Complication Of Systemic Sclerosis Research Articles

Diversity and epitope spreading of anti-RNA polymerase III antibodies in systemic sclerosis: a potential biomarker for skin and lung involvement.

Epitope spreading (ES), involving autoantibodies, plays a crucial role in the development and persistence of autoimmune reactions in various autoimmune diseases. This study aimed to investigate the relationship between ES of anti-RNA polymerase III (RNAP III) antibodies (ARAs) and the clinical manifestations of systemic sclerosis (SSc). We investigated whether intermolecular ES occurs among the subunits of the RNAP III complex and whether intramolecular ES targets the major antigen, RPC1, in SSc patients. To achieve this, we synthesized 17 full-length subunit proteins of the RNAP III complex and 5 truncated forms of RPC1 in vitro using a wheat germ cell-free translation system. Subsequently, we prepared antigen binding plates and measured autoantibodies in the serum of SSc patients. Autoantibodies against different RNAP III complex subunits were found in ARAs-positive SSc patients. The intermolecular ES indicators significantly correlated with the modified Rodnan total skin thickness score (mRSS) and surfactant protein-D, a biomarker of interstitial lung disease. However, the extent of disease on high-resolution computed tomography or pulmonary function tests did not show any significant correlation. Intramolecular ES indicator against RPC1 were significantly correlated with mRSS and renal crisis. Furthermore, longitudinal assessment of ES in RNAP III complex subunits correlated with mRSS and exhibited potential as a disease activity biomarker. Our findings indicate a correlation between ES levels and the severity of skin sclerosis or the risk of other complications in SSc. This study suggests that measuring ES in SSc serves as a novel biomarker for disease activity.

Understanding the gastrointestinal microbiome in systemic sclerosis: methodological advancements and emerging research.

This review highlights the role of the gastrointestinal (GI) microbiome in systemic sclerosis (SSc). We describe techniques for evaluating the GI microbiome in humans, and emerging research linking GI microbiome alterations (i.e., dysbiosis) and distinct SSc clinical manifestations. We also address the evolving treatment landscape targeting dysbiosis in SSc. Recent literature brings into focus the complex relationship between the GI microbiome and SSc pathogenesis. Advanced techniques (e.g., shotgun metagenomics, meta-transcriptomics) provide deeper insights into microbial taxonomy and active gene expression, exposing dysbiosis as a potential driver of SSc. New studies demonstrate that SSc patients who possess specific SSc clinical features, (e.g., interstitial lung disease), have unique GI microbiome profiles. Dysbiosis is associated with specific clinical features in patients with SSc. New tools for studying the GI microbiome have furthered our understanding of the relationship between dysbiosis and SSc complications. Therapeutic avenues such as dietary adjustments, probiotics, antibiotics, mindfulness practices, and fecal transplants offer potential for managing SSc and preventing its progression through GI microbiome modulation. By clarifying what is known about the relationship between the GI dysbiosis, GI dysfunction, and SSc, this review enhances our understanding of SSc pathogenesis and proposes targeted interventions.

Lung Involvement in Systemic Sclerosis—From Pathogenesis to Prediction

Systemic sclerosis (SSc) is a rare, multifactorial autoimmune disease characterized by widespread vascular damage and fibrosis. Pulmonary involvement is a significant manifestation of SSc, contributing to considerable morbidity and mortality. Therefore, identifying reliable biomarkers is of the utmost importance. This review explores emerging biomarkers to enhance diagnostic accuracy, prognostic assessment, and disease monitoring in SSc lung involvement. We discuss recent findings in immunological biomarkers, inflammatory indicators, and other parameters that can function as potential diagnostic and prognostic tools. A comprehensive understanding of these biomarkers could result in earlier and more accurate detection of pulmonary complications in SSc, aiding in timely intervention. Furthermore, we explore the advances in disease monitoring through innovative biomarkers, focusing on their roles in disease activity and treatment response. Integrating these novel biomarkers into current clinical practice and therapeutic protocols through clinical trials can revolutionize the management of SSc-related lung disease, ultimately improving patient outcomes and quality of life.

High-Protein Nutritional Supplements Improve Nutritional Status in Malnourished Patients with Systemic Sclerosis.

