Prevalence and evolution of scleroderma pattern at nailfold videocapillaroscopy in systemic sclerosis patients: Clinical and prognostic implications

doi:10.1016/j.mvr.2015.03.005

Microvascular Research

Volume 99, May 2015, Pages 92-95

https://doi.org/10.1016/j.mvr.2015.03.005 Get rights and content

Highlights

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Scleroderma pattern is the hallmark of microangiopathy in scleroderma patients.
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Scleroderma pattern is observed in more than 85% of scleroderma patients.
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Digital ulcers are clearly associated to scleroderma pattern.
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The association between scleroderma pattern and lung involvement should be studied.
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Nailfold capillaroscopy should be routinely assessed in scleroderma patients.

Abstract

Background

Microvascular involvement plays a decisive role in systemic sclerosis (SSc) pathogenesis occurring early in the course of the disease. Microangiopathy is responsible of important clinical manifestations, such as Raynaud's phenomenon, digital ulceration, and pulmonary arterial hypertension. Typical microvascular alterations, called scleroderma pattern, are detectable at nailfold capillaroscopy in a significant percentage of SSc patients; however its prevalence is highly variable in published studies.

Aim

The aims of this study are to evaluate the prevalence and the evolution of scleroderma pattern in SSc patients and analyze their demographic, clinical and prognostic characteristics according to capillaroscopic features.

Methods

Two hundred and seventy-five SSc patients, underwent at least two nailfold videocapillaroscopy during follow-up, were retrospectively enrolled.

Results

A scleroderma pattern was observed in 80% of patients at baseline and 87.1% during follow-up, and it was significantly associated to digital ulcers, interstitial lung disease, reduction of diffusion lung of carbon monoxide < 75%, teleangectasias and melanodermia, while sicca syndrome and arthralgias were associated to normal/nonspecific pattern. Digital ulcers, teleangectasias, sicca syndrome, and arthralgias remained independently associated with scleroderma pattern on multivariate analysis.

In conclusion, the main clinical manifestation correlated with scleroderma pattern is the occurrence of digital ulcers, and their appearance is strictly correlated with the variation of capillaroscopic feature during the time. Further studies should confirm the association between SSc pattern and lung fibrosis.

Introduction

Systemic sclerosis (SSc) is a connective tissue disease characterized by endothelial dysfunction, dysregulation of fibroblasts with collagen overproduction, and complex immune system abnormalities (Avouac et al., 2011, Ferri et al., 2014). A frequent consequence of this chronic disease is the multiple organ damage/failure responsible for marked impairment of the patient's quality of life and increased mortality (Avouac et al., 2011, Ferri et al., 2014). Vascular involvement plays a decisive role in SSc pathogenesis occurring early in the course of disease, typically with the appearance of Raynaud's phenomenon (Kahaleh, 2004). Microangiopathy is also directly responsible for some severe clinical manifestations, such as digital ulceration, pulmonary arterial hypertension and scleroderma renal crisis (Lambova and Müller-Ladner, 2010).

Capillaroscopy is an imaging technique, for the in vivo study of microcirculation, quick to perform, non-invasive, and not expansive (Grassi and De Angelis, 2007, Ingegnoli et al., 2013a). The first description of capillary abnormalities in systemic sclerosis (SSc) dates back to 1925 by Brown and O'Leary (1925) and these findings were thereafter called ‘scleroderma pattern’. In the last 3 decades many authors have investigated the scleroderma microangiopathy, and now the capillary abnormalities in SSc are well documented (Grassi and De Angelis, 2007, Ingegnoli et al., 2013a, Smith et al., 2012, Smith et al., 2013).

Recently, the presence of a scleroderma pattern has been included in classification criteria for SSc (van den Hoogen et al., 2013), but although it is detectable in a significant percentage of SSc patients, the prevalence of scleroderma pattern is highly variable in published studies (Bergman et al., 2003, Cutolo et al., 2006, Lambova and Müller-Ladner, 2011, Nagy and Czirják, 2004).

The aims of the study were to evaluate the prevalence and evolution of scleroderma pattern in a large cohort of SSc patients and analyze their demographic, clinical and prognostic characteristics in relation to the capillaroscopic features.

Section snippets

Patients

Two hundred and seventy-five SSc patients, referred to our Rheumatologic Centre from February 2005 to October 2014, classified according to 2013 criteria (van den Hoogen et al., 2013), were retrospectively enrolled. All patients who underwent at least two nailfold videocapillaroscopy (NVC) during follow-up were enrolled in the study. Demographic, clinical, and serological data were collected for all patients at any NVC time. To calculate survival rates the vital status of all patients was

Results

Two hundred and twenty patients (80%) showed a scleroderma pattern at the moment of the first evaluation (group 1) (Fig. 1), while in 55 patients (20%) scleroderma pattern was not observed (group 2). Among group 2, 23 (41.8%) showed nonspecific alterations, while NVC was normal in the remaining 32 patients (58.2%).

