Serum klotho concentrations inversely correlate with the severity of nailfold capillaroscopic patterns in patients with systemic sclerosis

Klotho is a transmembrane and soluble glycoprotein that governs vascular integrity. Previous studies have demonstrated reduced serum klotho concentrations in patients with systemic sclerosis (SSc), and it is known that klotho deficiency can impair the healing of digital ulcers related to microvessel damage. The aim of this study was to evaluate the association between serum klotho levels and nailfold capillaroscopic abnormalities in SSc patients. We retrospectively enrolled 54 consecutive patients with SSc diagnosed on the basis of the 2013 EULAR/ACR criteria [11 with diffuse SSc; 47 females; median age 68.0 years (IQ 18); median disease duration 11.0 years (IQ 7)]. Serum klotho concentrations were determined by means of an enzyme-linked immunosorbent assay. On the basis of the 2000 classification of Cutolo et al., 14 patients had normal nailfold capillaroscopic findings, 8 had an early scleroderma pattern, 21 an active scleroderma pattern, and 11 a late scleroderma pattern. The median serum klotho concentration was 0.29 ng/mL (IQ 1). Regression analysis of variation showed an inverse correlation between serum klotho concentrations and the severity of the capillaroscopic pattern (p=0.02; t -2.2284), which was not influenced by concomitant treatment. Logistic regression did not reveal any significant association between the risk of developing digital ulcers and nailfold capillaroscopic patterns, serum klotho levels, or concomitant medications. The presence of avascular areas significantly correlated with calcinosis (p=0.006). In line with previous studies, our findings confirm that klotho plays a role in preventing microvascular damage detected with nailfold capillaroscopy.

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POS1409 AUTOMATED DETECTION OF SCLERODERMIFORM PATTERNS USING CAPILLARY.IO

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4112 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 987.2-988

Author(s):

E. Ramos ◽

A. Guillén-Del-Castillo ◽

C. P. Simeón-Aznar ◽

B. Gracia Tello ◽

V. Fonollosa Pla ◽

...

Keyword(s):

Systemic Sclerosis ◽

Low Cost ◽

Group Versus ◽

Nailfold Capillaroscopy ◽

Microvascular Damage ◽

Patient Will ◽

The Difference ◽

Reading System ◽

Pattern Group ◽

Scleroderma Pattern

Background:A nailfold capillaroscopy procedure is a non-invasive, low-cost, and well-established examination that can be used to diagnose several rheumatic autoimmune diseases and support the necessary follow-up of patients. While the clinical implications of the technique are known, a rigorous and in-depth examination of nailfold capillaries remains as one of the major challenges to produce new advances in research and diagnosis, due to practical limitations for analysing the whole nailfold area of each patient. The difference between the different patterns established by Maricq and Cutolo makes it possible to predict the evolution that the patient will present. We introduce Capillary.io, an automatic image reading system able to recognize capillaries in images obtained with any microscope, generate automatic measurements of each capillary and take advantage of this information to report capillary morphology and patterns.Objectives:to determine the ability to detect active and early scerodermiform patterns of Capillary.io.Methods:Forty-nine complete capillaroscopies, reported by expert capillaroscopists according to the different patterns manually (gold standard), were compared with the pattern detection capability of Capillary.io. A scoring system based on the algorithm of the Spanish Capillaroscopy Study Group (GREC) was performed and interpreted by capillary.io for the global interpretation of each of the capillaroscopies analyzed.Results:Overall, 37 of the 49 capillaroscopies reported agreed with the diagnosed pattern (75.51%). Separately, the early pattern presented a concordance of 77.27% and the active pattern of 74.07%. In reference to the findings detected by the Capillary.io system, the mean overall density was 5.01 capillaries/mm in the group with the active pattern compared to 6.46 capillaries/mm in the early pattern. The density of dilations and megacapillaries was 2.81/mm and 1.21/mm in the active pattern group versus 4.69/mm and 0.4/mm in the early pattern group. Global diameters were greater in the active pattern group with an apical mean of 37.3 μm compared to 28.5 μm in the early pattern subgroup.Conclusion:Capillary.io is a simple, easy-to-learn web system for interpreting capillaroscopic images of nail folds. It can be a very useful tool to standardize the interpretation of capillaroscopic images, not only individually for each capillary, but also jointly through the detection of different patterns.References:[1]Chen K, Wang J, Pang J, Cao Y, Xiong Y, Li X, et al. MMDetection: Open MMLab Detection Toolbox and Benchmark. arXiv preprint arXiv:190607155 2019;.[2]Cutolo M, Pizzorni C, Sulli A. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis - Reply. The Journal of Rheumatology 2000 11;27:2722–2723.[3]Cutolo M, Trombetta AC, Melsens K, Pizzorni C, Sulli A, Ruaro B, et al. Automated assessment of absolute nailfold capillary number on videocapillaroscopic images: Proof of principle and validation in systemic sclerosis. Microcirculation 2018 May;25(4):e12447.[4]Smith V, Vanhaecke A, Herrick AL, Distler O, Guerra MG, Denton CP, et al. Fast track algorithm: How to differentiate a “scleroderma pattern” from a “non-scleroderma pattern”. Autoimmu- nity Reviews 2019 nov;18(11):102394.[5]Tavakol ME, Fatemi A, Karbalaie A, Emrani Z, Erlandsson BE. Nailfold Capillaroscopy in Rheumatic Diseases: Which Parameters Should Be Evaluated? BioMed Research International 2015;2015:1–17.Disclosure of Interests:Eduardo Ramos Shareholder of: Co-founder and shareholder of Capillary.io, Alfredo Guillén-Del-Castillo: None declared, Carmen Pilar Simeón-Aznar: None declared, Borja Gracia Tello Shareholder of: Co-founder and shareholder of Capillary.io, Vicent Fonollosa Pla: None declared, Albert Selva-O’Callaghan: None declared, Luis Sáez-Comet: None declared, Elena Martínez Robles: None declared, Juan José Rios: None declared, Gerard Espinosa: None declared, Jose Antonio Todolí Parra: None declared, Jose Luis Callejas-Rubio: None declared, Norberto Ortego: None declared, Begoña Marí-Alfonso: None declared, Mayka Freire: None declared, Patricia Fanlo: None declared

