Background: Systemic sclerosis (SSc) is a 
multisystem autoimmune disease which is classified into 
a diffuse cutaneous (dcSSc) and a limited cutaneous 
(lcSSc) subset according to the skin involvement. In 
order to better understand the vascular, immunological 
and fibrotic processes of SSc and to guide its treatment 
the EULAR Scleroderma Trials And Research (EUSTAR) group 
was formed in June 2004.
 Aims and Methods: EUSTAR collects prospectively 
the Minimal Essential Data Set (MEDS) on all sequential 
patients fulfilling the ACR diagnostic criteria in 
participating centres. We aimed to characterize 
demographic, clinical and laboratory characteristics of 
disease presentation in SSc and analysed EUSTAR baseline 
visits.
 Results: In April 2006, a total of 3656 patients 
(1349 with dcSSc and 2101 with lcSSc) were enrolled in 
102 centres and 30 countries. 1330 individuals had 
autoantibodies against Scl70 and 1106 against 
anticentromere antibodies. 87% of patients were female. 
On multivariate analysis, scleroderma subsets (dcSSc vs. 
lcSSc), antibody status and age at onset of Raynaud’s 
phenomenon, but not gender were independently associated 
with the prevalence of organ manifestations. 
Autoantibody status in this analysis appeared more 
closely associated with clinical manifestations than 
were SSc subsets.
 Conclusion: dcSSc and lcSSc subsets are 
associated with particular organ manifestations, but in 
this analysis the clinical distinction appeared 
superseded by an antibody based classification in 
predicting some scleroderma complications. The EUSTAR 
MEDS data base facilitates the analysis of clinical 
patterns in SSc and contributes to the standardised 
assessment and monitoring of SSc internationally.

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Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database

The endothelium forms an important part of the vasculature and is involved in promoting an atheroprotective environment via the complementary actions of endothelial cell-derived vasoactive factors. Disruption of vascular homeostasis can lead to the development of endothelial dysfunction which in turn contributes to the early and late stages of atherosclerosis. In recent years an increasing number of non-invasive vascular tests have been developed to assess vascular structure and function in different clinical populations. The present review aims to provide an insight into the anatomy of the vasculature as well as the underlying endothelial cell physiology. In addition, an in-depth overview of the current methods used to assess vascular function and structure is provided as well as their link to certain clinical populations.

/pdf/the-endothelium-and-its-role-in-regulating-vascular-tone-55qly0c1ga.pdf

The Endothelium and Its Role in Regulating Vascular Tone

Objective

To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies.



Methods

Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti–CENP-B), anti-Th/To, anti–topoisomerase I, and anti–RNA polymerase III (anti–RNAP III) autoantibodies by specific assays. Patients were studied prospectively.



Results

Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti–CENP-B and anti-Th/To antibodies predicted enlarged capillaries; these autoantibodies and anti–RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc.



Conclusion

In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.24038

Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: A twenty‐year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis

/pdf/2022-esc-ers-guidelines-for-the-diagnosis-and-treatment-of-1rt8fldu.pdf

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.

Raynaud's phenomenon.

Objective. To correlate microvascular abnormalities, evaluated by nailfold videocapillaroscopy (NVC), with the duration of both Raynaud's phenomenon (RP) and systemic sclerosis (SSc) from the date of diagnosis, in a large number of patients with SSc. Methods. Ninety-seven consecutive patients were recruited and distributed into 3 groups on the basis of the morphological NVC patterns observed: early (E), active (A), and late (L). In each group the age of patients, age at onset, and the duration of RP as well as of overt SSc were investigated and correlated with the different NVC pattern variables. Results. The early appearance of giant capillaries and hemorrhages (E pattern) is of great relevance for the early diagnosis of SSc. Therefore, these alterations are more evident in the active phase of the disease (A pattern). Conversely, the NVC observation of loss of capillaries and vascular architectural disorganization and the presence of ramified/bushy capillaries (L pattern) represents the clearest aspect of advanced SSc microvascular damage. These morphological alterations were found to correlate significantly with the duration of both RP and SSc, as well as with age of patients (p = 0.0001). No significant differences were observed when the variables were analyzed in the patients classified as having limited cutaneous SSc or diffuse cutaneous SSc. Conclusion. Classification of defined major nailfold patterns may be useful in assessing the appearance and progression of sclerodermic microangiopathy. As well, nailfold changes might represent a morphological reproduction of the evolution of SSc.

Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis.