Main clinical, serological and demographic features of the 275 SSc patients enrolled in the study are reported in Table 1.

No significant differences were observed for mean age at

Discussion

The present study evaluated for the first time the relationship between NVC features and clinical, demographic and laboratory characteristics on a large monocentric SSc population, although the retrospective collection of data may represent a limit.

Considering the whole follow-up, the frequency of scleroderma pattern in our population was 87.1%. Of interest, NVC pattern changed during follow-up in 11% of patients, confirming that microangiopathy is a dynamic process during the disease (Cutolo

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Cited by (25)

May capillaroscopy be a candidate tool in future algorithms for SSC-ILD: Are we looking for the holy grail? A systematic review
2020, Autoimmunity Reviews
Citation Excerpt :
Though an important study, it was excluded from this very systematic review as the relationship between NVC and incident SSc-ILD had not been analysed separately from progressive SSc-ILD [21]. And lastly, the fourth longitudinal study by Ghizzoni et al., was excluded as the study population was enrolled retrospectively [56]. This systematic literature review, on behalf of the EULAR Study Group on Microcirculation in Rheumatic Diseases, is the first to investigate associations between NVC and SSc-ILD in a standardised way. (
To investigate whether nailfold videocapillaroscopy (NVC), an increasingly worldwide used non-invasive tool to reliably evaluate the peripheral microcirculation, may be an outcome measure in future screening algorithms for systemic sclerosis related interstitial lung disease (SSc-ILD).
A systematic review to identify original research papers documenting an association between NVC and SSc-ILD was performed in 3 electronic databases according to the PRISMA guidelines. Subsequently, NVC parameters were subdivided according to the consented standardised capillaroscopic definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases / Scleroderma Clinical Trials Consortium on Capillaroscopy, into quantitative (capillary density, capillary dimension, capillary morphology and haemorrhages) and qualitative assessment (NVC pattern).
The systematic search identified 310 unique search results, of which 2 cross-sectional and 1 longitudinal study were retained. In both cross-sectional studies, the presence of SSc-ILD was found to be inversely associated with capillary density (p = .008 and p = .005). The presence of a severe (active/late) NVC pattern was evaluated and associated with the presence of SSc-ILD in one of the cross-sectional studies. In the longitudinal study, incident SSc-ILD was associated with progressive capillary loss (p = .03) and the conversion to a worse (active/late) NVC pattern (p = .001/p = .003).
This first systematic literature review investigating the role of NVC in SSc-ILD using standardised capillaroscopic definitions uncovered associations between NVC and (incident) SSc-ILD. If large prospective studies further corroborate and elucidate these findings, NVC might possibly be a candidate outcome measure to be integrated in screening algorithms for incident/progressive SSc-ILD.
Segmenting nailfold capillaries using an improved U-net network
2020, Microvascular Research
To assess the microcirculation in a patient's capillaries, clinicians often use the valuable and non-invasive diagnostic tool of nailfold capillaroscopy (NC). In particular, evaluating the images that result from NC is particularly important for diagnosing diseases in which the capillary morphology is altered. However, NC images are generally of poor quality, such that analyzing them is difficult and time consuming. Thus, the purpose of this work was to determine a way to segment the capillaries in poor-quality NC images accurately. To do this, we proposed using a deep neural network with a Res-Unet structure. The network combines the residual network (ResNet) and the U-Net to establish an encoding-decoding network and to deepen the layers in the network to preserve the features of the deep layer. The network was trained on 30 nailfold capillary images to discriminate the pixels belonging to capillaries, and it was then tested on a dataset consisting of 20 images to achieve a binarized map. The mean accuracy was 91.72% and the mean Dice score was 97.66% compared to the ground truth, which indicates that using Res-Unet to perform capillary segmentation in NC images had good performance.
Imbalanced serum levels of Ang1, Ang2 and VEGF in systemic sclerosis: Integrated effects on microvascular reactivity
2019, Microvascular Research
Citation Excerpt :
It leads to loss of endothelium integrity with ECs detachment and in consequence to deformations of microvessels with significant enlargement of the capillaries followed by capillary collapse and rarefaction (Altorok et al., 2014; Cutolo and Sulli, 2015; Fleming and Schwartz, 2008; Freemont et al., 1992; Kahaleh, 2008; Manetti et al., 2010; Matucci-Cerinic et al., 2017). These specific sequential abnormalities in microcirculation are reflected by nailfold videocapillaroscopy (NVC) morphological changes in form of enlarged loops/giants, capillary crush with microhaemorrhages and capillary loss (Cutolo et al., 2004, 2013, 2018; Ghizzoni et al., 2015; Smith et al., 2016a, 2016b). Decreased blood flow and tissue hypoxia normally stimulates angiogenesis with the formation of new capillaries from pre-existing vessels; however in SSc subsequent proangiogenic efforts lead to chaotic and insufficient vascular regeneration that finally evolves towards progressive microvascular loss further exacerbated by extracellular matrix (ECM) accumulation and progressive fibrosis (Distler et al., 2006; Kuwana et al., 2004; Manetti et al., 2010, 2016; Matucci-Cerinic et al., 2017; Mulligan-Kehoe and Simons, 2008).
