High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis

Objective. To determine active TGF-β1 (aTGF-β1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients.Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-β1 by PBMC. The aTGF-β1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR.Results. TGF-β1 serum levels were significantly higher in SSc patients than in HC (p< 0.0001). Patients with increased TGF-β1 serum levels were more likely to have diffuse subset (p= 0.02), digital ulcers (p= 0.02), lung fibrosis (p< 0.0001), positive antitopoisomerase I (p= 0.03), and higher modified Rodnan score (p= 0.046). Most of our culture supernatant samples had undetectable levels of TGF-β1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin.Conclusion. Raised active TGF-β1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.

Download Full-text

AB0566 NAILFOLD EXTENT OF REDUCED CAPILLARY DENSITY IS ASSOCIATED WITH DIGITAL ULCERS AND WITH AN INCREASED RISK OF DIGITAL ULCERS IN SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4173 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1580.2-1580

Author(s):

R. De Angelis ◽

F. Salaffi

Keyword(s):

Systemic Sclerosis ◽

Laboratory Data ◽

Quantitative Measure ◽

Capillary Density ◽

Optical Probe ◽

Typical Feature ◽

Slight Reduction ◽

Digital Ulcers ◽

Increased Risk ◽

Significant Difference

Background:A growing evidence supports the role of microvasculopathy as a primary pathogenic event in systemic sclerosis (SSc). The most commonly used imaging technique to identify microangiopathy in SSc is high magnification videocapillaroscopy (NVC), and reduced capillary density and/or capillary loss, which is a typical feature of “scleroderma microangiopathy”, easily identified by NVC, has been associated with digital ulcers (DUs). Different approaches have been proposed to measure capillary density or capillary loss. Some of these were qualitative methods, others semi-quantitative, others only concerned a limited nailfold area, without ever evaluating the overall density, which is more suitable for quantitative estimate.Objectives:To assess the association between the extent of different values of nailfold capillary density and the presence of DUs and to identify the risk of developing DUs, based on quantitative parameters.Methods:The study involved 54 SSc selected patients (47 women and 7 men, mean age 59.5 years, 50 with limited and 4 with diffuse). The study population came from an ongoing database, that includes clinical and laboratory data of patients with definite SSc. A videocapillaroscope (VideoCap® 3.0, DS Medica, Milan, Italy) with a 200x optical probe was used. During examination, eight fingers (fingers 2–5 of each hand), 4 fields per finger, according to the standard literature were assessed. For each patient, a total of 32 images were collected, then classified as having either “normal”, “non-specific” or the “scleroderma pattern” (SP). Capillary density was defined as the number of capillaries/mm in the distal row, regardless of its shape and morphology. Avascular areas were defined by the absence of loops within a width/area extending over more than 500 microns. For each patient, the SP images were further graded with no/slight reduction of the capillary density (7-9 loops/mm) (NOR), with a well-defined reduction of capillary density (6-4 loops/mm) (RED) and with loss of capillaries (<4) plus avascular areas (AA). Then, the overall percentages were calculated (the number with SP, the number with NOR, with RED and with AA, respect to 32), thus obtaining the quantitative measures. All data were analysed using the MedCalc® version 18.6; 64-bit (MedCalc Software, Mariakerke, Belgium).Results:A total of 1728 images were analyzed. Patients with DUs were 16/54 (29.6%). All patients had a SP, but only five patients showed a SP along the entire nailfold. A comparison between patients with or without DUs showed a significant difference both for the overall extent of AA (p=0.032), and particularly for the overall extent of RED (p<0.001). No significant difference was found regarding the overall extent of the SP (p=0.085). Factor significantly associated with DUs in multivariate analysis was the overall extent of RED (p=0.0286). The ROC curve was very effective at discriminating the capillary feature able to distinguish patients with DUs from patients without DUs. The discriminatory power of the overall extent of RED was very good, with an AUC of 0.948 (95 % CI 0.852 ± 0.990). Then, we calculated the cut-off values of the overall extent of RED for presence/absence of DUs with the highest combination of sensitivity and specificity. The resulting cut-off value (Yourden index of 0.825) was >68.7 (sensitivity 92.31 %; specificity 90.24 %) with a LR+ of 9.46.Conclusion:Our data strongly support that the capillary density between 4 and 6 loops/mm is the best capillaroscopic quantitative measure associated with DUs and able to discriminate the probability of having DUs. If all SSc-specific antibodies and/or other laboratory/clinical parameters are not yet available, the overall capillary density can allow physicians to assess SSc patients easily, regarding DUs and risk for developing DUs.Disclosure of Interests:None declared