(1) Background: Impaired nutritional status in systemic sclerosis (SSc) is prevalent. (2) Objective: This study aimed to identify pre-cachexia and malnutrition in SSc patients and to estimate the effectiveness of a high-protein oral nutritional supplement (ONS) in improving their nutritional status. (3) Materials and methods: The SSc population comprised 56 patients and a control group of 49 healthy persons. After a baseline clinical evaluation, bioelectrical impedance analysis (BIA), and laboratory tests, SSc patients were divided into well-nourished, pre-cachectic, and malnourished categories. SSc patients with a nutritional disbalance received a high-protein ONS once daily for 3 months. Patients were reassessed at 3 and 12 months after inclusion in the study. (4) Results: SSc patients, in comparison to the control group, had a significantly lower seven-point SGA value [6(0) vs. 7(1), p < 0.001)], lean tissue mass [LTM, 35.1 (10.5) vs. 40.1 (10.10), p = 0.008], and lean tissue index [LTI, 13.5 (3) vs. 14.9 (4), p = 0.009]. Of the 56 SSc patients, 40 (71.4%) were well nourished, 5 (8.9%) had pre-cachexia, and 11 (19.7%) were malnourished. A high-protein ONS in the pre-cachexia group stabilized the SGA value, anthropometric measurements, and BIA after 3 and 12 months. In malnourished patients, it significantly improved the SGA value [5(0) vs. 6(0), p = 0.002], LTI [12.1 (2.1) vs. 12.7 (3.2), p = 0.021] and LTM [31.1 (7.7) vs. 35.1 (9.1), p = 0.021], and that effect remained stable at 12 months. (5) Conclusion: Malnutrition is a common complication of SSc that can be improved with nutritional intervention.

Real-World Clinical Profile and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease: A Subgroup Analysis of Interstitial Lung Disease Data From an Interstitial Lung Disease (ILD) Specialty Clinic in India.

Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by dysregulated innate and adaptive immunity. Interstitial lung disease (ILD) is a common and serious complication of SSc, often leading to significant morbidity and mortality. Consistent demographic characteristics that aid in the early diagnosis of ILD in SSc are lacking. This study aims to identify clinical and demographic parameters associated with ILD in SSc patients and assess the safety and tolerability of nintedanibwith other immunosuppressants. This study is a subgroup analysis of data from the ILD clinic at All India Institute of Medical Sciences Raipur, collected between January 2022 and January 2024. We assessed the clinical and demographic profiles, high-resolution computed tomography thorax patterns, autoantibody profiles, lung function, and treatments used in the patients. We enrolled 57 patients with SSc-associated ILD. The mean age of the participants was 39.0 ± 11.1 years, with 53 (92.9%) being women. The mean body mass index was 20.4 ± 4.32 kg/m². Dyspnea was the most common symptom, followed by skin tightening and cough. Antinuclear antibody tests were positive in 92.9% of patients, and anti-Scl-70 antibodies were positive in 57.9%. Rheumatoid arthritis-SSc overlap was observed in 15.8% of patients. The mean predicted forced vital capacity was 46.5 ± 19.9%, the mean predicted total lung capacity was 64.5 ± 20.4%, and the mean predicted diffusing capacity for carbon monoxide was 46.2 ± 15.7%. The mean six-minute walk distance was 360.3 ± 81.2 meters, and the mean King's Brief Interstitial Lung Disease score was 63.9 ± 10.7. Common radiological abnormalities included ground-glass opacities in 57.8%, traction bronchiectasis in 43.8%, and honeycombing in 28.07%. The predominant ILD pattern was nonspecific interstitial pneumonia. Patients received a combination of prednisolone (5 mg/day) with mycophenolate mofetil (63.2%), hydroxychloroquine (17.5%), cyclophosphamide (12.3%), and methotrexate (7.02%). Nintedanib, the only antifibrotic used, was administered to 17 (29.8%) patients. ILD is relatively common in SSc, particularly in patients with diffuse cutaneous SSc and those with anti-topoisomerase antibodies. Female patients comprised the predominant population in this study. Patients tolerated mycophenolate mofetil and cyclophosphamide well. Nintedanib was the only antifibrotic used, and all patients tolerated the combination of antifibrotics and immunosuppressants well. Early diagnosis is crucial to slow disease progression and preserve lung function. Our results highlight the need for vigilant screening in high-risk groups and suggest that MMF, cyclophosphamide, and nintedanib can be safely incorporated into treatment regimens, offering a potential strategy to improve patient outcomes.