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AB0574 BENEFITS OF ILOPROST IN LONG – TERM STABILIZATION OR IMPROVEMENT IN NEOANGIOGENESIS IN SYSTEMIC SCLEROSIS: A 15 YEARS OBSERVATION COHORT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2869 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1584.2-1584

Author(s):

P. Faggioli ◽

L. Castelnovo ◽

A. Tamburello ◽

A. Laria ◽

A. M. Lurati ◽

...

Keyword(s):

Systemic Sclerosis ◽

Continuous Treatment ◽

Digital Ulcers ◽

Efficacy And Safety ◽

Raynaud Phenomenon ◽

Serious Adverse Events ◽

Microvascular Damage ◽

Skin Ulcers

Background:In Systemic Sclerosis (SSc) fibrosis is due to microcirculation damage with capillary necrosis, arteriolar intimal proliferation and local ischemia. loprost (ILO) is used IV for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in (SSc). We have already described (1) an improvement of peripheral vascularization with ILO, observed after 3 years treatment by capillaroscopy with an increase in the capillary number and mild regression of avascular areas and pericapillar oedemaObjectives:Our aim was to observe capillaroscopic changes in a cohort of 26 patients treated with ILO, once a month (25 – 50 ng each infusion) for an average time of 15 yearsMethods:We evaluated the initial and 2019 capillaroscopic picture of 26 SSc patients (24 W,2 M; median age 63.8Y) in continuous treatment with monthly infusion of ILO from 2004 to today. 6/26 were SCL70 positive;the remainder was positive for anticentromere AbResults:We documented stability of capillaroscopic picture in 62% of patients,an improvement in 19% and a worsening (mainly from early to active pattern) in 19%. Low adherence to therapy was observed among the worsened patients. Out of 8 patients with onset ulcers, only 3 patients still have skin ulcers, all with late stable capillaroscopic picture from onset.We have not documented serious adverse eventsConclusion:Our observations confirm the efficacy and safety of ILO in the treatment of SSc even after many years of treatment, resulting in a stabilization of microvascular damage, independent of disease severity.References:[1]Possible role of iloprost (stable analog of PG12) in promoting neoangiogenesis in systemic sclerosis. Faggioli P, Giani L, Mazzone A. Clin Exp Rheumatol. 2006 Mar-Apr;24(2):220-1. No abstract availableDisclosure of Interests:None declared

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Serum resistin is predictive marker of development of new digital ulcers in systemic sclerosis

Clinical and Experimental Medicine ◽

10.1007/s10238-021-00756-2 ◽

2021 ◽

Author(s):

Chiara Pellicano ◽

Giorgia Leodori ◽

Amalia Colalillo ◽

Luca Navarini ◽

Antonietta Gigante ◽

...

