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Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients
  1. A Sulli1,
  2. B Ruaro1,
  3. E Alessandri1,
  4. C Pizzorni1,
  5. M A Cimmino1,
  6. G Zampogna1,
  7. M Gallo2,
  8. M Cutolo1
  1. 1Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy
  2. 2Department of Internal Medicine, University of Genova, Genova, Italy
  1. Correspondence to Maurizio Cutolo, Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, no 6, Genova 16132, Italy; mcutolo{at}unige.it

Abstract

Objective The aim of this study was to identify possible correlations between nailfold microangiopathy severity, finger dermal thickness (DT) and fingertip blood perfusion (FBP) in systemic sclerosis (SSc) patients.

Methods Fifty-seven SSc patients and 37 healthy subjects were enrolled. All patients were evaluated by nailfold videocapillaroscopy (NVC) to classify and score the severity of microangiopathy. Both modified Rodnan skin score (mRss) and skin high-frequency ultrasound were used to detect finger DT. Laser Doppler flowmetry (LDF) was employed to detect FBP.

Results A positive correlation was found between nailfold microvascular damage severity and both ultrasound-DT (p=0.028) and mRss values (p<0.0001). In particular, both ultrasound-DT and mRss were found progressively higher in patients with ‘Early’, ‘Active’ or ‘Late’ NVC pattern of microangiopathy. A negative correlation was observed between nailfold microvascular damage severity and FBP (p<0.0001), showing the lowest FBP of the patients with more advanced NVC patterns. A negative correlation was observed between FBP, and both ultrasound-DT (p=0.007) and mRss values (p=0.0002). SSc patients showed a higher ultrasound-DT at the level of the fingers, as well as a lower FBP than healthy subjects (p<0.0001).

Conclusions This study demonstrates a relationship between nailfold microangiopathy severity, DT and FBP in SSc patients.

  • Systemic Sclerosis
  • Ultrasonography
  • Disease Activity

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Introduction

Peripheral microangiopathy is a dynamic event in systemic sclerosis (SSc), it being one of the best evaluable predictors of the disease development.1 It may be easily recognised and studied by nailfold videocapillaroscopy (NVC) that allows to classify and score the different patterns of microvascular damage.2–4 Laser Doppler flowmetry (LDF) can be carried out to assess and measure the blood perfusion at peripheral sites, and may correlate in SSc with microvascular damage as assessed by NVC.5

The modified Rodnan skin score (mRss) is employed to evaluate the severity of skin involvement.6 ,7 However, this method cannot identify slight alterations in dermal thickness, and has high intraobserver and interobserver variability.8 Several studies have reported the utility of high-frequency ultrasound in the early identification of the oedematous phase that may precede palpable skin involvement in SSc patients as well as its capability to reflect the overall severity of the skin involvement.9–11

The aim of this study was to identify possible correlations between nailfold microangiopathy severity, finger dermal thickness (DT) and fingertip blood perfusion (FBP) in SSc patients.

Patients and methods

Fifty-seven SSc patients were enrolled (six males and 51 females, mean age 63±10 SD years), after written informed consent to enter the study had been obtained. SSc patients met either the ACR criteria for SSc, or the Le Roy's criteria for the classification of early SSc.12 A healthy control group of 37 subjects was also evaluated (four males and 33 females, mean age 61±14 years). One and two smokers, respectively, were found in SSc patients and control subjects.

A complete medical history and clinical examination, including Raynaud's phenomenon and SSc duration and the modified Rodnan skin score (mRss), were carried out for all patients, and the presence of either limited (lcSSc) or diffuse (dcSSc) skin involvement was recorded. All SSc patients were taking aspirin. Several patients were taking prostanoids and/or endothelin-1 receptor antagonists on a cycle-based administration. Instrumental assessments were done during the treatment-free period of at least 1 month. Any patients on other drugs that could potentially influence blood perfusion were excluded from the study.

Nailfold videocapillaroscopy

NVC was performed in each patient to assess morphological microvascular damage using a videocapillaroscopy optical probe, equipped with a 200× contact lens, connected to image analysis software (Videocap, DS Medica, Milan, Italy). The same operator performed the NVC examination in all SSc patients, according to previous published methods.1–4 Each capillary abnormality was scored by a validated semiquantitative rating scale by considering the average of eight fingers.3 ,13 The appropriate NVC pattern of microangiopathy was assigned to the SSc patients on the basis of their nailfold capillary abnormalities: ‘Early’ NVC pattern (11 patients), ‘Active’ NVC pattern (20 patients), and ‘Late’ NVC pattern (26 patients).2–4 In addition, the microangiopathy evolution score (MES) was also calculated as previously reported.3 ,4

High-frequency ultrasound and modified Rodnan skin score (mRss)

High-frequency ultrasound was performed in both SSc patients and controls to evaluate DT (ultrasound-DT) at the level of the dorsum of the middle phalanx of the third finger on both the right and left hands, and the average value was recorded in millimetres. A My Lab 25 ultrasound system equipped with an 18 MHz probe was used (Esaote, Genoa, Italy). The same operator performed the ultrasound in all subjects, and after blind double assessment of pictures the intraoperator reproducibility was 95%.

DT was also assessed by mRss in SSc patients at the level of the dorsum of the fingers bilaterally, as reported in the literature, and the average score of the fingers was calculated.6 ,10 ,14

Laser Doppler flowmetry

LDF was performed in both SSc patients and controls to analyse the FBP by the Periflux System 5000, equipped with a thermostatic probe (Perimed, Milan, Italy). The patients stayed in a waiting room at 23–24°C for at least 30 min before the assessment. FBP was detected at the level of the fingertips bilaterally, as previously reported.5 The results were expressed as perfusion units (PU). The same operator performed the examination, and there was a 92% reproducibility of the LDF assessment.

