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Rheumatology Advance Access originally published online on August 10, 2007
Rheumatology 2007 46(10):1566-1569; doi:10.1093/rheumatology/kem190
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity

P. Caramaschi, S. Canestrini, N. Martinelli, A. Volpe, S. Pieropan, M. Ferrari1, L. M. Bambara, A. Carletto and D. Biasi

Dipartimento di Medicina Clinica e Sperimentale and 1Dipartimento di Scienze Biomediche e Chirurgiche - Universitá di Verona, Italy.

Correspondence to: Paola Caramaschi, Dipartimento di Medicina Clinica e Sperimentale, Policlinico G.B. Rossi, P.le Scuro, 37134 Verona, Italy. E-mail: paola.caramaschi{at}azosp.vr.it


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate in a large group of scleroderma patients, the association of nailfold videocapillaroscopic patterns with both demographic and clinical features.

Methods. One hundred and three Italian patients (91 women and 12 men, mean age 54.3 years, median disease duration 7 yrs, 68 with limited and 35 with diffuse subset of disease), consecutively enrolled for the study, underwent nailfold videocapillaroscopy; the microvascular alterations were classified into three different patterns, early, active and late. The nailfold videocapillaroscopic patterns were correlated with such numerous clinical features as sex, age, disease duration, disease subset, disease activity, haematochemical data, involvement of skin, heart, lung and peripheral vessels.

Results. Nailfold videocapillaroscopic patterns were significantly associated with disease subsets (P = 0.018). Severity of skin, lung, heart and peripheral vascular involvement progressively increased across nailfold videocapillaroscopic patterns, from early to late pattern (P < 0.001 for cutaneous and peripheral vascular involvement; P = 0.003 and 0.002 for lung and heart involvement, respectively) as well as homocysteine plasma levels (P = 0.02). Patients with late pattern showed an increased risk to have an active disease [OR (odds ratio) 3.50; 95% CI (confidence interval) 1.31–9.39], to present digital ulcers (OR 5.74; 95% CI 2.08–15.89) and moderate to severe skin (OR 5.28; 95% CI 1.93–14.19), heart (OR 5.75; 95% CI 2.04–16.21) and lung involvement (OR 4.41; 95% CI 1.63–11.92).

Conclusions. Our study showed that scleroderma microangiopathy correlates with disease subset and severity of peripheral vascular, skin, heart and lung involvement; patients with late pattern showed an increased risk to have an active disease and to show a moderate/severe skin or visceral involvement compared to patients with early and active patterns. Therefore nailfold videocapillaroscopy, a simple, non-invasive and non-expensive investigation, is useful in staging scleroderma patients and also provides prognostic information.

KEY WORDS: Systemic sclerosis, nailfold videocapillaroscopy


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc) is a multisystemic disorder of the connective tissue, characterized by microvascular damage with associated cutaneous and internal organ fibrosis and specific immunologic abnormalities. The clinical expression, severity and progression are rather heterogeneous; the disease may progress very slowly with no or mild visceral injury, whereas sometimes it dramatically evolves with early severe organ damage [1].

The pathogenesis of SSc is very complex and still largely unknown [2], but vascular perturbation is supposed to be a primary event, which may trigger and drive the fibrotic process. Several factors have been incriminated as possible triggering agents of vascular injury such as anti-endothelial antibodies [3], mechanisms of molecular mimicry [4], microchimerism phenomenon [5] and oxidative stress [6].

Histopathological hallmarks of SSc are perivascular infiltrates and a reduced capillary density, which precede the excessive accumulation of extracellular matrix proteins. The peculiar vascular involvement affects primarily small arteries and capillaries and causes reduced blood flow and tissue ischaemia, supporting the typical clinical manifestations of this unique autoimmune disorder.

Nailfold videocapillaroscopy (NVC) is a suitable tool for the assessment of SSc microvasculopathy [7–9]; the aim of the present study was to evaluate the association between nailfold videocapillaroscopic patterns with both clinical manifestations and haematochemical data in a large group of SSc patients.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Study population
One hundred and three Italian patients (91 women and 12 men, mean age 54.3 ± 13.6 yrs, median disease duration 7 yrs with minimum–maximum range 1–46 yrs) were consecutively enrolled for the study between January and May 2006. All patients fulfilled the American College of Rheumatology criteria for the diagnosis of SSc [10]. The distinction between limited cutaneous SSc (lSSc) and diffuse cutaneous SSc (dSSc) was made according to the criteria of LeRoy et al. [11]. All the patients gave written informed consent.

Patients were receiving a wide range of drugs, including vasodilators (101 patients), cyclophosphamide (9 patients), low dose prednisolone (<10 mg/day) (23 patients), aspirin (77 patients) and H2-receptor antagonists (83 patients).

Patients underwent examination and laboratory evaluation comprehensive of full blood count, ESR, renal and liver function indexes, fasting total homocysteine, antinuclear and anti-ENA antibody determination. Homocysteine levels were determined by high-performance liquid chromatography method with fluorescent detection [12] (normal <15 µmol/l). Anticentromere antibodies (ACA) were tested by indirect immunofluorescence on HEp-2 cells; anti-Scl70 antibodies were determined by ELISA.