Keyword(s):

Systemic Sclerosis ◽

Predictive Marker ◽

Microvascular Dysfunction ◽

Digital Ulcers ◽

Resistin Level ◽

Microvascular Damage ◽

Baseline Serum ◽

Kaplan Meier ◽

Serum Resistin Level

AbstractSystemic sclerosis (SSc) is autoimmune disease characterized by endothelial dysfunction and microvascular damage. Resistin has been implied in microvascular dysfunction. Objective of this study is to evaluate the association between baseline resistin and development of new digital ulcers (DUs) in SSc patients. At baseline, serum resistin has been assessed in 70 female SSc patients and 26 healthy controls (HC). In SSc patients, clinical assessment was performed at baseline and after a 52-weeks follow-up. Serum resistin level was increased in SSc patients compared to HC [5.89 ng/ml (2.5 ng/ml–8.1 ng/ml) vs 2.3 ng/ml (0.4 ng/ml–2.4 ng/ml), p = 0.0004)]. Resistin was lower (p = 0.005) in SSc patients with early capillaroscopic pattern than patients with active or late capillaroscopic pattern [2.49 ng/ml (0.89 ng/ml–5.81 ng/ml) vs 7.11 ng/ml (3.48 ng/ml–11.35 ng/ml) and 6.49 ng/ml (3.35 ng/ml–8.87 ng/ml), respectively]. After a 52-weeks follow-up, 34 (48.6%) patients developed new DUs. Median serum resistin was significantly higher in patients with new DUs than in patients without new DUs [6.54 ng/ml (3.35 ng/ml–11.02 ng/ml) vs 4.78 ng/ml (1.06 ng/ml–7.6 ng/ml), p = 0.019]. Kaplan–Meier curves show a significantly reduced free survival from DUs in patients with increased resistin (p = 0.002). In multivariate analysis, resistin is associated with the development of new DUs. Increased serum resistin level is a predictive marker of new DUs in SSc.

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Raynaud’s Phenomenon and Plasma Endothelin: Correlations with Capillaroscopic Patterns in Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.081030 ◽

2009 ◽

Vol 36 (6) ◽

pp. 1235-1239 ◽

Cited By ~ 52

Author(s):

ALBERTO SULLI ◽

STEFANO SOLDANO ◽

CARMEN PIZZORNI ◽

PAOLA MONTAGNA ◽

MARIA ELENA SECCHI ◽

...

Keyword(s):

Systemic Sclerosis ◽

Plasma Levels ◽

Rating Scale ◽

Raynaud’S Phenomenon ◽

Raynaud's Phenomenon ◽

Digital Ulcers ◽

Microvascular Damage ◽

Morphological Alterations ◽

Primary Raynaud’S Phenomenon ◽

Clinical Measures

Objective.We evaluated endothelin (ET)-1 plasma levels and some clinical measures in patients with primary Raynaud’s phenomenon (PRP), and in patients with systemic sclerosis (SSc) and secondary RP (SRP), in the latter according to their different nailfold videocapillaroscopy (NVC) patterns of microangiopathy (early, active, and late).Methods.Ninety-nine patients with SSc, 49 with PRP, and 45 control subjects were studied. NVC was performed in all patients to distinguish the pattern of microvascular damage, and the morphological alterations were scored by a semiquantitative rating scale. ET-1 plasma levels were evaluated in all individuals by ELISA.Results.ET-1 plasma levels were significantly higher (p = 0.001) in patients with both PRP and SRP, compared to controls. A significant positive correlation (p = 0.03) was found between ET-1 plasma levels and SRP duration, but not between ET-1 plasma levels and PRP duration. Significant correlations were observed in patients with SSc between ET-1 plasma levels and clinical measures (e.g., digital ulcers), as well as the score value of single NVC measures, such as the number of capillaries, “ramified” capillaries, and enlarged capillaries (p < 0.05). Finally, the highest ET-1 plasma levels were found in patients with SSc showing the late pattern of microangiopathy when compared to the early pattern (p = 0.03) and to controls (p = 0.003).Conclusion.Highest ET-1 plasma levels were detected in the more advanced stage of the SSc microangiopathy, namely the late NVC pattern, characterized by capillary loss and increased tissue fibrosis; this might support the involvement of ET-1 in the progression of the microvascular/fibrotic SSc damage.