Elevated neutrophil extracellular traps in systemic sclerosis-associated vasculopathy and suppression by a synthetic prostacyclin analog

ObjectivesNeutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release.MethodsBlood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined.ResultsNeutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation.ConclusionOur study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients.

Abstract 1099: Single-cell Transcriptomic And Epigenic Profiling Identifies Sox6 As A Key Regulator Of Arterial Endothelial Cell Phenotype In Systemic Sclerosis-associated Pulmonary Hypertension

Background: Pulmonary hypertension (PH) frequently arises as a complication of systemic sclerosis (SSc), and is a major cause of death among patients with this condition. Pulmonary vasculopathy in SSc is characterized by endothelial dysfunction with subsequent remodeling of the pulmonary vasculature, especially arterioles and small arteries. Characterization of transcriptional regulators driving the pathological changes in arterial endothelial cells (ECs) is critical to understanding pathogenic mechanisms underlying SSc-associated vasculopathy. Methods and Results: We performed single-cell multiome sequencing to simultaneously profile the transcriptome and epigenome of explanted lung tissue from SSc-PH patients (n = 9) and healthy donors (n = 6). We identified co-regulated genes and candidate enhancer regions associated with transcription factors (TFs) across different EC cell states using SCENIC+. Gene regulatory network analysis revealed SOX6 as a key transcription factor for the arterial EC phenotype associated with SSc-PH. 71 genes and 153 regions were predicted to be regulated by SOX6. Notably, SOX6 was the only SOX family member significantly upregulated in SSc-PH arterial ECs (fold change = 40.0, adjusted p-value = 6.1*10 -21 ). Putative bound TF motif instances accounting for chromatin accessibility in the candidate enhancer regions were identified using the base-resolution deep learning model, ChromBPNet. Consistent with SCENIC+ predictions, cell-state specific ChromBPNet models revealed higher putative TF occupancy at SOX motif instances across the genome. In addition, we identified SOX/ETS composite motif instances showing higher putative occupancy in SSc-PH arterial ECs, which may support cooperative binding of SOX proteins with ETS family members. Conclusions: These data provide novel insight into transcriptional regulatory programs of arterial ECs in SSc-PH and highlight SOX6 as a key contributor.

P135 Association of Serum Anti-Muscarinic 3 Antibodies with Gastrointestinal Disease in Systemic Sclerosis

Abstract Background/Aims Gastrointestinal (GI) complications of systemic sclerosis (SSc) are frequent and debilitating with symptoms ranging from reflux to faecal soilage. The pathogenesis of GI disease in SSc is poorly understood. Circulating antibodies against Muscarinic type 3 Receptors (anti-M3R) have been implicated in GI smooth muscle dysfunction and neural activation impairment. We examine whether anti-M3R antibodies associate with objective measures of gastrointestinal symptoms. Methods Sera were collected from SSc patients fulfilling the American College of Rheumatology (ACR) classification criteria for SSc. Healthy control (HC) sera were obtained from age-matched volunteers. SSc patients completed the UCLA GIT 2.0 (UCLA GIT) questionnaire. Serum anti-M3R antibodies were measured using specific enzyme-linked immunosorbent assay (ELISA)(CellTrend GmbH, Germany). SSc sera had elevated anti-M3R antibodies if the concentration exceeded two standard deviations above the mean of HC sera. Statistical comparisons were made using Fisher’s exact test and two sample t-test. Results Sera from 40 SSc patients and five HC were assayed for anti-M3R antibodies. Anti-M3R antibody was higher in SSc patients in comparison to HC (1547 vs 1183U/ml, p = 0.33). Anti-M3R antibody levels were significantly elevated in nine (23%) SSc patients. Cohort characteristics were compared based on anti-M3R antibody levels for SSc patients (Table 1). Group demographics were similar in gender, age and disease duration. There was a trend for higher anti-M3R antibodies in limited compared with diffuse cutaneous SSc subset (66.7 vs 32.2, p = 0.12). Although there was no significant association between Anti-M3R antibody level and GIT score (r = 0.014 p = 0.51), SSc patients with elevated anti-M3R antibody did report numerically more severe reflux symptoms (1.24 vs 0.8, p = 0.23) and fewer lower GI domains of severe soilage (0.56 vs 0.87, p = 0.37) and constipation (0.28 vs 0.52, p = 0.2). Conclusion These results show that there is a subset of SSc patients with elevated anti-M3R antibodies which could be pathogenic by perturbing cholinergic neurotransmission in the GI tract. The trend observed of elevated anti-M3R antibodies with more severe GI symptoms warrants further exploration in a larger cohort of SSc. If confirmed, our findings provide mechanistic rationale for reported benefit from intravenous immunoglobulin on symptom severity in SSc GI disease. Disclosure E. Roblin: None. C. Beesley: None. R. Maclean: None. F. Ahmed: None. C. Murray: None. V.H. Ong: None. C. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