Skin, vascular, lung and heart involvement
In all the patients skin involvement was assessed by the modified Rodnan skin score (mRSS) [13].

The same operator evaluated peripheral vascular involvement in agreement with criteria proposed by Medsger et al. [14].

All the patients underwent the following instrumental investigations: electrocardiogram; chest radiograph; pulmonary function test with diffusing capacity for carbon monoxide (DLCO) adjusted to haemoglobin; Doppler echocardiogram to evaluate left ventricular ejection fraction and to estimate pulmonary artery systolic pressure (sPAP); estimated sPAP was considered abnormal if ≥35 mmHg. Pulmonary and cardiac involvement was then evaluated based on a severity scale classification proposed by Medsger et al. [14]. The disease activity was assessed according to Valentini et al. [15].

The same operator, blind to clinical features, performed NVC in all the patients, using an optical probe videocapillaroscopy equipped with 100x and 200x contact lenses and connected to an image analysis software (Videocap; DS MediGroup, Milan, Italy). The microvascular alterations were classified into three different patterns—early, active and late—according to Cutolo et al. [16].

All investigations were performed at our hospital as part of the normal clinical evaluation of our SSc patients.

Statistical analysis
All the analyses were performed with SSPS 13.0 statistical package (SPSS Inc., Chicago, IL, USA). Distribution of continuous variables in groups was expressed as mean ± S.D. Logarithmic transformation was performed for skewed variables, i.e. for homocysteine levels; therefore this variable was expressed as geometric mean with 95% confidence interval (CI) and the statistical differences concerning this parameter were also computed on the corresponding log-transformed values.

Quantitative data were assessed using the Student's t-test or by ANOVA with Tukey's post hoc comparison of the means and with polynomial contrasts analysis for linear trend, when indicated. Associations between qualitative variables were analysed with the chi-square ({chi}2) test, {chi}2-test for linear trend or Fisher exact-test, when indicated. To assess the association between NVC patterns and disease severity/organ involvement, odds ratio (OR) with 95% CI was also calculated by univariate logistic regression analysis, comparing patients with most severe pattern, the late pattern, with those with a less advanced pattern, i.e. early and active.

A value of P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Demographic and clinical characteristics of SSc patients
The clinical characteristics of the 103 patients are summarized in Table 1.


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  		TABLE 1. Clinical and laboratory characteristics of the 103 enrolled patients affected by systemic sclerosis [data expressed as absolute number (%) unless otherwise indicated]

 
NVC pattern and clinical and laboratory phenotypes
Thirty-six subjects (34.9%) had an early, 45 (43.7%) an active and 22 (21.4%) a late NVC pattern (Table 1). Table 2 shows the characteristics of patients on the basis of NVC pattern. Because of the low number of patients with a severe lung or heart involvement, we grouped them together with those with a moderate involvement.


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  		TABLE 2. Clinical and laboratory characteristics on the basis of nailfold videocapillaroscopic pattern [data expressed as absolute number (%) unless otherwise indicated]

 
NVC was significantly associated with SSc subset (P = 0.018 by {chi}2-test), with early and active pattern more present among patients with lSSc, whereas the late pattern was more represented among patients with dSSc. Furthermore, subjects with late pattern were more represented among patients with active disease (OR 3.50; 95% CI 1.31–9.39).

There was a highly significant correlation of NVC pattern with skin involvement evaluated by mRSS, which progressively increased from early to late pattern (P < 0.001 by ANOVA with polynomial contrasts analysis for linear trend). Considering a threshold level for the mRSS value, patients with late pattern had an increased risk of high mRSS, i.e. ≥15 (OR 5.28; 95% CI 1.93–14.49, P = 0.001 by {chi}2-test).

The NVC pattern was highly significantly associated also with peripheral vascular involvement, as well as with digital ulcers (P < 0.001 by {chi}2-test in both the analyses). The severity of vascular involvement progressively increased by the worsening of NVC pattern ({chi}2 for linear trend = 19.298, P < 0.001) and patients with late pattern had a markedly increased risk of digital ulcers (OR 5.74; 95% CI 2.08–15.89, P < 0.001 by {chi}2-test).

Similarly, across the NVC patterns—from early to late pattern, the severity of lung and of heart involvement progressively increased ({chi}2 for linear trend = 8.673, P = 0.003 and {chi}2 for linear trend = 10.539, P = 0.002, respectively). Patients with late pattern had an increased risk of moderate-severe lung involvement (OR 4.41; 95% CI 1.63–11.92), as well as of moderate-severe heart involvement (OR 5.75; 95% CI 2.04–16.21). Remarkably, we noted a significant trend of DLCO and forced vital capacity (FVC) levels across NVC patterns with the lowest values in the late pattern (P < 0.001 and P = 0.010 by ANOVA with polynomial contrasts analysis for linear trend, respectively). Furthermore, the late pattern was associated with an increased risk of interstitial lung disease (ILD) at chest radiography evaluation (OR 3.62; 95% CI 1.28–10.21).