Download Full-text

AB0621 TOLERABILITY AND SAFETY OF ACETYLSALICYLIC ACID IN PATIENTS WITH SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6335 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1606.2-1606

Author(s):

L. Verardi ◽

E. De Lorenzis ◽

G. Natalello ◽

L. Gigante ◽

U. La Porta ◽

...

Keyword(s):

Systemic Sclerosis ◽

Adverse Events ◽

Low Dose ◽

Disease Duration ◽

Rank Test ◽

Digital Ulcers ◽

Log Rank Test ◽

Gastrointestinal Intolerance ◽

Male Sex ◽

Observation Period

Background:Systemic Sclerosis (SSc) is characterized by an increased incidence of macro- and microvascular complications. Current evidences on efficacy, safety and tolerability of acetylsalicylic acid (ASA) in SSc patients are limited, and the indication to this treatment is based on the experience of each single centre or physician. Esophagus and stomach are the portions of the digestive tract that are more frequently affected by adverse events due to ASA exposure.Objectives:We evaluated the incidence of adverse events associated with low-dose ASA treatment in a cohort of patients affected by SSc.Methods:Demographic data and disease features of 302 patients affected by SSc treated with low-dose ASA were collected and patients were followed-up for a median period of 6.9 years (range: 0-20 years). The proportion of patients taking ASA for secondary prevention for cardiovascular disease was also noted. The incidence of discontinuation of the drug, gastrointestinal intolerance, bleeding and death in the observation period was recorded.Results:Patients had a median age of 54.0 years (19.6-89.4); 91.9% were female, 13.2% were smokers and 44.0% had a BMI≥30Kg/m2. The prevalence of ischemic heart disease, peripheral vascular disease and stroke was of 8.6%, 5.3% and 3.3%, respectively; 48.7% of the patient took ASA in primary cardiovascular prevention. Therapy started after a median disease duration of 4.8 years (range: 0.0- 30.1 years) since the first non-Raynaud symptom and 56.6% of patients had an early disease (less than three years of disease duration). During the observation period, 30 patients (14.3 per 1000 person-years) discontinued ASA after an average period of assumption of 4.6 years (range: 0.3-18.0 years). The main adverse events were heartburn, dyspepsia and hematochezia, recorded in 18 patients (8.6 per 1000 person-years). Eight of them (3.8 per 1000 person-years) had evidence of digestive tract bleeding. Five patients (2.4 per 1000 person-years) discontinued ASA due to recurrent epistaxis. Twenty-eight patients (13.4 per 1000 person-years) died in the follow-up period, 16 of these (7.6 per 1000 person-years) because of SSc-related causes. None of them had evidence of major bleeding. We used Kaplan-Meier analysis to evaluate the incidence of ASA discontinuation. The history of digital ulcers (Log rank test X24.7, p=0.037) and male sex (Log rank test X24.3, p=0.03) were associated with a higher cumulative ASA discontinuation rate due to gastrointestinal intolerance.Conclusion:In our cohort of SSc patients, ASA resulted safe and well tolerated in most cases, despite the risk of gastroesophageal abnormalities due to disease. Although this comforting results, taking in account the lack of controlled-randomized trials about efficacy and safety, the choice to start antiplatelet therapy with ASA should be mandatorily preceded by a careful evaluation of risks and benefits. Furthermore, an attentive monitoring for possible adverse effects is needed during ASA treatment. Patients with digital ulcers and male sex could present less drug tolerability.References:[1]Valentini G et al. Ann Rheum Dis 2019. Beckett VL et al. Arthritis Rheum 1984. Kavian N et al. Vascul Pharmacol 2015. Lavie CJ et al. Curr Probl Cardiol 2017.Disclosure of Interests:Lucrezia Verardi: None declared, Enrico De Lorenzis: None declared, Gerlando Natalello: None declared, Laura Gigante: None declared, Umberto La Porta: None declared, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Silvia Laura Bosello Speakers bureau: Abbvie, Pfizer, Boehringer

