title: 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.
authors.affiliation: Angiology and Vascular Surgery Service and Clinical Immunology Unit, Centro Hospitalar do Porto, Praça da Revista o Tripeiro, n° 42, hab 23, 4150-789, Porto, Portugal. heitor.ivone@gmail.com.|Clinical Immunology Unit, Porto, Portugal. heitor.ivone@gmail.com.
authors.forename: Ivone
authors.initials: I
authors.lastname: Silva
authors.affiliation: CINTESIS - Center for Research in Health Technologies and Information Systems Porto, Porto, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Clinical Pathology Department, Centro Hospitalar do Porto (CHP), Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Clinical Immunology Unit, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Almeida
authors.affiliation: Angiology and Vascular Surgery Service and Clinical Immunology Unit, Centro Hospitalar do Porto, Praça da Revista o Tripeiro, n° 42, hab 23, 4150-789, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Almeida
authors.affiliation: Abel Salazar Biomedical Health Institute, Porto, Portugal.|Multidisciplinary Unit for Biomedical Investigation (UMIB), University of Porto, Porto, Portugal.
authors.forename: Artur
authors.initials: A
authors.lastname: Águas
authors.affiliation: Clinical Immunology Unit, Porto, Portugal.|Abel Salazar Biomedical Health Institute, Porto, Portugal.|Multidisciplinary Unit for Biomedical Investigation (UMIB), University of Porto, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vasconcelos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D000071063:Endoglin; D019332:Endothelin-1 / Q000097:blood*; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005385:Fingers / Q000098:blood supply / Q000473:pathology*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020678:Microscopic Angioscopy; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011928:Raynaud Disease / Q000175:diagnosis* / Q000209:etiology; D011956:Receptors, Cell Surface / Q000097:blood; D012595:Scleroderma, Systemic / Q000150:complications / Q000175:diagnosis*; D014456:Ulcer / Q000175:diagnosis* / Q000209:etiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; D019332:Endothelin-1; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A
keywords: Capillaroscopy; Digital ulcer; Endothelin-1; Flow-mediated dilatation; VEGF