Systemic sclerosis (SSc) is a diffuse fibrotising disease characterised by early vascular involvement. Raynaud’s phenomenon (RP) and digital ulcerations are characteristic clinical features together with capillary morphological abnormalities. Nailfold capillary changes in SSc may be easily investigated by nailfold capillary microscopy and many attempts were made in the last years to identify disease-specific capillary abnormalities, as well as to define specific capillaroscopic patterns of microangiopathy.1^–3 Recently, we described by nailfold videocapillaroscopy (NVC) three different patterns of microvascular damage (namely “scleroderma pattern”: “early”, “active” and “late”).4 5 As NVC has been proposed as an essential tool in evaluating the classification criteria for SSc, as well as an early diagnostic tool to differentiate between primary and secondary RP, the scoring of the capillary abnormalities has become of great importance.6 7 The aim of the present study was to define a scoring system to quantify the specific capillary abnormalities, as observed by NVC.

METHODS

Patients

Ninety patients with SSc (85 women, five men) (mean age 52 (13) years) were longitudinally evaluated by NVC for an average time of 72 (23) months (follow-up from 36 to 127 months).

The patients met the criteria for the classification of early SSc and were recruited from the Videocapillaroscopy Service for the Diagnosis of Vascular and Connective Tissue Diseases at the University of Genova.7 Informed consent was obtained from all patients.

Fifty-nine patients were found affected by limited cutaneous SSc (skin involvement of the fingers, hands, forearms, toes, feet, legs, neck and face), and 31 showed diffuse cutaneous SSc (skin involvement of arms, thighs, chest, abdomen and back).8

During the study, the patients were variably treated with iloprost or other vasodilators, low-dose aspirin, calcium channel blockers, proton pump inhibitors, non-steroidal anti-inflammatory drugs, as well as with immunosuppressive agents such as methotrexate (low dosage: 7.5–10 mg/week), or cyclosporin A (2.5–3 mg/kg). No systemic serious diseases other than SSc were found concomitant.

Nailfold videocapillaroscopy

The same operator performed the NVC in each patient every 6 months by using an optical probe videocapillaroscopy equipped with magnification 200× contact lens and connected to image analysis software (Videocap, DS MediGroup, Milan, Italy). The same operator performed the NVC examination during follow-up, without information of previous scores, or patient clinical conditions. At the end of the collection, images were scored for each patient at baseline and at the end of follow-up and results separately, also controlled by two further experts. Briefly, each subject was inside the building for a minimum of 15 min before the nailfold was examined and the room temperature was 20–22°C. The nailfold (distal row) of the second, third, fourth and fifth finger was examined in each patient.

The following capillaroscopic parameters were considered according to previous observations: presence of enlarged and giant capillaries, haemorrhages, loss of capillaries, disorganisation of the microvascular array, and capillary ramifications.5 9 The above-mentioned parameters were defined as follows: (a) enlarged capillary: an increase in capillary diameter (homogeneous or irregular) >20 μm; (b) giant capillary: homogeneously enlarged loops with a diameter >50 μm; (c) microhaemorrhage: dark mass due to haemosiderin deposit; (d) loss of capillaries: reduction of the capillary number below normal range (the normal range was adopted from the literature: average of nine capillaries per linear millimetre, counted at distal row of the nailfold); (e) disorganisation of the microvascular array: irregular capillary distribution and orientation, together with shape heterogeneity of the loops; (f) capillary ramifications: branching, bushy or coiled capillaries, often originated from a single normal sized capillary.9^–11

Scoring system

A semiquantitative rating scale to score each capillary abnormality was adopted (0 = no changes, 1 = less than 33% of capillary alterations/reduction, 2 = 33–66% of capillary alterations/reduction, 3 = more than 66% of capillary alterations/reduction, per linear millimetre) according to previous studies.1 5 12 The mean score value for each capillaroscopic parameter was calculated from the analysis of four consecutive fields (one linear millimetre for each one) in the middle of the nailfold, in each digit; the average score values from the eight digits were added together, and the final value divided for eight fingers. The resulting value represents the score for each capillaroscopic parameter analysed (fig 1).

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Figure 1 The mean score value for each capillaroscopic parameter was calculated from the analysis of four consecutive fields (one linear millimetre for each one) in the middle of the nailfold, in each digit; the average score values from the eight digits (both hands together) were added together, and the final value divided for eight fingers. The resulting value represents the score for each capillaroscopic parameter.