Download Full-text

POS0329 GASTROINTESTINAL INVOLVEMENT IN SYSTEMIC SCLEROSIS: PATHOGENETIC ROLE OF GUT MICROBIOME, CYTOKINES AND ADIPOKINES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1904 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 392.1-392

Author(s):

E. Pigatto ◽

M. Schiesaro ◽

M. Caputo ◽

M. Beggio ◽

P. Galozzi ◽

...

Keyword(s):

Systemic Sclerosis ◽

Gut Microbiome ◽

Serum Levels ◽

High Serum ◽

Healthy Population ◽

Gastrointestinal Involvement ◽

Degrading Bacteria ◽

Gi Symptoms ◽

Low Levels ◽

The Impact

Background:Gastrointestinal (GI) involvement is very common in patients with Systemic Sclerosis (SSc). The pathophysiology of GI manifestations has not yet been defined. Cell-mediated immunological reactions appear to lead to endothelial damage resulting in fibrosis. The risk of developing malnutrition reinforces the need to better understand GI pathophysiology in these patients.Objectives:The study aimed to evaluate GI symptoms (GIT 2.0) and malnutrition status (MUST) and to determine specific bacterial changes in gut microbiome by investigating the possible presence of positive hot spots in bacterial species in SSc patients and their potential role in the disease progression. We also evaluated serum levels of adipokines and cytokines involved in the pathogenesis of SSc and their role, in addition to gut microbiome, in predicting the onset of GI involvement and malnutrition in SSc patients.Methods:We enrolled 25 scleroderma patients (EULAR/ACR 2013 criteria). UCLA-SCTC GIT 2.0 questionnaire to evaluate GI symptoms and MUST to investigate the risk of malnutrition were used. Gut microbiome was analyzed and the samples were subjected to extraction for the 16S rRNA gene (Earth Microbiome Project and the NIH-Human Microbiome Project). The microbiome was investigated at phenotypic and genotypic level. Serum levels of cytokines and adipokines (adiponectin and leptin) were evaluated by ELISA.Results:79.9% of patients had GERD and 63.5% abdominal distension at GIT 2.0 questionnaires. 48% of patients had moderate risk of malnutrition (MUST=2) and 12% had high risk (MUST=3). Gut microbioma: 19 patients (76%) had low similarity and 11 (44%) low diversity compared to the healthy population. The prevailing enterotypes of gut microbiome was Bacteroides (80%) and Prevotella (20%). The genotypic evaluation showed a reduced concentration of: gluten-digesting (Lactobacillus); lactose-digesting (Faecalibacterium); vitamin K-producing (Enterococcus, Desulfovibrio and Veillonella); acetaldehyde-degrading bacteria. 24 patients (96%) showed a reduction in bacteria devoted to maintaining weight control (Bifidobacterium and Ruminococcus). The patients had an altered intestinal permeability with less mucolytic bacteria (Bacteroides) and reduced production of LPS (Enterobacter and Escherichia). Low levels of butyrate (Eubacterium and Clostridium), acetate and propionate were found for SCFA-producing bacteria. Potentially pathogenic bacteria were also investigated: Salmonella was found in 14 (56%), Klebsiella in 9 (36%) and Enterococcus Faecalis in 3 (12%) patients. 11 (44%) patients had elevated serum levels of IL10 and IL12; 4 (16%) had high value of leptin. Correlation was found in patients who had a reduced concentration of gluten-digesting bacteria and MUST. Elevated MUST was correlated with serological increase in IL17A and IFN-α. Serum levels of IL12 and IL10 were found to correlate with specific bacteria alterations: high concentration of acetaldehyde-producing bacteria and low levels of acetaldehyde-degrade bacteria (also correlated with high serum levels of IL6), mucolytic bacteria and producers of hydrogen sulphide, acetate and propionate. Finally, reduced levels of mucolytic bacteria and acetate producing bacteria correlated with high serum leptin levels.Conclusion:The relationship between the gut microbiome and SSc seems to be multifactorial. In our study genotypic changes of gut microbioma might play a role in damaging the permeability of the mucosa and increasing risk of malnutrition. The evaluation of gut microbiome and cytokine profile is probably going to be of value in the follow-up of SSc. However, further studies are needed to clarify the impact of GI dysbiosis on the immune system in SSc.References:[1]Patrone V. et al. Gut microbiota profile in systemic sclerosis patients with and without clinical evidence of gastrointestinal involvement, Sci Rep. 2017; 7: 14874Disclosure of Interests:None declared