Statistical analysis

Statistical analysis was carried out by parametric procedures, and confirmed by non-parametric tests. Student's t test, not assuming equal variances, and Mann–Whitney U test, were performed to compare unpaired groups of variables, and Kruskal–Wallis test was used to compare continuous variables with nominal variables with more than two levels. Multiple and linear regression, along with Spearman's rank correlation tests, were employed to search for possible relationships between variables. p Values lower than 0.05 were considered statistically significant. Results are given as mean±SD, along with mean differences, correlation coefficients and 95% lower and 95% upper CIs to report effect sizes.

Results

Ultrasound-DT was found progressively higher in SSc patients with the ‘Early’, ‘Active’ and ‘Late’ NVC patterns of microangiopathy (see table 1 for statistical significance, mean differences and 95% lower and 95% upper CIs). Furthermore, there was a statistically significant positive correlation between MES and ultrasound-DT (see figure 1 for statistical significance, correlation coefficient and CIs). A positive correlation was also found between MES and mRss (figure 1), as well as mRss was found progressively higher in patients with ‘Early’, ‘Active’ and ‘Late’ patterns of microangiopathy (table 1).

Table 1

Clinical findings in systemic sclerosis (SSc) patients and control subjects (CNT)

Figure 1

Correlation between nailfold microangiopathy severity, fingertip blood perfusion (FBP), and dermal thickness evaluated by both high-frequency ultrasound (ultrasound-DT) and modified Rodnan skin score (mRss). MES, microangiopathy evolution score; r, correlation coefficient.

A progressive decrease of FBP was observed in patients with different pattern of microangiopathy, namely ‘Early, ‘Active’ and ‘Late’ (table 1). In addition, a statistically significant negative correlation was found between MES and FBP degree (figure 1).

A negative correlation was observed in SSc patients between FBP and ultrasound-DT, as well as between FBP and mRss (figure 1).

Correlations between other variables are reported in figure 2. Differences between dcSSc and lcSSc patients concerning ultrasound-DT, mRss, MES and FBP are reported in table 1, as well as differences between SSc patients and controls.

Figure 2

Correlation between dermal thickness (DT), evaluated by both high-frequency ultrasound (ultrasound DT, as millimetre) and modified Rodnan skin score (mRss) with duration of both Raynaud's phenomenon (RP) and systemic sclerosis (SSc). Correlation between left and right third finger for ultrasound-DT and fingertip blood perfusion (FBP, as perfusion units) are also reported.

Intraoperator variability in assessing DT by high-frequency ultrasound technique was 5%.

Discussion

This study reports relationships between nailfold microangiopathy and both skin thickness and peripheral blood perfusion in SSc patients. In particular, present results show that nailfold microangiopathy severity, evaluated by NVC, correlates positively with DT, as detected by both high-frequency ultrasound and mRss, and negatively with FBP. This is a valuable observation since the degree of microvascular involvement has already been correlated with internal organ involvement in SSc patients.4 ,15 ,16 In particular, SSc clinical symptoms have been found to progress together with the microvascular nailfold changes, and a predictive value of baseline NVC patterns for future severe organ involvement was shown, with stronger odds according to worsening scleroderma patterns.4 ,16 ,17

In this study, a decrease of FBP was observed in patients with progressive severity of microangiopathy, (from ‘Early’ to ‘Active’ and ‘Late’ NVC pattern) and higher microangiopathy evolution score; low FBP represents an additional risk factor for peripheral ischaemic lesions, most frequently observed in SSc patients with advanced microangiopathy.4 ,5

As a matter of fact, the continuous development of new ultrasound probes should improve the objective evaluation of skin thickness due to oedema and/or fibrosis in SSc patients, and ultrasound examination has been proposed as a non-invasive method to evaluate skin involvement in SSc clinical practice.10 Of note, DT may be related to either oedema or fibrosis, and the 18 MHz probe used in this study is insufficient to differentiate between the two clinical conditions. However, the differentiation between oedema and fibrosis by echography is actually a matter of discussion even by using transducers with higher frequency.11

Previous studies proved skin ultrasound to be a reliable tool with low interobserver and intraobserver variability.10 ,18 ,19 In agreement with these reports, our investigation confirms the low intraobserver variability of high-frequency ultrasound in measuring DT in SSc patients (5%). According to previous reports, only dermal thickness measurement was considered during high-frequency ultrasound assessment of SSc skin, because of the high variability of the epidermal thickness measurement.10 Interestingly, a positive significant correlation was found between skin ultrasound and mRss regarding DT in SSc patients.10 ,11

The present study demonstrates a lack of correlation between ultrasound-DT values and both SSc and RP duration.11 ,20

Patients with lcSSc showed lower DT, lower MES and higher FBP than those with diffuse SSc. This is of interest because even if this study did not evaluate possible associations between organ involvement and vascular/skin impairment, other investigations report that patients with lcSSc are likely to have less severe organ involvement (at least in the first years of the disease) than those with dcSSc. Independently from limited or diffuse disease subset, SSc patients with lower organ involvement are likely to have less severe nailfold microangiopathy extent as well as higher peripheral blood perfusion degree.4 ,5 ,15 ,16

A limitation of this study is that Raynaud's phenomenon severity was not assessed, and possible associations between this clinical entity and peripheral instrumental findings remain to be investigated.

In conclusion, this study demonstrates correlations between nailfold microangiopathy, DT and peripheral blood perfusion in SSc patients.

References

Footnotes

  • Handling editor Tore K Kvien

  • Contributors This manuscript has been seen and approved by all the authors who have devoted necessary attention to ensure the integrity of the work.

  • Competing interests None.

  • Ethics approval Institutional Review Board approval.

  • Provenance and peer review Not commissioned; externally peer reviewed.