Background. Microvascular lesions are a predominant feature in systemic sclerosis (SSc) and seem to play a central pathogenetic role. Recently, we graded scleroderma microangiopathy by nailfold videocapillaroscopy (NVC) into three NVC patterns (early, active and late). The aim of the present study was to confirm, in a larger number of SSc patients, the presence of three patterns of microvascular damage, and to detect any possible relationship between these patterns and both specific serum autoantibodies and the subsets of cutaneous involvement. Methods. Two hundred and forty-one consecutive patients (227 women and 14 men) affected by SSc were recruited. One hundred and forty-eight patients were affected by limited cutaneous SSc (lSSc) and 93 patients by diffuse cutaneous SSc (dSSc). The ages at onset of Raynaud’s phenomenon (RP) and SSc, the durations of RP and SSc, ANA and antitopoisomerase I (anti-Scl70) and anticentromere (ACA) antibodies were investigated in all patients. The SSc patients were subdivided on the basis of the NVC pattern into three groups. Results. A statistically significant correlation was found between the NVC patterns and the durations of both RP and SSc (P<0.001). Enlarged and giant capillaries, together with haemorrhages, constituted the earliest NVC finding in SSc (early NVC pattern). These abnormalities were mostly expressed in the active NVC pattern. Loss of capillaries, ramified capillaries and vascular architectural disorganization were increased in the late NVC pattern. Age and the duration of both RP and SSc were lower in 24 patients complaining of RP alone. Anti-Scl70 antibodies were statistically less frequent in the early vs both the active and the late NVC pattern, whereas no significant correlation was found between the presence of anti-Scl70 antibodies and the duration of either RP or SSc. ACA positivity was more frequent in patients with longer RP duration. Patients with lSSc had shorter SSc duration and showed the early or active NVC pattern more frequently. Conversely, patients with dSSc showed longer disease duration and mostly showed the late NVC pattern. Conclusions. NVC is an appropriate tool for differential diagnosis between primary and secondary RP through the clear recognition of the early NVC scleroderma pattern. This study confirms, in a large number of SSc patients, the existence of three distinct NVC patterns that might reflect the evolution of SSc microangiopathy. The presence of anti-Scl70 antibodies seems be related to earlier expression of the active and late NVC patterns of SSc microvascular damage. The presence of ACA seems to be related to delayed expression of the late NVC pattern.

Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis

Raynaud’s phenomenon (RP) represents the most frequent clinical aspect of cardio/microvascular involvement and is a key feature of several autoimmune rheumatic diseases. Moreover, RP is associated in a statistically significant manner with many coronary diseases. In normal conditions or in primary RP (excluding during the cold-exposure test), the normal nailfold capillaroscopic pattern shows a regular disposition of the capillary loops along with the nailbed. On the contrary, in subjects suffering from secondary RP, one or more alterations of the capillaroscopic findings should alert the physician of the possibility of a connective tissue disease not yet detected. Nailfold capillaroscopy (NV) represents the best method to analyse microvascular abnormalities in autoimmune rheumatic diseases. Architectural disorganization, giant capillaries, haemorrhages, loss of capillaries, angiogenesis and avascular areas characterize >95% of patients with overt scleroderma (SSc). The term ‘SSc pattern’ includes, all together, these sequential capillaroscopic changes typical to the microvascular involvement in SSc. The capillaroscopic aspects observed in dermatomyositis and in the undifferentiated connective tissue disease are generally reported as ‘SSc-like pattern’. Effectively, and early in the disease, the peripheral microangiopathy may be well recognized and studied by nailfold capillaroscopy, or better with nailfold video capillaroscopy (NVC). The early differential diagnosis between primary and secondary RP is the best advantage NVC may offer. In addition, interesting capillaroscopic changes have been observed in systemic lupus erythematosus, anti-phospholipid syndrome and Sjogren’s syndrome. Further epidemiological and clinical studies are needed to better standardize the NCV patterns. In future, the evaluation of nailfold capillaroscopy in autoimmune rheumatic diseases might represent a tool for the prediction of microvascular heart involvement by considering the systemic microvascular derangement at the capillary nailfold.

Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement?

Objective. To quantify in patients with systemic sclerosis (SSc) the absolute nailfold capillary number/mm (the absolute number of capillaries, observable in the first row, in 1 mm per field) and fingertip blood perfusion (FBP) during longterm therapy with the endothelin receptor antagonist bosentan (BOSE) and the synthetic analog of prostacyclin PGI2 iloprost (ILO) by multiple diagnostic tools. Observed values were correlated with clinical outcomes. Methods. Thirty patients with SSc already receiving intravenous ILO (80 μg/day) for 5 continuous days (every 3 mos) were recruited in the clinic. Fifteen patients continued such treatment (ILO group), while in 15 patients BOSE (125 mg twice/day) was added (ILO + BOSE group) because of the onset of pulmonary arterial hypertension or digital ulcers (DU). The followup period was 4 years (T0–T4). Every year the following were evaluated: absolute nailfold capillary number/mm by nailfold videocapillaroscopy, FBP by laser Doppler flowmetry, DU incidence, DLCO, systolic pulmonary arterial pressure (sPAP), renal arterial resistive index, and other biomarkers. From T2 to T4, laser speckled contrast analysis was added. Nonparametric tests were used for statistical analysis. Results. Limited to the ILO + BOSE group, absolute capillary number/mm and FBP showed a progressive increase independently from other variables. In addition, during followup there was a significant reduction (80%) in the incidence of new DU, whereas DLCO and sPAP did not worsen. Conclusion. The study shows in patients with SSc with up to 4 years of combined therapy a progressive significant recovery in structure and function of microvasculature linked to improved clinical outcomes, independent of disease severity.

https://www.jrheum.org/content/jrheum/43/11/2033.full.pdf

Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis

C. Pizzorni

Papers

Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis.

Nailfold videocapillaroscopic patterns and serum autoantibodies in systemic sclerosis

Nailfold capillaroscopy is useful for the diagnosis and follow-up of autoimmune rheumatic diseases. A future tool for the analysis of microvascular heart involvement?

Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis

Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients