Endothelial Dysfunction and Nailfold Videocapillaroscopy Pattern as Predictors of Digital Ulcers in Systemic Sclerosis: a Cohort Study and Review of the Literature

Abstract

Raynaud's phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760-0.932), lower values of FMD (AUC 0.754, 95%CI 0.643-0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649-0.866), ADMA (AUC 0.634, 95%CI 0.511-0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579-0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14-0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41-10.26) and late NVC pattern (HR 2.29, 95%CI 0.97-5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06-77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up.

Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study

“…While the current study found that the capillary density on the third digit of the dominant hand was sufficient for predicting the risk of new DUs, it is still necessary to evaluate at least 4 digits per hand for the diagnosis of SSc in patients with Raynaud's phenomenon. The study also indicated that the NVC pattern may play a role in predicting DUs, confirming the results of smaller studies that have shown that the late SSc NVC pattern is associated with an increased risk of DUs . Ideally, future studies would encompass NVC‐based indices assessing eventual disease‐modifying characteristics of treatment on the clinical complications of SSc such as DUs .…”

Disturbed microcirculation in the hands of patients with systemic sclerosis detected by fluorescence optical imaging: a pilot study

“…diffuse subtype of SSc, late pattern of capillaroscopy, history of DU or markers for endothelial dysfunction [9–12]. Various imaging methods have been suggested to measure vasculopathy in patients with systemic sclerosis and to link its extent to the existence of current or future digital ulcers.…”

“…Other studies focused on capillaroscopic patterns (i.e. early, active and late) and found associations to the presence as well as the development of digital ulcers [11, 12, 20–24]. While these studies have not provided concrete values of specificity and sensitivity, we calculated levels of around 36% and 89% respectively using their provided data [11, 12, 20, 23, 24].…”

Position article and guidelines 2018 recommendations of the Brazilian Society of Rheumatology for the indication, interpretation and performance of nailfold capillaroscopy

“…Several studies have consistently shown that devascularization and distortion of the capillary architecture-which characterize late microvascular injury among patients with SSc-are strong predictors of complications involving target organs, such as the skin, lungs, heart, gastrointestinal tract, and kidneys (B) [28,[89][90][91], (C) [92], (D) [93].…”