Diagnostic approaches and treatments of systemic sclerosis patient with interstitial lung disease

Background: Systemic sclerosis or scleroderma is a rare disease with multiple complications which may include interstitial lung disease. The findings of diffuse type of systemic sclerosis, moderate restriction in pulmonary function test, interstitial pneumonia in chest x-ray, and ground glass opacity in thoracic CT-scan establish the diagnosis of interstitial lung disease associated with systemic sclerosis. We present a case of interstitial lung disease in a systemic sclerosis case, which was approached and treated comprehensively to slow the progression. Case Presentation: A 40-year-old female was admitted to the rheumatology polyclinic of Dr. Soetomo Hospital Surabaya with persistent dry cough for two years in June 2021. The patient also complained of breathlessness, painful joints, swollen knees, and morning stiffness three months prior to admission. The positive results of antinuclear antibody and rheumatoid factor were identified in 2016, which suggested autoimmune disease of scleroderma and being treated with azathioprine 50 mg twice a day, methylprednisolone 4 mg once a day, chloroquine 200 mg once a day, and calcium lactate once a day. The examinations in 2020 showed moderate restriction from the pulmonary function test, bilateral lung parenchymal infiltrates from the chest x-ray, and ground-glass opacity from the chest computed tomography scan (CT-scan). The patient was monthly prescribed cyclophosphamide 500 mg intravenously for six months as the substitution of azathioprine, methylprednisolone 4 mg once a day, and aspirin 100 mg once a day. The latest worsening condition led the patient to receive the substitution of cyclophosphamide which was mycophenolate mofetil 360 mg twice a day, along with aspirin 100mg and methylprednisolone 4 mg once a day, respectively. Conclusion: As a rare disease, the complications of systemic sclerosis should be anticipated. In this case, interstitial lung disease occurred following nearly five years of systemic sclerosis course which required immunosuppressive agents to enhance the efficacy of treatment. Comprehensive treatment with tight monitoring is necessary to slow the disease progression.

Incidence of Systemic Vasculitis and Clinical Outcomes in Systemic Sclerosis: 2-Years Follow-Up of Asymptomatic Positive for Anti-Neutrophilic Cytoplasmic Antibody.

Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) overlap with systemic sclerosis (SSc) is uncommon. We aimed to determine the incidence of AAV and define clinical outcomes relevant to asymptomatic screening positive for ANCA in SSc after 2 years of follow-up. The study was a cohort study of 185 Thai adult SSc patients testing for ANCA and having a 2-year follow-up at the Scleroderma Clinic, Khon Kaen University, Thailand. The incidence of AAV and outcomes of those who tested positive for ANCA were evaluated. A total of 185 SSc patients were tested for ANCA, of whom 21.6% were positive for either cytoplasmic ANCA, perinuclear ANCA (p-ANCA), anti-myeloperoxidase (anti-MPO), or anti-proteinase3 antibody. Only one 52-year-old female patient with dcSSc, negative for initial ANCA test, developed AAV (microscopic polyangiitis) 7 months after the first ANCA test for an incidence of AAV of 0.27 per 100-person-years (95% CI 0.01-1.5). She was positive for p-ANCA and anti-MPO. Eight of those who had an initial test were positive for ANCA and underwent a repeated test. Only two cases persisted as positive for ANCA (1 anti-MPO and 1 anti-PR3) and had no clinicals suspicious of vasculitis. Four cases that had ANCA turned to a negative result. AAV is a rare complication in SSc, so ANCA may not have any role as a screening test for AAV as it cannot predict the development of AAV in SSc. We suggest testing for ANCA only in SSc patients with clinicals suspicious of AAV.

History of pre-eclampsia does not appear to be a risk factor for vascular phenotype in women with systemic sclerosis

BackgroundVascular phenotype is associated with a poor prognosis in systemic sclerosis (SSc). The identification of its risk factors could facilitate its early detection.ObjectivesTo explore risk factors for a vascular phenotype...

Paul Klee’s progressive dyspnea: A series of historical and clinical vignettes, part V

Paul Klee (1879–1940), the 20th-century Swiss-German artist, suffered and died from complications of systemic sclerosis (SSc, scleroderma). This is the fifth in a series of clinical and historical vignettes wherein Klee’s cardiopulmonary symptoms are described with an emphasis on how progressive dyspnea impacted Klee’s life.

Superiority of systemic bleomycin to intradermal HOCl for the study of interstitial lung disease

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune dysregulation, and multi-organ fibrosis. Interstitial lung disease (ILD) is a complication of SSc and a leading cause of SSc-death. The administration of hypochlorous acid (HOCl) intradermally in the mouse (HOCl-SSc) purportedly shows several features typical of SSc. We studied the model by injecting BALB/c mice daily intradermally with HOCl for 6-weeks, an exposure reported to induce lung fibrosis. On day 42, the skinfold thickness and the dermal thickness were two and three times larger respectively in the HOCl group compared to controls. HOCl treatment did not result in histological features of pulmonary fibrosis nor significant changes in lung compliance. Automated image analysis of HOCl mice lungs stained with picrosirius red did not show increased collagen deposition. HOCl injections did not increase pulmonary mRNA expression of pro-fibrotic genes nor induced the production of serum advanced oxidation protein products and anti-topoisomerase 1 antibodies. Immune cells in bronchoalveolar lavage fluid (BALF) and whole lung digests were not increased in HOCl-treated animals. Since lung fibrosis is proposed to be triggered by oxidative stress, we injected HOCl to Nrf2−/− mice, a mouse deficient in many antioxidant proteins. Lung compliance, histology, and BALF leukocyte numbers were comparable between Nrf2−/− mice and wild-type controls. We conclude that the HOCl-SSc model does not manifest SSc-lung disease.

In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case–control study

BackgroundSome myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM).ObjectivesTo assess the significance of DH/BS...

Coadministration of 3′5-dimaleamylbenzoic acid and quercetin decrease pulmonary fibrosis in a systemic sclerosis model

Systemic sclerosis (SSc) is an autoimmune disease characterized by microvascular compromise and fibrosis. Pulmonary fibrosis, a prominent pulmonary complication in SSc, results in impaired lung function due to excessive accumulation of extracellular matrix components. This study aimed to investigate the effects of coadministration of 3′5-dimaleamylbenzoic acid (AD) and quercetin (Q) on key events in the development and maintenance of pulmonary fibrosis in a bleomycin (BLM)-induced SSc mouse model. The model was induced in CD1 mice through BLM administration using osmotic mini pumps. Subsequently, mice were treated with AD (6 mg/kg) plus Q (10 mg/kg) and sacrificed at 21 and 28 days post BLM administration. Histopathological analysis was performed by hematoxylin and eosin staining and Masson's trichrome staining. Immunohistochemistry was used to determine the expression of proliferation, proinflammatory, profibrotic and oxidative stress markers. The coadministration of AD and Q during the fibrotic phase of the BLM-induced SSc model led to attenuated histological alterations and pulmonary fibrosis, reflected in the recovery of alveolar spaces (30 %, p < 0.01) and decreased collagen deposits (50 %, p < 0.001). This effect was achieved by decreasing the expression of the proliferative markers cyclin D1 (87 %, p < 0.0001) and PCNA (43 %, p < 0.0001), inflammatory markers COX-2 (71 %, p < 0.0001) and iNOS (84 %, p < 0.0001), profibrotic markers α-SMA (80 %, p < 0.0001) and TGF-β (81 %, p < 0.0001) and the lipid peroxidation marker 4-HNE (43 %, p < 0.01). The antifibrotic effect of this combined therapy is associated with the regulation of proliferation, inflammation and oxidative stress, mechanisms involved in the development and progression of the fibrotic process. Our novel therapeutic strategy is the first approach to propose the use of the combination of prooxidant and antioxidant compounds as a potential strategy for SSc-associated pulmonary fibrosis.