Finally, we found a significant correlation between NVC pattern and plasma homocysteine concentration that progressively increased from the early to the late pattern (P = 0.020 by ANOVA with polynomial contrasts analysis for linear trend).

No significant differences were found for the distribution of sex, age, disease duration, autoantibody profile, estimated sPAP, haemoglobin, ESR and creatinine levels across NVC patterns; patients with late pattern tended to be older and to have a longer disease duration than those with early and active pattern although the difference did not reach a statistical significance.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
NVC is a simple, non-invasive and non-expensive investigation to assess capillary morphology; it has recently become an useful tool to diagnose and to follow-up microangiopathy in SSc patients. The classification of NVC abnormalities in three pattern—early, active and late—is relatively recent [16]; longitudinal studies will show if the three patterns are consecutive steps of the microvascular scleroderma damage.

At present, very few studies have correlated NVC patterns with demographic and clinical features of SSc patients. It has been reported that late NVC pattern is related to the age of patients and the disease duration [16, 17] as well as to the diffuse pattern of the disease [17]; moreover anti-Scl70 antibodies seem to be more frequent in patients with active and late patterns than in those with early NVC pattern [17]. The present study confirms a correlation between late NVC pattern and diffuse subset of disease; on the contrary no correlation has been found between NVC pattern and autoantibody profile. Patients with late NVC pattern were older and had a longer disease duration in comparison with patients with early and active pattern, but the difference did not reach statistical significance.

Differently from the previous studies, we have taken into consideration not only demographic features, autoantibody profile and SSc subset, but also clinical characteristics in relation to NVC pattern. We found out that the progression of skin, lung, heart and peripheral vascular involvement were all related to the worsening of microangiopathy as directly assessed by NVC. The correlation between NVC patterns and clinical manifestations of SSc may be due to common pathogenetic mechanisms, involving microvasculature at different levels and supports the concept that microvessel injury is the pivotal lesion of the complex pathogenesis of the disease. As expected, a very strong correlation was found between NVC pattern and digital ulcers, a severe manifestation of peripheral vascular involvement that heavily affects the quality of life.

Moreover, a strong correlation was observed between NVC pattern and DLCO; either ILD or pulmonary hypertension impair DLCO; it was also suggested that isolated DLCO reduction might be indicative of lung microangiopathy [18]. A positive correlation between a component of DLCO—the diffusing capacity of the alveolocapillary membrane—and NVC abnormalities was previously reported [19].

Moreover, the disease activity was more frequent in patients with late NVC pattern than in patients with early-active NVC abnormalities.

The factors responsible for the different expression of the disease are largely unclear; it is known that the autoantibody profile is associated with disease subset, race, age and some clinical manifestations as digital ulcers, ILD and renal crisis [20]. Besides autoantibodies, several prognostic markers are available in order to predict survival and risk of visceral involvement. The extent of skin sclerosis is a relevant factor in the prognosis, having been associated with both severe morbidity and survival [21]. Serum levels of soluble adhesion molecules as VCAM-1 and E-selectin have been reported to be useful markers for monitoring clinical progression because they reflect disease severity [22]; then, serum levels of surfactant protein-D and KL-6 are associated to the risk of ILD [23, 24]. Nevertheless, to our knowledge, there is not any parameter correlating with the most relevant clinical features of SSc; some prognostic markers are useful to predict a single clinical expression of the disease [25]. Our study showed that NVC patterns were correlated with the principal SSc manifestations and among these lung and heart involvement heavily weighs on mortality. Therefore, besides diagnostic role, NVC could acquire prognostic relevance in the global assessment of a single patient. Prospective studies are necessary to evaluate if NVC may influence therapeutic choices.

Concerning haematochemical parameters, we observed a progressive increase of homocysteine plasma levels from early to active and above all to late NVC pattern. In SSc, hyperhomocysteinaemia may represent an aggravating factor able to worsen the clinical course of the disease through the multiple pathways by which homocysteine alters the normal properties of vascular system; hyperhomocysteinaemia may further weigh on the SSc vascular dysfunction negatively interfering with the delicate regulation of vascular tone and may strengthen the injury caused by oxidative stress [26, 27].

In conclusion, our study showed that in SSc patients microvessel damage, as directly observed by NVC, is related to disease subset and disease severity affecting different sites as peripheral circulation, skin, heart and lung; patients with late pattern showed an increased risk to have an active disease and to be affected by a moderate/severe skin or visceral involvement, compared to patients with early and active patterns. Therefore, this simple tool helps to staging the patient affected by SSc and provides prognostic information.

The authors have declared no conflicts of interest.

Formula


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum (2000) 43:2437–44.[CrossRef][Web of Science][Medline]
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Submitted 27 February 2007; revised version accepted 20 June 2007.
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This Article
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