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Clinical Reviews in Allergy & Immunology
Published in: Clinical Reviews in Allergy & Immunology 2/2015

01-10-2015

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

Authors: Ivone Silva, Andreia Teixeira, José Oliveira, Isabel Almeida, Rui Almeida, Artur Águas, Carlos Vasconcelos

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2015

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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.
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Literature
1.
Muller-Ladner U, Distler O, Ibba-Manneschi L, Neumann E, Gay S (2009) Mechanisms of vascular damage in systemic sclerosis. Autoimmunity 42(7):587–595CrossRefPubMed
2.
Ghizzoni C, Sebastiani M, Manfredi A, Campomori F, Colaci M, Giuggioli D et al (2015) Prevalence and evolution of scleroderma pattern at nailfold videocapillaroscopy in systemic sclerosis patients: clinical and prognostic implications. Microvasc Res 99:92–95CrossRefPubMed
3.
Flavahan NA (2008) Regulation of vascular reactivity in scleroderma: new insights into Raynaud’s phenomenon. Rheum Dis Clin N Am 34(1):81–87, vii CrossRef
4.
Hummers LK, Hall A, Wigley FM, Simons M (2009) Abnormalities in the regulators of angiogenesis in patients with scleroderma. J Rheumatol 36(3):576–582PubMedCentralCrossRefPubMed
5.
Galluccio F, Matucci-Cerinic M (2011) Two faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis. Autoimmun Rev 10(5):241–243CrossRefPubMed
6.
Amanzi L, Braschi F, Fiori G, Galluccio F, Miniati I, Guiducci S et al (2010) Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology (Oxford, England) 49(7):1374–1382CrossRef
7.
Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P et al (2002) Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis Rheum 46(9):2410–2420CrossRefPubMed
8.
Hachulla E, Clerson P, Launay D, Lambert M, Morell-Dubois S, Queyrel V et al (2007) Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 34(12):2423–2430PubMed
9.
Hudson M, Fritzler MJ (2014) Diagnostic criteria of systemic sclerosis. J Autoimmun 48–49:38–41
10.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39(2):257–265CrossRefPubMed
11.
Cutolo M, Pizzorni C, Secchi ME, Sulli A (2008) Capillaroscopy. Best Pract Res Clin Rheumatol 22(6):1093–1108CrossRefPubMed
12.
Avouac J, Walker UA, Hachulla E, Riemekasten G, Cuomo G, Carreira PE, et al. (2014) Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study. Ann Rheum Dis
13.
Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P et al (2011) Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 70(1):32–38PubMedCentralCrossRefPubMed
14.
Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E et al (2004) Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50(12):3985–3993CrossRefPubMed
15.
Manfredi A, Sebastiani M, Carraro V, Iudici M, Bocci M, Vukatana G, et al. (2014) Prediction risk chart for scleroderma digital ulcers: a composite predictive model based on capillaroscopic, demographic and clinico-serological parameters. Clin hemorheol Microcirc
16.
Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C et al (2011) Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis 70(3):476–481CrossRefPubMed
17.
Silva I, Almeida J, Vasconcelos C (2015) A PRISMA-driven systematic review for predictive risk factors of digital ulcers in systemic sclerosis patients. Autoimmun Rev 14(2):140–152CrossRefPubMed
18.
Cutolo M, Smith V (2013) State of the art on nailfold capillaroscopy: a reliable diagnostic tool and putative biomarker in rheumatology? Rheumatology (Oxford, England) 52(11):1933–1940CrossRef
19.
Rossi D, Russo A, Manna E, Binello G, Baldovino S, Sciascia S et al (2013) The role of nail-videocapillaroscopy in early diagnosis of scleroderma. Autoimmun Rev 12(8):821–825CrossRefPubMed
20.
Caramaschi P, Canestrini S, Martinelli N, Volpe A, Pieropan S, Ferrari M et al (2007) Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity. Rheumatology (Oxford, England) 46(10):1566–1569CrossRef
21.
Smith V, Decuman S, Sulli A, Bonroy C, Piettte Y, Deschepper E et al (2012) Do worsening scleroderma capillaroscopic patterns predict future severe organ involvement? a pilot study. Ann Rheum Dis 71(10):1636–1639CrossRefPubMed
22.
Lambova S, Muller-Ladner U (2011) Capillaroscopic findings in systemic sclerosis -- are they associated with disease duration and presence of digital ulcers? Discov Med 12(66):413–418PubMed
23.
