface as well as a quantitative and qualitative tear shortage.⁴⁶ In addition to these mechanism, the disorders of the eyelids, which have been previously described, may act an important role in DES development.

Mencel et al. showed up results of conjunctival biopsies from 21 SSc patients in 1993. Microscopic analysis of the samples indicated inhomogeneous epithelial cell growth, a considerable loss of goblet cells, and weakening of the conjunctival epithelium and its keratinization.⁴⁷ However, there was no relationship between the intensity of the alterations and the severity of the illness or the symptoms of patients. Each biopsy showed also significant mast cells infiltration and half of them in the degranulation stage, suggesting active mediator release from mast cells granules and possible involvement in tissue fibrosis in scleroderma. In addition, skin and lip biopsies revealed similar histopatologic findings as well.⁴⁸ Regardless the duration of illness, signs of fibrosis around conjunctival capillaries and underneath the epithelium were found in every histopatologic sample, with plenty of active fibroblasts, bundles of collagen fibers, and thickening of capillary walls.⁴⁷

Overall, the prevalence of DES in SSc ranged from 48.9% to 64.7% in the first investigations, with Rentka et al. curiously reporting an imbalance between objective parameters and subjective symptoms in the course of SSc.^13,43 In a recent retrospective study, Gagliano et al. reported that 84% of SSc patients developed severe DES, with women being more severely affected. Non-invasive tear break-up time (NIF-TBUT), tear film lipid layer thickness (LLT), the two most significant parameters for the diagnosis of lipid tear dysfunction, were substantially diminished, along with Schirmer test I values.⁴⁹ Moreover, the mean tear osmolarity, ranging around 290–295 mOsm/L in healthy people, was found to be 328.51 ± 23.8 mOsm/L in SSc patients. This parameter was presented as an indicator of the DES evolutionary process to severity and showed also a correlation with the Modified Rodnan skin score (mRSS).⁴⁹

At last, it is fundamental to remember that secondary Sjögren’s syndrome might coexist with SSc and cause symptoms of DES. Biopsies from individuals with primary Sjögren’s syndrome were also examined in the aforementioned by Mancel et al., revealing distinct traits of conjunctival alterations in the two disorders, since fibrosis was not seen in any of the primary Sjogren syndrome samples, being exclusively related to SSc.⁴⁷

Moreover, due to its extensive vascularization, the conjunctiva is severely impacted by vasculopathy during SSc. Conjunctival vascular congestion, neovascularization, telangiectasia, and varicose vein dilatation have been reported,¹⁵ with rates of conjunctival tortuosity and dilatation around 60% among the 30 individuals tested for Ratilglia et al.’s analysis.⁴⁰ Conversely, the research by West and Barnett among the 38 patients with SSc, highlighted vascular sludging inside the conjunctiva in 71% of cases and dilated vessels in 50%. Additionally, it was noticed that the alterations in the conjunctival blood vessels match those discovered by nailfold capillaroscopy during SSc assessment.³⁸

Cornea

Collagen fibers, primarily collagen types I and V, are the main components of corneal stroma, which makes up 90% of the cornea’s overall thickness.⁵⁰ Due to the extensive collagen deposition that occurs in SSc, particularly in the skin and internal organs, studies were conducted to assess the possible effects on corneal tissue, outlining contradictory results.⁵¹

In an examination of 32 SSc patients, Serup et al. found an increased central corneal thickness (CCT), particularly in the first 8 years of the illness,⁵² while Gomes et al. reported that there was no appreciable variation in corneal thickness between the 37 patients with SSc and the control group.^53,54 On the contrary, Sahin Atik et al. found a statistically insignificant trend for decreasing CCT.⁴¹

Emre et al. found that corneal biomechanical properties in SSc patients differed from healthy subjects due to higher corneal resistance factor (CRF) and IOP values, likely due to ultrastructural corneal morphology.⁵⁵ Using a Pentacam camera, Şahin et al. reported thinner CCT and corneal volume (CV) in SSc patients compared to healthy controls in an anterior segment analysis, with coexisting DES being linked to lower CCT values.⁵⁶ Finally, a recent research by Nagy et al., taking into account a variety of confounding variables, found significant negative relationships between corneal characteristics, age, and illness duration. This research highlighted reduced pachymetric and increased corneal anterior surface power values in SSc patients, with slightly lower CV and ACD values.⁵⁷

In conclusion, more extensive research on bigger patient populations is needed to fully understand how SSc affects corneal thickness. Significant changes in corneal structure, being an avascular tissue therefore less prone to autoimmune insult, may be detectable only with a long-term surveillance.