Download Full-text

AB0545 GASTROINTESTINAL INVOLVEMENT IN SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4868 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1569.2-1569

Author(s):

A. Argibay ◽

I. Novo ◽

M. Ávila ◽

P. Diéguez González ◽

M. Estévez Gil ◽

...

Keyword(s):

Systemic Sclerosis ◽

Gastroesophageal Reflux ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Biliary Tree ◽

Motility Disorder ◽

Anatomical Site ◽

Digital Ulcers ◽

Lung Involvement ◽

Imaging Results

Background:Systemic sclerosis (SSc) is a chronic, connective tissue disease with an autoimmune pattern characterized by inflammation, fibrosis and microcirculation changes leading to internal organs malfunctions. The gastrointestinal tract (GIT) is affected in up to 90% of patients with SSc. Any part of the GIT from the mouth to the anus can be affected. There are few descriptive studies about SSc-related GIT involvement.Objectives:We aimed to characterize the GIT involvement in patients with SSc.Methods:This retrospective study included all patients from SSc cohort of our autoimmune diseases unit in a tertiary referral centre. All patients fulfilled SSc criteria proposed by the American College of Rheumatology. All subjects’ histories were evaluated. Laboratory and imaging results were obtained from the hospital files. Patients with digestive manifestations were compared with patients without GIT involvement. Chi2 and t-student were used, using the statistical package SPSS25.0.Results:83 subjects with SSc were included, 68 (81,9%) of them were women. The mean age at the onset of SSc was 62,1 ± 15,3 years (range 26-89) with a mean follow-up of 9,6 ± 7,4 years. 80,7% of patients had limited SSc, 12% diffuse SSc, 4.8% SSc sine scleroderma and 2,4% early SSc. Considering the immunological profile 12 (14,5%) had Scl70 antibodies, 49 (59%) anticentromere and 21 (25,3%) had ANA antibodies without specificity for anti-Scl70 or anticentromere. 37,3% patients had lung involvement, 20,5% scleroderma and 30,1% digital ulcers. 79,5% of SSc patients were treated with proton pump inhibitors or H2 blockers. 53 (63,9%) patients with SSc had GIT involvement. In 11 patients (20,7%) digestive involvement was diagnosed before SSc (mean 26,2 months). Esophageal involvement occurred in 83%, gastric involvement in 28,3%, intestine involvement in 24,5% and liver and biliary tree involvement in 26,4%. See table 1. No significant differences in age, sex, SSc subtype, autoantibody profile, lung involvement, skin disease, mortality and therapy were observed between patients with or without GIT manifestations. There were no deaths associated with GIT involvement. The most common pharmacologic therapy used was proton pump inhibitors (86,8%), domperidone (20,8%) and antibiotic rotation (17%).EsophagealGastricIntestinalLiver and biliary tree44/53 (83%)15/53 (28,3%)12/53 (24,5%)14/53 (26,4%)Esophageal motility disorder 8 (15,1%)Gastroparesis 6 (11,3%)Small bacterial overgrowth 7 (13,2%)Primary biliary cholangitis 9 (17%)Gastroesophageal reflux 40 (75,5%)Abdominal pain /nausea 10 (18,9%)Colonic inertia 1 (1,9%)Autoimmune hepatitis 3 (5,7%)Dysphagia 11 (20,8%)Subacute gastritis 7 (13,2%)Diarrhea 6 (11,3%)Cholestatic liver enzymes 11 (20,8%)Flatulence / abdominal discomfort 6 (11,3%)Cirrhosis 2 (3,8%)Conclusion:Almost two thirds of our cohort of SSc have symptomatic gastrointestinal disease. GIT manifestations are heterogeneous. Symptoms are non-specific and overlapping for a particular anatomical site. Esophagus is the most commonly affected. More than seventy-five per cent of patients experience symptoms of gastroesophageal reflux. We did not find differences among patients with and without SSc GIT disease. 17% of patients had a Reynold’s syndrome.References:[1]Alastal Y et al. Gastrointestinal manifestations associated with systemic sclerosis: results from the nationwide inpatient simple. Ann Gastroenterol 2017; 30 (5): 1-6.[2]Savarino E et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology. 2013; 52(6):1095–100.[3]Steen VD et al. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis and rheumatism. 2000; 43(11):2437–44.Disclosure of Interests:None declared