Alivernini S, De Santis M, Tolusso B, Mannocci A, Bosello SL, Peluso G et al (2009) Skin ulcers in systemic sclerosis: determinants of presence and predictive factors of healing. J Am Acad Dermatol 60(3):426–435CrossRefPubMed
24.
Sulli A, Secchi ME, Pizzorni C, Cutolo M (2008) Scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients. Ann Rheum Dis 67(6):885–887CrossRefPubMed
25.
Smith V, De Keyser F, Pizzorni C, Van Praet JT, Decuman S, Sulli A et al (2011) Nailfold capillaroscopy for day-to-day clinical use: construction of a simple scoring modality as a clinical prognostic index for digital trophic lesions. Ann Rheum Dis 70(1):180–183CrossRefPubMed
26.
Sebastiani M, Manfredi A, Colaci M, D’Amico R, Malagoli V, Giuggioli D et al (2009) Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. Arthritis Rheum 61(5):688–694CrossRefPubMed
27.
Kim HS, Park MK, Kim HY, Park SH (2010) Capillary dimension measured by computer-based digitalized image correlated with plasma endothelin-1 levels in patients with systemic sclerosis. Clin Rheumatol 29(3):247–254CrossRefPubMed
28.
Ennis H, Moore T, Murray A, Vail A, Herrick AL (2014) Further confirmation that digital ulcers are associated with the severity of abnormality on nailfold capillaroscopy in patients with systemic sclerosis. Rheumatology (Oxford, England) 53(2):376–377CrossRef
29.
Cutolo MHA, Distler O et al (2013) Nailfold videocapillaroscopy and other predictive factors associated with new digital ulcers in systemic sclerosis. Data from the CAP study. Ann Rheum Dis 72(S3):146CrossRef
30.
Sebastiani M, Manfredi A, Vukatana G, Moscatelli S, Riato L, Bocci M et al (2012) Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study. Ann Rheum Dis 71(1):67–70CrossRefPubMed
31.
Sebastiani M, Manfredi A, Lo Monaco A, Praino E, Riccieri V, Grattagliano V et al (2013) Capillaroscopic Skin Ulcers Risk Index (CSURI) calculated with different videocapillaroscopy devices: how its predictive values change. Clin Exp Rheumatol 31(2 Suppl 76):115–117PubMed
32.
Sebastiani M, Manfredi A, Cassone G, Giuggioli D, Ghizzoni C, Ferri C (2014) Measuring microangiopathy abnormalities in systemic sclerosis patients: the role of capillaroscopy-based scoring models. Am J Med Sci
33.
Zhang L, Wan YN, Zhao JH, Wang YJ, Wang YX, Yan JW, et al. (2014) The Association Between Systemic Sclerosis, Arginine and Asymmetric Dimethylarginine. Inflammation
34.
Kahaleh B, Mulligan-Kehoe MJ (2012) Mechanisms of Vascular Disease. J. Varga et al. (eds), Scleroderma: from pathogenesis to comprehensive managment:227–46
35.
Kim NH, Rubin LJ (2002) Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther 7(1):9–19CrossRefPubMed
36.
Kahaleh MB, Sherer GK, LeRoy EC (1979) Endothelial injury in scleroderma. J Exp Med 149(6):1326–1335CrossRefPubMed
37.
Yamane K, Miyauchi T, Suzuki N, Yuhara T, Akama T, Suzuki H et al (1992) Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 19(10):1566–1571PubMed
38.
Sulli A, Soldano S, Pizzorni C, Montagna P, Secchi ME, Villaggio B et al (2009) Raynaud’s phenomenon and plasma endothelin: correlations with capillaroscopic patterns in systemic sclerosis. J Rheumatol 36(6):1235–1239CrossRefPubMed
39.
Aghaei M, Gharibdost F, Zayeni H, Akhlaghi M, Sedighi S, Rostamian AR et al (2012) Endothelin-1 in systemic sclerosis. Indian Dermatol Online J 3(1):14–16PubMedCentralCrossRefPubMed
40.
41.
Dimitroulas T, Sandoo A, Kitas GD (2012) Asymmetric dimethylarginine as a surrogate marker of endothelial dysfunction and cardiovascular risk in patients with systemic rheumatic diseases. Int J Mol Sci 13(10):12315–12335PubMedCentralCrossRefPubMed
42.
Dooley A, Gao B, Bradley N, Abraham DJ, Black CM, Jacobs M et al (2006) Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine. Rheumatology (Oxford, England) 45(6):676–684CrossRef
43.
Cotton SA, Herrick AL, Jayson MI, Freemont AJ (1999) Endothelial expression of nitric oxide synthases and nitrotyrosine in systemic sclerosis skin. J Pathol 189(2):273–278CrossRefPubMed
44.
Pyke KE, Tschakovsky ME (2005) The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 568(Pt 2):357–369PubMedCentralCrossRefPubMed
45.
46.
Au K, Singh MK, Bodukam V, Bae S, Maranian P, Ogawa R et al (2011) Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum 63(7):2078–2090PubMedCentralCrossRefPubMed
47.
Takahashi T, Asano Y, Amiya E, Hatano M, Tamaki Z, Takata M et al (2014) Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis. Modern Rheumatol / Jpn Rheumatism Assoc 24(1):106–111CrossRef
48.