Iris and pupil

Transillumination defect and vascular deformation are the prevailing iris abnormalities detected during ophthalmologic examinations of patients with SSc. Vessel deformation is especially conspicuous in individuals with a pale iris.³⁸ Iris alterations were documented by Szucs et al. in 13.7% of patients and Gomes et al. in 8.9%.^13,39 Vasculopathy affecting the iris as a component of the uvea is hypothesized to be the cause of these alterations, subsequently resulting in vascular disorders and epithelial atrophy of the iris.³⁹

Moreover, studies on the variation of pupil diameter in SSc patients were conducted, starting from the assumption that either the central and peripheral nervous systems may be affected in this pathology. Particularly, an examination of the pathogenesis of Raynaud’s phenomenon revealed that the parasympathetic nervous system activity was decreased, while sympathetic nervous system activity increased.^58,59

Bertinotti and del Rosso investigated the impact of substance P, a pupil constrictor acting directly on the sphincter pupillae muscle, on the basal pupil diameter of SSc patients in two different studies.^60,61 In patients with SSc, the basal diameter of the pupil was reportedly smaller in comparison to the control group, while substance P induced a more pronounced constriction of the pupil. Interestingly, patients with limited scleroderma exhibited these alterations more prominently than those with generalized scleroderma: these findings are consistent with the more pronounced dysfunction of the peripheral nervous system reported in lcSSc.⁶²

Retina and choroid

Retinal anatomy benefits of some specific characteristics: the absence of resident fibroblasts, an immunologically favourable microcirculation and an adrenergic vasomotor innervation, may all shield it from the fibrosis and vasculopathy processes that take place in SSc. On the other side, being the choroid the most vascularized area of the eye, a large impact of SSc-related abnormalities would be expectable at this level. Nevertheless, a lot of contradicting findings have been reported in literature.^63,64

In the very first reports, no links between SSc and retinopathy were found.⁶⁵ Successively, Gomes et al. reported retinal microvascular abnormalities, such as vascular tortuosity, arteriovenous nicking, and widespread and localized arteriolar constriction in 28.9% of SSc patients. Furthermore, compared to control eyes, SSc eyes had a greater frequency (34%) of retinal alterations, including microhaemorrhage, vascular tortuosity, hard exudates, and macular degeneration.^13,14 In contrast, Cheung et al. discovered that retinal vascular tortuosity correlated with concurrent hypertension in this kind of patients.⁶⁶

According to MacLean and Guthrie’s histopathological research, SSc eyes showed thickened precapillary basement membrane, swelled endothelial cells, obliterated tiny vessel lumen and patches of choroidal ischemia.⁶⁷ Consistently with this research, Farkas’s post-mortem histopathologic investigation in advanced SSc revealed necrosis as a fundamental defect in the choroidal vasculature, along with abnormalities of the basement membrane and endothelial cells, including widespread thickening of the basement membrane and enlargement of the endothelium.¹²

New insights on retino-choroidal impairment were reported thanks to fluorescein angiography (FA). Serup et al. showed late phase angiographic alterations (33%), suggesting that SSc patients with no indication of concurrent arterial disorders and no history or further proof of recognized ocular disease had impaired choroidal perfusion, with consequent hyperfluorescence of the retinal pigment epithelial layer.⁶⁸ Similarly, Grennan et al. reported about 50% rate of choroidal non-perfusion patches, mostly visible in cases of severe dcSSc.⁶⁹ Waszczykowska et al. identified vascular abnormalities in 55% of cases, including delayed filling of choroidal lobules, peripheral artery occlusion, thinning of retinal pigment epithelium and choroidal capillaries, ischemic areas surrounded by intraretinal extravasation and microaneurysms, peripheral capillary non-perfusion, and enhanced capillary network.⁴⁶ Furthermore, reports of choroidal sclerosis and choroidal artery leakage using indocyanine green angiography (ICGA) were published.^70,71

With the advent of OCT, several novel findings on systemic pathologies became detectable. Several investigations on SSc patients reported considerable choroid thinning when compared to controls.^72–74 Nevertheless, a significant step ahead in recognizing subtle microvascular alterations in these patients was made thanks to OCT angiography (Table 2). First in 2019, Ranjbar et al. demonstrated decreased perfusion in all layers of the choroid in the submacular area in individuals with systemic sclerosis using OCTA.⁷⁵

Table 2. Review of recent reports regarding SSc microvascular changes using OCTA.