Download Full-text

AB1076 COLOR DOPPLER HIGH- FREQUENCY ULTRASOUND OF DIGITAL ARTERIES IN PATIENTS WITH SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5395 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1827.3-1827

Author(s):

O. Alekseeva ◽

N. Yudkina ◽

A. Demina ◽

A. Volkov ◽

E. Nasonov

Keyword(s):

Blood Flow ◽

Systemic Sclerosis ◽

Color Doppler ◽

Laboratory Data ◽

Clinical Signs ◽

Vascular Complications ◽

Nailfold Capillaroscopy ◽

Exclusion Criterion ◽

Digital Ulcers ◽

Linear Probe

Background:Systemic sclerosis (SSc) can lead to vascular complications such as digital ulcers or pitting scars (DU/PS). These changes develop in most patients with SSc and exacerbate their condition. However, there are no methods for dynamic assessment of the vascular involvement. The dynamics of capillaroscopic changes is very slow.Objectives:The aim of the study was to compare blood flow parameters of digital arteries in SSc patients and healthy individuals and to compare with nailfold capillaroscopy and clinical signs of ischemia (DU/PS).Methods:32 SSc patients, mean age 49,5 [42,0; 59,0] yrs and 26 ‘healthy’, mean age 43,5 [33,0; 57,0], were included. Groups of patients differed by gender and age. The exclusion criterion was the presence of obliterating vascular disease of the upper extremities. An Esaote MyLab Twice US system with 22 MHz linear probe was used. A total of SSc patients and controls underwent Color Doppler ultrasonography (CDUS) of 376 (256 + 208) digital arteries to compare blood flow velocity, resistive indices (RIs) and presence of occlusion. Nailfold capillaroscopy, clinical and laboratory data were also evaluated.Results:In digital arteries, pulsatility index (PI), peak systolic velocity (PSV) and end-diastolic velocity (EDV) were significantly lower and RI higher in SSc patients compared with controls (PSV: 13,28 [9,88; 16,7] vs17,45 [12,65; 22,5] cm/s, p=0,008; EDV: 2,68 [1,78, 4,05] vs 6,37 [4,75; 8,5] cm/s, p=0,000; RI: 0,78 [0,69; 0,81] vs 0,68 [0,59; 0,74], p=0,005; PI: 1,73 [1,32; 2,19] vs 1,22 [0,99; 1,55], p=0,002).We did not find any correlation between two methods. Also, we did not reveal any correlation between DU/PS, clinical, laboratory data and CDUS, but we found relationship between DU/PS and avascular areas or capillaroscopic findings (r= 0,37, p=0,045 and r= 0,40, p=0,03 correspondingly).Conclusion:Blood flow is significantly decreased in digital arteries in SSc, but clinical features of vasculopathy depend on microcirculatory disorders. It is important to continue research to find methods for dynamic evaluation of microcirculatory changes.References:noDisclosure of Interests:None declared

Download Full-text