Subclinical coronary atherosclerosis, detected by computer tomography with coronary calcium score, and the occurrence of major cardiovascular events at 5 years of follow-up in a cohort of patients with systemic sclerosis

BackgroundSpreading data describe cardiovascular disease (CVD) as a growing cause of hospitalization in systemic sclerosis (SSc) patients. Although interstitial lung disease and pulmonary arterial hypertension (PAH) remain the principal causes of mortality, the presence of CVD has been shown to further increase mortality in SSc patients. Few and contrasting data are available on cardiovascular impairment, particularly of subclinical coronary arteries disease, in SSc patients. The aims of this study were: 1) to determine the demographic, clinical, and cardiovascular differences between the groups of SSc patients with and without subclinical coronary atherosclerosis (SCA) assessed by coronary calcium score; 2) to verify the performance of cardiovascular risk scores in SSc for detection of SCA major cardiovascular events (MCVE); 3) to evaluate the risk factors associated to MCVE in 5 years of follow-up in this study group of patients. MethodsSixty-seven SSc patients were enrolled in this study. SCA was assessed using quantification of coronary calcium score by computerized tomography, reported as Agatson. Evaluation of common cardiovascular risk scores, carotid plaques by Doppler ultrasonography, the history of peripheral artery disease (PAD), lipid profiles, and clinical and laboratiristic characteristics of SSc were assessed at baseline visits for each patient. Factors associated with the presence of SCA were assessed by multivariate logistic analysis. A five years prospective study was performed for the evaluation of MCVE occurrence and its possible predictors. ResultsThe prevalence of SCA was 42% (Agatston scores of 266.04 ± 455.9 units) in our group of SSc patients. Patients with SCA were principally older (p = 0.0001) and had higher rates of CENP-B antibodies (57% vs 26%; p = 0.009), pulmonary arterial hypertension (PAH) (25% vs 3%; p = 0.008), dysphagia (86% vs 61%; p = 0.027), and users of statins (36% vs 8%; p = 0.004), carotid plaque (82% vs 13%; p = 0.0001), PAD (79% vs 18%; p = 0.0001), and metabolic syndrome (25% vs 0%; p = 0.002) than patients without SCA. Metabolic syndrome (OR: 8.2, p = 0.0001), presence of a PAD (OR: 5.98, p = 0.031), and carotid plaque (OR: 5.49, p = 0.010) were the main factors associated with SCA in SSc patients, by multivariate regression analysis. MCVE occurred in 7 patients. By multivariate COX regression analysis unique predictor of MCVE in 5 years of follow-up in our SSc patients was the presence of PAH (HR: 10.33, p = 0.009). Of note, the contemporary presence of PAH and SCA (defined as "not pure" pattern of PAH) was observed in 71% of patients with the occurrence of MCVE ConclusionThis study evidenced the high presence of the new “not pure” pattern of PAH, which could worsen the outcome in SSc in a medium-term (5 years) observation period. Furthermore, our data confirmed a higher cardiovascular impairment in SSc due to the presence of both SCA, mainly associated with typical cardiovascular risk factors, and PAH, life-threatening complications of SSc, that is the principal cause of the occurrence of MCVE in our SSc patients. A careful assessment of cardiovascular involvement in SSc and a more aggressive therapeutic strategy for preventing CAD and treating PAH should be highly suggested to reduce MCVE in SSc patients.

Antivinculin Antibodies in Systemic Sclerosis: Associations With Slow Gastric Transit and Extraintestinal Clinical Phenotype.

The gastrointestinal (GI) tract is commonly affected in systemic sclerosis (SSc). A positive association between antivinculin antibody levels and GI symptom severity is reported in SSc. We sought to examine whether antivinculin antibodies associate with measures of GI dysmotility and extraintestinal clinical phenotype in SSc. A total of 88 well-characterized patients with SSc and GI disease were assayed for antivinculin antibodies by enzyme-linked immunosorbent assay. Whole-gut scintigraphy, GI symptom scores, and clinical features of SSc were compared between patients with and without antibodies. Twenty of 88 (23%) patients had antivinculin antibodies, which were more prevalent in patients with slow gastric transit (35% versus 22%). In the univariate analyses, patients who were positive for antivinculin antibodies were more likely to have limited cutaneous disease (odds ratio [OR] 9.60 [95% confidence interval (95% CI) 1.19, 77.23]) and thyroid disease (OR 4.09 [95% CI 1.27, 13.21]). Such patients were also less likely to have lung involvement based on a Medsger Severity Score of ≥2 (OR 0.25 [95% CI 0.07, 0.92]). Higher levels of antivinculin autoantibodies were associated with less gastric emptying (β coefficient -3.41 [95% CI -6.72, -0.09]). The association between antivinculin antibodies and each of these clinical features remained significant in the multivariable model. In particular, the presence of antivinculin antibodies (β coefficient -6.20 [95% CI -12.33, -0.063]) and higher levels of antivinculin antibodies (β coefficient -3.64 [95% CI -7.05, -0.23]) were each significantly associated with slower gastric transit. Antivinculin antibodies associate with slower gastric transit in SSc and may provide insight into GI complications of SSc.