Study authors	OCTA devices	Scan width (mm^2)	No. of eyes SSc/controls	Findings in FD patients
Ranjbar et al.^Citation75	Spectral Domain	3 × 3	12/12	↓VD in CC and Sattler’s Layer
Hekimsoy et al.^Citation76	Spectral Domain	6 × 6	45/45	↓VD in SCP in fovea, parafovea, perifovea, whole image ↓VD DCP only in fovea = FAZ parameters and VD in CC
Rommel et al.^Citation77	Spectral Domain	3 × 3	30/30	↓VD in SCP and DCP =VD in CC ↓VD in Sattler’s and Haller’s Layers
Rothe et al.^Citation78	Spectral Domain	3 × 3	24/24	↓VD in SCP, =VD in DCP and FAZ parameters
Carnevali et al.^Citation79	Spectral Domain	3 × 3	20/20	↓VD in DCP =VD in SCP
Fang et al.^Citation80	Spectral Domain	3 × 3	32/32	↓VD in SCP in all regions of ETDRS map
Mihailovic et al.^Citation81	Spectral Domain	Macula: 3 × 3 Optic nerve: 4.5 × 4.5	22 (7 VEDOSS)/22	↓VD in SCP and CC ↓VD in radial peripapillary capillary network =VD in DCP and FAZ parameters ↓VD in CC also in VEDOSS
Ertuk et al. (2023)	Spectral Domain	Macula: 3 × 3 Optic nerve: 4.5 × 4.5	22 PRP 19 VEDOSS 38 SSc (25 lcSSc, 13 dcSSc	↓VD in SCP and DCP in SSc vs. PRP ↓VD in foveal SCP in lcSSc vs. VEDOSS ↓VD in RNFL peripapillary optic disc in lcSSC vs. VEDOSS and PRP =VD in CC among all groups

OCTA = Optical Coherence Tomography Angiography, SSc = systemic sclerosis; lcSSc = limited cutaneous SSc; VEDOSS = Very Early Disease Of Systemic Sclerosis; VD = vessel density; CC = choriocapillaris; DCP = Deep Capillary Plexus; SCP = Superficial Capillary Plexus, FAZ = Foveal Avascular Zone; ETDRS = Early Treatment Diabetic Retinopathy Study; PRP = Primary Raynaud Phenomenon; RNFL = Retinal Nerve Fiber Layer.

Successively, Hekimsoy et al. demonstrated changes in foveal capillary plexus vessel density (VD) between SSc eyes and healthy control eyes. The foveal, parafoveal, and perifoveal VDs at the superficial capillary plexus (SCP), as well as the foveal VD at the deep capillary plexus (DCP), were considerably lower in SSc eyes as compared to control eyes, while dcSSc and lcSSc showed no differences in terms of OCTA parameters.⁷⁶ Patients with SSc have been shown to have thinner central macular thickness (CMT) and subfield central thickness (SFCT) on OCT, which is associated with reduced choroidal perfusion.⁷⁶ Hekimsoy’s observations of decreased SCP and DCP perfusion in SSc were validated by Rommel et al., which also showed lower macular volume (MV) in SSc patients, compared to healthy eyes.⁷⁷

Additionally, Rothe et al. showed that SSc patients had less macular visual loss (MVD), with the majority of the alterations occurring in the SCP.⁷⁸ Contrary to this, Carnevali et al. demonstrated that SSc patients had impairments in the microvasculature, primarily in the DCP, and that patients with SSc and digital ulcers had lower VD in the SCP.⁷⁹ Finally, a recent research brought on by Fang et al. highlighted that SSc patients have substantially lowered VD in the SCP in all subregions of the macular ETDRS map, with a positive association between inner retinal thickness and VD.⁸⁰ Further, they suggested that superficial VD could become a biomarker for early identification of retinal abnormalities in SSc.⁸⁰