Furthermore, three capillaroscopic parameters, namely the loss of capillaries, the disorganisation of the microvascular array and the capillary ramifications, were longitudinally evaluated by the semiquantitative scale (score 0–3 for every parameter), to assess the evolution of the SSc microvascular damage.5 The scores of these parameters were also added together to globally assess the variation of the SSc microangiopathy during the time (“microangiopathy evolution score”: score 0–9). The expression of these three nailfold capillary abnormalities was already found increased during the progression of SSc.4 5 Giant capillaries and haemorrhages were not considered of critical value in assessing the evolution of the SSc microangiopathy, as these abnormalities are evident only in the early stages of the disease and then disappear or become rare in the advanced stages.5

Autoantibody detection

Total antinuclear antibodies, as well as the antitopoisomerase I (anti-Scl70) and the anticentromere antibodies were searched in all patients. Antinuclear antibodies were detected by indirect immunofluorescence using HEp-2 cells as substrate (Euroimmun, Luebeck, Germany). Anti-Scl70 antibodies and anticentromere antibodies were evaluated using an enzyme-linked immunosorbent assay (Euroimmun).

Statistical analysis

The statistical analysis was carried out by non-parametric tests. Wilcoxon test was performed to compare the paired groups, and Mann–Whitney U test to compare the unpaired groups of variables. Regression and Spearman rank tests were used to evaluate any possible correlation between continuous variables. p<0.05 was considered statistically significant.

RESULTS

At the end of the follow-up, the score for each NVC parameter significantly changed. The variation of the score of the six capillaroscopic parameters is reported in table 1, along with statistical significances.

In particular, the scores of the following parameters: irregularly enlarged capillaries, loss of capillaries, disorganisation of the microvascular array, and capillary ramifications, increased during the follow-up. On the contrary, as expected, the scores for giant capillaries and haemorrhages decreased during the time. The expert evaluators agreed on the assessments.

The “microangiopathy evolution score” significantly increased at the end of the follow-up in 53 of 90 patients (59%), confirming the evolution of the microangiopathy (see table 2, also for statistical significance).

On the contrary, 22 patients (24%) showed a significant decrease of the “microangiopathy evolution score” at the end of follow-up. The score did not change during follow-up in 15 patients with SSc (17%).

No statistically significant correlations were found between different scoring parameters and different autoantibodies or different skin involvement subsets in the analysed patients (not shown).

The possible influence of the different specific therapies on the evolution of the microangiopathy was not reported in the present study, as the aim of the investigation was to define a scoring system.

DISCUSSION

The results point out that a simple scoring system should be employed to quantify the SSc microangiopathy and confirms that the score for each NVC parameter significantly changes during the follow-up of patients with SSc.

Furthermore, this report suggests that tracking three parameters, namely capillary loss, disorganisation of the microvascular array, and capillary ramifications, it should be used to survey the evolution of the SSc microangiopathy, as the relative scores usually increase during the progression of the microvascular damage.

On the contrary, the scores of giant capillaries and haemorrhages are usually found to decrease during the time. However, these two parameters are still crucial for the early diagnosis of the “scleroderma pattern”.5

We recently described by NVC three different patterns of microvascular damage in SSc (namely “early”, “active” and “late”) that were found to correlate with the duration of the disease and that characterise the evolution of the microangiopathy.4 5 Therefore, the present longitudinal study defined a scoring system to quantitate the specific capillary abnormalities, as observed using the NVC. As a matter of fact, the scoring of nailfold capillary abnormalities is of great value to monitor the microangiopathy during the time.

Interestingly, no statistically significant correlations were found between different scoring parameters and different autoantibodies or different skin involvement subsets in the analysed patients, confirming previous observations that similar NVC features may be found in both patients with limited or diffuse SSc.5

Some patients were treated with methotrexate or cyclosporin A. Incidentally, several patients that showed a decrease of their score at the end of follow-up were those treated with cyclosporin A. In our previous investigations, cyclosporin A induced NVC changes.13 However, the present study was not addressed to evaluate the therapeutic effects of immunosuppressors on NVC pattern expression and progression.

All these observations are of prognostic value, as the capillaroscopic score was found a sensitive tool to quantify and to monitor the evolution of the SSc microvascular damage. In particular, the evaluation of the score for selected NVC parameters seems helpful to quantify the minimal modifications of the SSc microangiopathy.

In addition, the calculation of the capillaroscopic score might be useful to assess the rate of microvascular involvement in SSc in connection with clinical parameters and different therapies, as already partially assessed in other studies by considering the whole NCV patterns (“early”, “active” or “late”).14

At the present time there is no evidence that specific changes are related to any clinical parameter; however, recently a significant variation of the capillaroscopic parameters in patients with Raynaud’s phenomenon was reported, indicating the transition from the primary to the secondary phenomenon.15

A multicentre study is ongoing to validate the scoring system over a larger number of patients, by testing also intra- and interobserver variability.