Microangiopathy is a hallmark of systemic sclerosis (SSc). It is a progressive process from an early inflammatory and proangiogenic environment to insufficient microvascular repair with loss of microvessels. The exact underlying mechanisms remain ill-defined. Aim of the study was to investigate whether imbalanced angiopoietins/VEGF serum profile should be related in SSc to the altered microvascular reactivity characterized by aberrant angiogenesis and avascularity.
Serum levels of Angiopoietin-1 (Ang1), Angiopoietin-2 (Ang2) and VEGF were measured by ELISA in 47 SSc patients and 27 healthy controls. Microvascular alterations were assessed by nailfold videocapillaroscopy (NVC).
Serum concentrations of Ang1 were significantly lower [mean (S.D.): 21516.04 (11,441.035) pg/ml], and Ang2 significantly increased [25,89.55 (934.225) pg/ml] in SSc as compared with the control group [Ang1: 28,457.08 (10,431.905) pg/ml; Ang2: 1556.23 (481.255) pg/ml, p < 0.01, respectively], whereas VEGF did not differ significantly. The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004]. Formation of giant capillaries with vascular leakage and collapse was associated with significant increase in VEGF and concomitant Ang1 deficiency. Capillary loss was related to significant increase in VEGF with respect to those with preserved capillary number (395.12 ± 256.27 pg/mL vs. 254.80 ± 213.61 pg/mL) whereas elevated Ang2 levels induced more advanced capillary damage as indicated by the presence of the “Late” NVC pattern.
We found that serum levels of Ang1, Ang2 and VEGF are differentially expressed in SSc and altered Ang1/Ang2 profile might underlay the aberrant angiogenesis in SSc despite increase in VEGF. For the first time we identified that significant deficiency of Ang1 might be involved in early capillary enlargement, followed by collapse and lack of stable newly-formed vessels in VEGF-enriched environment, whereas Ang2 levels seem to increase later in disease progression and advanced microvascular damage (“Late” NVC pattern).
Does nailfold capillaroscopy help predict future outcomes in systemic sclerosis? A systematic literature review
2018, Seminars in Arthritis and Rheumatism
Citation Excerpt :
Subsequent studies have identified associations between NC changes and a number of clinical features including cardiopulmonary disease [14], digital ulcers (DU) [15], calcinosis cutis [16], telangiectases [17], acro-osteolysis [16], and others [18]. A number of cross-sectional studies reporting associations between NC appearances and clinical phenotype have speculated about the prognostic and/or predictive value of NC in SSc but lacked longitudinal assessments to confirm this [14,15,18,19]. Prognostic studies seek to predict future outcomes in individuals based on clinical and non-clinical factors [20].
Nailfold capillaroscopy (NC) is an important diagnostic tool in systemic sclerosis (SSc). Confirmation of NC as a prognostic factor could facilitate earlier intervention and slow disease progression in SSc. We undertook a systematic literature review to evaluate the prognostic value of NC in predicting SSc disease progression.
Standardised searches of EMBASE and MEDLINE were undertaken to identify longitudinal studies of adult subjects with SSc reporting the prognostic value of NC for any aspect of disease progression and/or survival. Non-English, non-original research, animal studies, non-adult studies and non-full length reports were excluded from the analysis (PROSPERO 2017:CRD42017071719). Wide heterogeneity in study design, prognostic factor measurement and study outcomes necessitated a qualitative data synthesis. The “QUality In Prognosis Studies” (QUIPS) risk-of-bias tool was used to assess study quality. Study selection, data extraction and risk-of-bias assessment were each undertaken independently by 2 reviewers and consensus reached where necessary.
Of 942 retrieved articles, 18 studies fulfilled the inclusion criteria. The majority of studies (17/18, 94%) reported positive associations between baseline NC appearances (using a variety of qualitative, semi-quantitative and quantitative NC endpoints) and clinical outcomes including digital ulcer (DU) occurrence/healing, survival, disease progression (using domains of Medsger disease severity scale), calcinosis, skin progression, pulmonary arterial hypertension (PAH), and/or a composite analysis of “cardiovascular events”. Application of the QUIPS tool identified a moderate-high risk of potential bias in 6/18 studies for study participation, 3/18 studies for study attrition, 10/18 for prognostic factor measurement, 5/18 for outcome measurement, 13/18 for confounders and 13/18 for statistical analyses. Study quality limited the strength of the conclusions drawn from these studies. The most important source of potential bias across the studies was insufficient adjustment for potential confounders; such as existing DU disease in studies evaluating future DU occurrence. Recent work suggests NC evolution is an important predictor of disease progression in SSc.