Ocular microvasculature involvement was recently identified by Mihailovic et al., even in individuals with early stages of SSc (VEDOSS), who showed decreased VD of the choriocapillaris, while patients with confirmed SSc had a significantly lower VD of their optic nerve head capillary density compared to VEDOSS patients. Starting from these assumptions, they hypothesized that OCTA imaging may acquire a prognostic value to assess the likelihood for individuals with RP to develop SSc, such as nailfold capillaroscopy.⁸¹ Furthermore, they reported al negative association between the skin score and the SCP’s VD, supporting the idea that microvascular changes are a general and pathogenetic relevant phenomenon in SSc, consistent with a recent study claiming correlation between skin scores and oral vascular density scores.⁸²

When compared to patients with primary RP, those with SSc and VEDOSS showed significantly reduced median values of SCP, DCP, and optic disc VDs, according to Ertuk et al. in a novel research.⁸³ Furthermore, when compared to patients with VEDOSS, those with lcSSc showed the most significant variations in terms of foveal SCP VDs, RNFL-VDs, entire and peripapillary optic disc VDs, and FAZ perimeter.⁸³ Thanks to its celerity of convenience of use in clinical practice and interobserver repeatability, also compared to classic diagnostic tests such as nailfold video-capillaroscopy, the authors stated that OCTA could become a useful tool to distinguish between SSc and SSc precursors.⁸³

Glaucoma

Several studies have examined the link between SSc and the prevalence of glaucoma. Open-angle glaucoma was discovered by Gomes et al. to be present in 11.1% of participants, greater than the prevalence in the general population.^13,39 The hypothesis from which the increased prevalence of glaucoma is derived, lies in microvascular impairment, including perfusion and circulation in the blood vessels of the optic nerve.¹³ Moreover, in their analysis of 61 patients with SSc, Allanore et al. discovered higher rates of defects in the vision fields and cup/disc areas >0.3 when compared to healthy subjects, but keeping intraocular pressures within normal range. Based on these findings, they suggested a possible correlation between SSc and normal tension glaucoma, which was later challenged by Chan and Liu given the inadequacy of the IOP measurement, along with methodological flaws in the analysis of the field of vision data.^84,85

Therefore, further study is needed to determine why SSc individuals have a higher risk of developing glaucoma.

Conclusions

Although knowledge of ocular involvement in systemic diseases has incredibly broadened in recent years, conclusive statements on the effect of SSc on the eye are yet to be made. The eyelid, conjunctival, dry eye syndrome, and retinal perfusion problems are now the most well-documented ocular signs of SSc, and they all arise from the primary characteristics of the underlying illness, vasculopathy and fibrosis.

On the other side, a direct link between the intensity and type of ocular alterations and the evolution of systemic diseases has not been clearly determined, till now. Unknown factors influence the incidence and severity of ocular changes, including the autoantibody profile, the severity of skin fibrosis, the development of organ alterations, the severity of microcirculation changes, and the severity of the inflammatory process.

This is why recent studies focused on retino-choroidal abnormalities, highlighted by new non-invasive technologies, such as OCTA, which are able to assess the most subtle changes to vascular architecture. Even more than simple diagnostic tools to confirm SSc-related vasculopathy, in the future OCTA could play a double role in the management of these patients: on one side acting as a potential tool for early SSc identification and discriminating between disease stages (RP, VEDOSS and confirmed SSc); on the other side highlighting the effects of systemic therapy on microvascular changes.

The direction seems set, and future studies will tell us what role ocular involvement will play in the management algorithm of SSc.

Contributorship statement

Conceptualization, M.M.C.; methodology, M.M.C.; validation, E.C. and M.R.; formal analysis, F.G and F.B.; investigation, M.M.C.; writing—original draft preparation, M.M.C; writing—review and editing T.C. and G.G.; project administration, S.R. All authors have read and agreed to the published version of the manuscript.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images.

Data sharing statement

The data that support the findings of this study are available from the corresponding author, MMC, upon reasonable request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors reported no funding associated with this work.