Distler O, Distler JH, Scheid A, Acker T, Hirth A, Rethage J et al (2004) Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res 95(1):109–116CrossRefPubMed
49.
Koch AE, Distler O (2007) Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther 9(2):S3PubMedCentralCrossRefPubMed
50.
Farouk HM, Hamza SH, El Bakry SA, Youssef SS, Aly IM, Moustafa AA et al (2013) Dysregulation of angiogenic homeostasis in systemic sclerosis. Int J Rheum Dis 16(4):448–454CrossRefPubMed
51.
Avouac J, Vallucci M, Smith V, Senet P, Ruiz B, Sulli A et al (2013) Correlations between angiogenic factors and capillaroscopic patterns in systemic sclerosis. Arthritis Res Ther 15(2):R55PubMedCentralCrossRefPubMed
52.
Ferri C, Giuggioli D, Sebastiani M, Colaci M (2007) Treatment of severe scleroderma skin ulcers with recombinant human erythropoietin. Clin Exp Dermatol 32(3):287–290CrossRefPubMed
53.
Mulligan-Kehoe MJ, Drinane MC, Mollmark J, Casciola-Rosen L, Hummers LK, Hall A et al (2007) Antiangiogenic plasma activity in patients with systemic sclerosis. Arthritis Rheum 56(10):3448–3458CrossRefPubMed
54.
Hebbar M, Peyrat JP, Hornez L, Hatron PY, Hachulla E, Devulder B (2000) Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum 43(4):889–893CrossRefPubMed
55.
Fujimoto M, Hasegawa M, Hamaguchi Y, Komura K, Matsushita T, Yanaba K et al (2006) A clue for telangiectasis in systemic sclerosis: elevated serum soluble endoglin levels in patients with the limited cutaneous form of the disease. Dermatology (Basel, Switzerland) 213(2):88–92CrossRef
56.
Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S (2014) The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun 48–49:50–52CrossRefPubMed
57.
Voswinkel J, Francois S, Simon JM, Benderitter M, Gorin NC, Mohty M, Fouillard L et al (2013) Use of mesenchymal stem cells (MSC) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clin Rev Allergy Immunol 45(2):180–192CrossRefPubMed
58.
Moinzadeh P, Nihtyanova SI, Howell K, Ong VH, Denton CP (2012) Impact of hallmark autoantibody reactivity on early diagnosis in scleroderma. Clin Rev Allergy Immunol 43(3):249–255CrossRefPubMed
59.
Salazar GA, Assassi S, Wigley F, Hummers L, Varga J, Hinchcliff M et al (2015) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum 44(6):680–686CrossRefPubMed
60.
Bose N, Chiesa-Vottero A, Chatterjee S (2015) Scleroderma renal crisis. Semin Arthritis Rheum 44(6):687–694CrossRefPubMed
61.
Maverakis E, Patel F, Kronenberg DG, Chung L, Fiorentino D, Allanore Y et al (2014) International consensus criteria for the diagnosis of Raynaud’s phenomenon. J Autoimmun 48–49:60–65CrossRefPubMed
62.
Srivastava N, Hudson M, Tatibouet S, Wang M, Baron M, Fritzler MJ, et al. (2015)Thinking outside the box-The associations with cutaneous involvement and autoantibody status in systemic sclerosis are not always what we expect. Semin Arthritis Rheum
63.
Tani C, Carli L, Vagnani S, Talarico R, Baldini C, Mosca M et al (2014) The diagnosis and classification of mixed connective tissue disease. J Autoimmun 48–49:46–49CrossRefPubMed
64.
Hudson M, Fritzler MJ (2014) Diagnostic criteria of systemic sclerosis. J Autoimmun 48–49:38–41CrossRefPubMed
65.
Mitchell RN (2013) Learning from rejection: what transplantation teaches us about (other) vascular pathologies. J Autoimmun 45:80–89CrossRefPubMed
66.
Massie C, Hudson M, Tatibouet S, Steele R, Huynh T, Friztler MJ et al (2014) Absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: a multicenter study of 689 patients. Semin Arthritis Rheum 44(3):338–344CrossRefPubMed
67.
Luo Y, Wang Y, Wang Q, Xiao R, Lu Q (2013) Systemic sclerosis: genetics and epigenetics. J Autoimmun 41:161–167CrossRefPubMed
68.
Floreani A, Franceschet I, Cazzagon N, Spinazze A, Buja A, Furlan P et al (2015) Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. Clin Rev Allergy Immunol 48(2–3):192–197CrossRefPubMed
69.
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A et al (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65(11):2737–2747PubMedCentralCrossRefPubMed
Metadata
Title
Endothelial Dysfunction and Nailfold Videocapillaroscopy Pattern as Predictors of Digital Ulcers in Systemic Sclerosis: a Cohort Study and Review of the Literature
Authors
Ivone Silva
Andreia Teixeira
José Oliveira
Isabel Almeida
Rui Almeida
Artur Águas
Carlos Vasconcelos
Publication date
01-10-2015
Publisher
Springer US
Published in
Clinical Reviews in Allergy & Immunology / Issue 2/2015
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-015-8500-0

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