OA28 CCL24 serum concentration predicts both vascular and fibrotic complications in systemic sclerosis: rationale for a biological target driven basket trial across disease subsets

Abstract Background/Aims CCL24 is a novel target that was found to play a dual role in advancing pro-inflammatory and pro-fibrotic processes in systemic sclerosis (SSc). Previous studies reported that skin and serum CCL24 levels are elevated in SSc and that blocking of CCL24 was effective in preventing and attenuating experimental-induced fibrosis in murine models as well as interfering with endothelial cell activation. Here we tested the concentration of CCL24 in an observational cohort of patients with SSc and available clinical follow-up to determine its clinical value in predicting fibrotic and vascular complications of the disease. Methods Consecutive patients from a single-centre observational cohort were enrolled in this analysis. Clinical data were collected according to the EUSTAR minimal essential data set. Serum Concentration of CCL24 was measured by Luminex assay (Myriad RBM) and defined as “high” for patients over the upper quartile of the healthy control population (110 ng/ml). Interstitial lung disease (ILD) was defined by at least 10% parenchymal involvement at a high-resolution CT scan of the chest, while digital ulcer (DU) disease was defined by the presence of current or history of DU in the previous 6 months. Progressive fibrotic ILD was defined as previously described, according to Erice's criteria within 24 months. Clinical features were compared between CCL24 high vs low by Chi-Square and T-student tests. R software was employed for statistical analysis. Results 189 SSc patients (13% male) fulfilling 2013 ACR/EULAR classification criteria were enrolled in this study. Median (IQR) disease duration was 4 (IQR 2-10) years. 37 (27%) had diffuse cutaneous SSc, 60 (32%) had ILD, and 90 (48%) had DU disease. 52 patients (26%) were CCL24 High. These patients had a higher prevalence of DU (60%, p = 0.042), a higher median (IQR) mRSS [4(2-7) vs 2(0-5), p = 0.036) and showed a higher prevalence of ILD (42% vs 28%, p = 0.055); this was more significant among patients with limited cutaneous SSc (7% vs 12%, p = 0.037). Most importantly, among patients with PF-ILD (19/43 with available 24-month follow-up), 44% had significantly higher CCL24 serum concentration at baseline, compared to stable patients (1150 [817-1593] vs 725 [460-955]; p = 0.017). Consistent with these findings, in patients with ILD, having high CCL24 gave double the chance of progressing within 24 months (66% vs 32% of CCL24 low; p = 0.03). Conclusion We show here that within the context of an observational cohort of unselected patients, CCL24 serum concentration is associated with the presence of DU as well as worse skin and lung fibrotic involvement, suggesting that this molecule may be involved in both vascular and fibrotic manifestations of SSc. These results informed the rationale for a target-enriched basket randomized controlled trial to test the biological and clinical effect of CCL24 inhibition in SSc across cutaneous disease subsets. Disclosure E. De Lorenzis: None. A. Mor: None. R. Ross: None. S. Di Donato: None. R. Aricha: None. H. Levi: None. I. Vaknin: None. F. Del Galdo: Other; FDG received consultancies and research support from Abbvie, AstraZeneca, Boheringer-Ingelheim, Capella, Chemomab, Ergomed, Janssen, Kymab, Mitsubishi-Tanabe.

