Clinical Manifestations Of Systemic Sclerosis Research Articles

Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway

Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.

Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: amulticenter CRDC cohort in China.

The presence of circulating antinuclear antibodies (ANAs) is ahallmark of immune dysregulation in patients with systemic sclerosis (SSc). Avariety of ANAs are associated with unique sets of disease manifestations and are widely used in clinical practice in SSc. This study aimed to investigate the clinical features of SSc patients negative for ANAs in aChinese Rheumatism Data Center (CRDC) multicenter cohort in China. Patients were prospectively recruited between April 2008 and June 2019 from 154 clinical centers nationwide, and all cases fulfilled the 2013 ACR/EULAR classification criteria for systemic sclerosis. Results for antinuclear antibodies were intensively collected. Demographic, clinical, and laboratory data were compared between ANA-positive SSc patients and those negative for ANAs. Antinuclear antibodies were detected in 2129 of 2809patients enrolled in the study; 4.2% of patients were negative. There were more males among ANA-negative SSc patients (29/60 vs. 294/1746, p < 0.001). The incidence of certain critical organ involvement, including gastroesophageal reflux (5.6% vs. 18.5%, p = 0.002), interstitial lung disease (65.2% vs. 77.9%, p = 0.015), and pulmonary arterial hypertension (11.5% vs. 29.0%, p = 0.006) was significantly lower in ANA-negative patients than in ANA-positive patients. The proportion of abnormal erythrocyte sedimentation rate (32.4% vs. 47.6%, p = 0.013) and IgG elevation (14.3% vs. 37.0%, p = 0.003), an indicator of disease activity, was significantly lower in ANA-negative patients than in ANA-positive patients. Antinuclear antibodies are strongly associated with the clinical manifestations of systemic sclerosis, with ANA-negative SSc patients tending to exhibit relatively milder disease.

Raynaud’s phenomenon and positive antinuclear antibodies as first manifestation of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes): a case report

BackgroundPOEMS syndrome is a rare paraneoplastic syndrome caused by plasma cell disorder almost always lambda restricted. Secondary Raynaud’s phenomenon is an overlooked skin manifestation of the disease even though it is present in twenty percent of patients. On POEMS syndrome have not been described positive antinuclear antibodies (ANA) and this could lead to a misdiagnosis of autoimmune disease, mainly systemic sclerosis.Case presentationA 47-year-old man presented with color changes on fingertips consistent with biphasic Raynaud’s phenomenon; an antinuclear antibody test was positive (at 1:320 titers in a speckled pattern) with normal nailfold capillaroscopy. Clinical features of systemic sclerosis were absent. Twenty-four months later, the patient presented symmetric sensorimotor demyelinating polyneuropathy, and he was diagnosed with Guillain–Barre syndrome; treatment with intravenous gammaglobulin had an incomplete response. Raynaud’s phenomenon persisted associated with acrocyanosis, white nails, and positive ANA (1:1280 in a nucleolar pattern). POEMS syndrome was suspected, and serum protein electrophoresis (SPEP) was done. The SPEP revealed polyclonal gammopathy, and serum immunofixation showed monoclonal (M)-protein (IgG lambda). Serum vascular endothelial growth factor concentration showed increased levels. The patient was diagnosed with POEMS syndrome, and treatment with lenalidomide and dexamethasone improved the Raynaud’s phenomenon, acrocyanosis, and white nails, but the neurological response was partial.ConclusionsPOEMS syndrome may mimic clinical manifestations of systemic sclerosis v.g. Raynaud’s phenomenon, skin thickening, telangiectasia, and positive ANA. Raynaud’s phenomenon may precede other clinical manifestations of POEMS syndrome by several months. It is necessary to have a high index of suspicion for the diagnosis, especially in patients with peripheral polyneuropathy and monoclonal paraprotein. The significance of positive ANA in this condition is unknown and deserves further investigation.

Functionally Active Antibodies to the Angiotensin II Type 1-Receptor Measured by a Luminometric Bioassay Do Not Correlate With Clinical Manifestations in Systemic Sclerosis: A Comparison With Antibodies to Vascular Receptors and Topoisomerase I Detected by ELISA.

Objectives1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT1R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ETA1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance.MethodsSera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT1R. Patients’ sera were also tested by commercially available ELISA for anti-AT1R, -ETA1- and by an in-house ELISA for anti–topo-I-abs.ResultsFifty-two percent of the SSc-patients had functionally active anti-AT1R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT1R-, -ETA1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT1R-, and -ETA1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT1R-, -ETA1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT1R, and ETA1 were associated with digital ulcers, pulmonary- and esophageal manifestation.ConclusionsFunctionally active anti-AT1R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.

Gender differences in clinical features and outcomes of a Portuguese systemic sclerosis cohort.