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FRI0257 CAPILLAROSCOPIC VERY EARLY MORPHOLOGICAL AND QUANTITATIVE SPECIFIC ABNORMALITIES ANTICIPATE THE DEVELOPMENT OF THE “SCLERODERMA PATTERN” IN PATIENTS WITH RAYNAUD’S PHENOMENON

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4956 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 712.2-713

Author(s):

M. Pendolino ◽

C. Pizzorni ◽

S. Paolino ◽

F. Goegan ◽

E. Gotelli ◽

...

Keyword(s):

Systemic Sclerosis ◽

Raynaud’S Phenomenon ◽

Raynaud's Phenomenon ◽

Apical Region ◽

Nailfold Videocapillaroscopy ◽

Research Support ◽

Microvascular Damage ◽

First Time ◽

Present Pilot Study ◽

Scleroderma Pattern

Background:Nailfold videocapillaroscopy (NVC) abnormalities in subjects with isolated Raynaud’s phenomenon (RP) may be present before transition to secondary RP(SRP) and development of a NVC “scleroderma pattern” and are known to predict for evolution to a connective tissue disease (CTD) within few years [1]. In a previous study, we have demonstrated that the very early increase of capillary diameter over 30 μm is an independent predictor for development of Systemic Sclerosis (SSc) associated SRP [2].Objectives:Present pilot retrospective study aimed to investigate in a cohort of patients affected by CTD–related RP the presence of very early capillaroscopic morphological and quantitative abnormalities in the acquired pictures of NVC performed before the development of the NVC scleroderma-pattern. In particular, the study was addressed to identify a “very early”scleroderma pattern, in order to intercept patients with RP at high risk of evolution in a CTD, specifically SSc.Methods:We selected the NVCs of 273 SSc patients presenting one of the validated NVC “scleroderma patterns”. We enrolled 26 SSc patients having a NVC analysis performed before the development ofthe “very early”NVC pattern. As controls, we evaluated 26 patients affected by other CTDs with stable non-scleroderma pattern over time. The 16 images per patient obtained by NVC examination were analyzed for total number of capillaries, number and the limbs diameters of capillaries with a diameter >30 μm, and microhemorrhages. Statistical analysis was performed using non-parametric tests.Results:All 26 SSc patients showed dilated capillaries with a diameter >30 μm in their previous NVC. Patients later developing scleroderma pattern had statically higher number and percentage of capillaries with a diameter >30 μm (p=0.0004 and p=0.0005), as well as a larger apical dilatation >40 μm (p=0.002). A progressive and significant increase in all capillary diameters were only detected in patients later diagnosed for SSc (apical p=0.006, venous p=0.02, arterial p=0.03). A significant homogeneous and progressive dilation was observed from the apical region and then involving both venous and arterial branches, only in SSc patients (p=0.002).Conclusion:Present pilot study demonstrates, for the first time that, before to develop a validated NVC scleroderma-pattern, all potential SSc patients present significant very early morphological and quantitative NVC changes. In particular, the progressive and homogeneous capillary loop dilation over 40 μm in over 40% of total number capillaries significantly could contribute to identify RP patients who will develop a SSc pattern after 4-5 years.References:[1]Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J Rheumatol. 2000;27:155-60.[2]Trombetta AC, et al. J Rheumatol 2016;43:599-606.Disclosure of Interests:Monica Pendolino: None declared, Carmen Pizzorni: None declared, Sabrina Paolino: None declared, Federica Goegan: None declared, Emanuele Gotelli: None declared, Carlotta Schenone: None declared, Francesco Cattelan: None declared, Massimo Patanè: None declared, Elisa Alessandri: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

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Association Between Centromere- and Topoisomerase-specific Immune Responses and the Degree of Microangiopathy in Systemic Sclerosis

The Journal of Rheumatology ◽

10.3899/jrheum.191331 ◽

2020 ◽

pp. jrheum.191331

Author(s):

Nina M. van Leeuwen ◽

Corrie M. Wortel ◽

Cynthia M. Fehres ◽

Jaap A. Bakker ◽

Hans U. Scherer ◽

...

Keyword(s):

Logistic Regression ◽

Systemic Sclerosis ◽

Autoimmune Response ◽

Digital Ulcers ◽

Serum Samples ◽

Microvascular Damage ◽

Autoantibody Production ◽

Baseline Serum ◽

Pulmonary Arterial ◽

Isotype Expression

Objective Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentromere antibody (ACA)– and antitopoisomerase antibody (ATA)–specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc). Methods ACA and ATA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG–positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed. Results In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43–6.60), interstitial lung disease (OR 3.41, 95% CI 1.11–10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05–17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05–4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity. Conclusion We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc.

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