High levels of potential bias relating to study confounding and statistical analysis make it difficult to draw conclusions regarding the prognostic role of NC in SSc. There is strong evidence supporting an association between NC abnormalities (particularly capillary loss) and disease severity (particularly vascular manifestations such as DU, calcinosis and PAH). Evolution of NC appearances may represent a more important predictor of disease progression which could have important implications for the future use of NC in the routine longitudinal assessment and management of SSc.
Capillary density: An important parameter in nailfold capillaroscopy
2017, Microvascular Research
Nailfold capillaroscopy is one of the various noninvasive bioengineering methods used to investigate skin microcirculation. It is an effective examination for assessing microvascular changes in the peripheral circulation; hence it has a significant role for the diagnosis of Systemic sclerosis with the classic changes of giant capillaries as well as the decline in capillary density with capillary dropout. The decline in capillary density is one of microangiopathic features existing in connective tissue disease. It is detectable with nailfold capillaroscopy. This parameter is assessed by applying quantitative measurement. In this article, we reviewed a common method for calculating the capillary density and the relation between the number of capillaries as well as the existence of digital ulcers, pulmonary arterial hypertension, autoantibodies, scleroderma patterns and different scoring system.
Specific Autoantibodies and Microvascular Damage Progression Assessed by Nailfold Videocapillaroscopy in Systemic Sclerosis: Are There Peculiar Associations? An Update
2023, Antibodies
Background: Specific autoantibodies and nailfold videocapillaroscopy (NVC) findings are serum and morphological diagnostic hallmarks of systemic sclerosis (SSc) as well as useful biomarkers which stratify the microvascular progression and prognosis of patients. Methods: The aim of our narrative review is to provide an update and overview of the link between SSc-related autoantibodies, used in clinical practice, and microvascular damage, evaluated by NVC, by exploring the interaction between these players in published studies. A narrative review was conducted by searching relevant keywords related to this field in Pubmed, Medline and EULAR/ACR conference abstracts with a focus on the findings published in the last 5 years. Results: Our search yielded 13 clinical studies and 10 pre-clinical studies. Most of the clinical studies (8/13, 61.5%) reported a significant association between SSc-related autoantibodies and NVC patterns: more specifically anti-centromere autoantibodies (ACA) were associated more often with an “Early” NVC pattern, whereas anti-topoisomerase autoantibodies (ATA) more frequently showed an “Active” or “Late” NVC pattern. Five studies, instead, did not find a significant association between specific autoantibodies and NVC findings. Among the pre-clinical studies, SSc-related autoantibodies showed different mechanisms of damage towards both endothelial cells, fibroblasts and smooth muscle vascular cells. Conclusions: The clinical and laboratory evidence on SSc-related autoantibodies and microvascular damage shows that these players are interconnected. Further clinical and demographic factors (e.g., age, sex, disease duration, treatment and comorbidities) might play an additional role in the SSc-related microvascular injury whose progression appears to be complex and multifactorial.

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^☆: The authors declare no financial support or other benefits from commercial sources for the work reported in the manuscript, or any other financial interests that any of the authors may have, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work.

¹: Cecilia Ghizzoni and Marco Sebastiani equally contributed to the article.

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Prevalence and evolution of scleroderma pattern at nailfold videocapillaroscopy in systemic sclerosis patients: Clinical and prognostic implications☆

Highlights

Abstract

Background

Aim

Methods

Results

Introduction

Section snippets

Patients

Results

Discussion

Autoimmun. Rev.

Microvasc. Res.

Microvasc. Res.

Microvasc. Res.

Am. J. Med. Sci.

Practical Statistics for Medical Research

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group

Ann. Rheum. Dis.

The handheld dermatoscope as a nailfold capillaroscopic instrument

Arch. Dermatol.

Skin capillaries in scleroderms

Arch. Intern. Med.

Quantitation of microcirculatory abnormalities in patients with primary Raynaud's phenomenon and systemic sclerosis by video capillaroscopy

Rheumatology (Oxford)

Serological markers in progressive systemic sclerosis: clinical correlations

Ann. Rheum. Dis.

Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis

J. Rheumatol.

Capillaroscopy and rheumatic diseases: state of the art

Z. Rheumatol.