E020 Pneumatosis intestinalis with spontaneous pneumoperitoneum in a patient with systemic sclerosis-myositis overlap syndrome: a case report and review of the literature

Abstract Background/Aims Pneumatosis intestinalis (PI) is a rare complication of systemic sclerosis (SSc), characterised by submucosal and/or subserosal collections of free gas, forming cystic lesions within the gastrointestinal (GI) tract. Methods A 67-year-old man with SSc-myositis overlap syndrome presented acutely unwell with worsening abdominal pain, bloating, bloody diarrhoea and vomiting for three weeks. He was afebrile and haemodynamically stable. His abdomen was distended with generalised tenderness but soft and regular bowel sounds were audible. There were no palpable organomegaly or signs of peritonism. He had raised CRP, serum amylase, serum lactate and pre-renal acute kidney injury. He tested positive for ANA Hep2 (speckled) and anti-Mi-2b. His contrast-enhanced CT abdomen and pelvis displayed extensive pneumatosis changes, moderately dilated small bowel loops and pneumoperitoneum without portal venous gas or acute thrombotic occlusion in the main-stem superior or inferior mesenteric arteries. He was managed conservatively with bowel rest, elemental diet, cycling antibiotics for small intestinal bacterial overgrowth (SIBO) and commenced on end-of-life care as surgical exploration was deemed too risky considering that he has exceedingly poor cardiac reserve. He made a surprisingly excellent recovery and his repeat CT scans at approximately 11 weeks showed a complete resolution of pneumatosis intestinalis and pneumoperitoneum. Results PI in SSc generally runs a benign course and is usually managed conservatively. The development of PI is multifactorial, involving a complex interplay between mechanical, biochemical, bacterial and drug factors. PI is usually asymptomatic but patients can present with GI and constitutional symptoms or peritonism. CT scan is the most preferred diagnostic modality for PI. Conservative management is preferable to surgical intervention after careful exclusion of acute surgical causes. The underlying cause of PI should be appropriately addressed and managed in all cases. The management of PI is based on the severity of symptoms and it includes bowel rest, elemental diet or parenteral nutrition, antibiotics, high concentration oxygen, hyperbaric oxygen therapy and/or octreotide. Our patient was managed conservatively as he did not exhibit clinical signs of peritonism or bowel ischaemia and surgical interventions were deemed too risky. He was treated with and has responded well to cycling oral antibiotics for SIBO which was thought to be contributory to his PI. Conclusion This case illustrates that PI with or without pneumoperitoneum could be a rare complication of SSc, and contrary to common belief, it is usually benign and managed conservatively with favourable outcome. An accurate interpretation of its clinical significance is crucial as acute presentations and ambiguous imaging findings can simulate acute surgical emergency leading to diagnostic dilemma and unnecessary or risky surgical interventions. However, emergency laparotomy should be considered in patients who exhibit signs of peritonism or bowel ischaemia and therefore timely involvement of surgeons and multidisciplinary team is essential. Disclosure K. Lim: None. S. Knights: None. J. Pauling: None. J. Gotto: None.

The Clinical Significance of Serum Biomarkers of the Intestinal Barrier in Systemic Sclerosis: A Cross-Sectional Study.

Systemic sclerosis (SSc) is an immune-mediated connective tissue disease. Recent studies reported differences in the composition of intestinal microbiota (dysbiosis) in patients with SSc compared to nonsclerodermic subjects. Dysbiosis may disrupt the intestinal barrier, which leads to immunological activation via microbial antigen and metabolite translocation. The study aimed to assess the differences in intestinal permeability between SSc patients and controls and to examine the correlation between intestinal permeability and complications of SSc. The study comprised 50 patients with SSc and 30 matched subjects. Serum intestinal permeability markers: intestinal fatty acid binding protein, claudin-3, and lipopolysaccharides (LPS) were determined using an enzyme-linked immunosorbent assay. SSc patients had a significantly increased concentration of LPS compared to control subjects (232.30 [149.00-347.70] versus 161.00 [83.92-252.20] pg/mL, p < 0.05). The patients with shorter SSc duration (≤6 years) had an increased concentration of LPS and claudin-3 compared to the subgroup with longer disease length: LPS (280.75 [167.30-403.40] versus 186.00 [98.12-275.90] pg/mL, p < 0.05), and claudin-3 (16.99 [12.41-39.59] versus 13.54 [10.29-15.47] ng/mL, p < 0.05). The patients with esophageal dysmotility had a decreased LPS level compared to those without this complication (188.05 [102.31-264.40] versus 283.95 [203.20-356.30] pg/mL, p < 0.05). Increased intestinal permeability in SSc may exacerbate the course of the disease and increase the risk of developing complications. Lower LPS levels in SSc might be a hallmark of esophageal dysmotility.