Evidence for the role of sex in the clinical manifestations of systemic sclerosis (SSc) patients is emerging. Some multicenter cohorts have shown that male SSc patients have more severe disease and worse survival. To assess the differences in clinical manifestations and survival in Portuguese SSc patients according to gender. Data from male and female adult SSc patients included in the Rheumatic Diseases Portuguese Register (Reuma.pt) were analysed and compared. Survival was calculated for patients included in Reuma.pt. within the first two years of diagnosis (inception cohort). In total, 1054 adult patients with SSc were included, 12.5% males. No differences in demographic features and comorbidities were found between the sexes, except for a higher rate of cigarette smokers among men. Diffuse cutaneous SSc and anti-topoisomerase antibodies were more prevalent in males than females. Additionally, male patients presented significantly more myositis, interstitial lung disease and gastric involvement. There were no differences in the patterns of drug use between the sexes. During follow-up, more deaths were reported in men than women (12.1% vs 7.3%, p= 0.04). The overall 1-, 3-, and 5-year survivals from diagnosis of the inception cohort (N= 469) for men vs women were 96.4% vs 98.2%, 93% vs 95.9%, and 75.8% vs 93.2%, respectively, with statistically significant differences (p< 0.01). This study confirms the existence of gender differences in clinical and immunological SSc features. Although SSc is less common in men than women, men have a more severe expression of skin and internal organ involvement and worse survival. Key Points • There are differences in SSc disease manifestations between sexes. • Males more commonly have diffuse cutaneous SSc, anti-topoisomerase antibodies, pulmonary and musculoskeletal involvement. • In the inception cohort, men had worse survival rates than women.

Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.

Heart injury in juvenile systemic sclerodermy (clinical case)

Juvenile systemic sclerosis (JSS) has many clinical manifestations that differ from adults. Early diagnosis is problematic. The course of the disease and the severity of the prognosis depend on the involvement of internal organs in the process, first of all, the heart, lungs, kidneys. Cardiac pathology is a frequent and prognostically unfavorable target of the scleroderma process in adults, but it is rarely diagnosed in children. The aim of the work was to study the features of the clinical manifestations of systemic sclerosis in a child with severe heart disease. A polymorphism of the clinical symptoms of severe heart damage with the development of dilated cardiomyopathy in a one-year-old child with systemic sclerosis is presented. The features of the case are the early debut of systemic sclerosis in a child with a burdened hereditary history of autoimmune pathology (psoriasis in the father and grandmother), rapid progression of the autoimmune process, severe heart damage by the type of non-compact (dilated) cardiomyopathy, positive clinical dynamics when using pathogenetic therapy. Early detection of cardiovascular lesions using modern diagnostic methods, timely implementation of adequate therapy in a multidisciplinary team and regular cardiovascular screening can improve the prognosis, quality of life and reduce mortality.

Dysphagia, reflux and related sequelae due to altered physiology in scleroderma.

Systemic sclerosis is a connective tissue disease that presents with significant gastrointestinal involvement, commonly in the esophagus. Dysphagia is a common clinical manifestation of systemic sclerosis and is strongly related to esophageal dysmotility. However, there are multiple other contributing factors in each step in the physiology of swallowing that may contribute to development of severe dysphagia. The oral phase of swallowing may be disrupted by poor mastication due to microstomia and poor dentition, as well as by xerostomia. In the pharyngeal phase of swallowing, pharyngeal muscle weakness due to concurrent myositis or cricopharyngeal muscle tightening due to acid reflux can cause disturbance. The esophageal phase of swallowing is most commonly disturbed by decreased peristalsis and esophageal dysmotility. However, it can also be affected by obstruction from chronic reflux changes, pill-induced esophagitis, or Candida esophagitis. Other contributing factors to dysphagia include difficulties in food preparation and gastroparesis. Understanding the anatomy and physiology of swallowing and evaluating systemic sclerosis patients presenting with dysphagia for disturbances in each step can allow for development of better treatment plans to improve dysphagia and overall quality of life.

Dysbiosis and Gut Microbiota Modulation in Systemic Sclerosis.

Gastrointestinal (GI) involvement is an early manifestation in systemic sclerosis (SSc), affecting more than 90% of patients, and severe GI disease is a marker of poor prognosis and mortality. Recent studies have hypothesized that alterations of the intestinal microbiota, known as dysbiosis, may represent 1 of the possible environmental factors influencing SSc disease status. In addition, specific microorganisms may be associated with SSc pathogenesis, progression, and GI manifestations. Therapeutic approaches aiming to modulate the intestinal microbiota have emerged, as alternatives to treat GI symptoms, and dietary interventions, probiotic administration, and fecal microbiota transplantation are potential therapies for SSc patients. However, given the complexity and variability of pathogenesis and clinical manifestations in SSc, these therapies need to be combined with additional interventions that target other disease components. Here, we summarize studies addressing intestinal dysbiosis in SSc and discuss the potential of microbiota modulators to treat SSc-related GI disorders.

Circulating Galectin-1 and Galectin-3 in Sera From Patients With Systemic Sclerosis: Associations With Clinical Features and Treatment.

Systemic Sclerosis (SSc) is a rheumatic disease characterized by fibrosis, microvascular damage and immune dysregulation. Two major subsets, limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc) can be defined, according to the extent of skin involvement. Increasing evidence indicates a role for galectins in immune and vascular programs, extracellular matrix remodeling and fibrosis, suggesting their possible involvement in SSc. Here, we determined serum levels of galectin (Gal)-1 and Gal-3 in 83 SSc patients (dcSSc n = 17; lcSSc n = 64; ssSSc n = 2), and evaluated their association with clinical manifestations of the disease. Patients with dcSSc showed lower Gal-3 levels, compared to lcSSc (p = 0.003), whereas no considerable difference in Gal-1 levels was detected between groups. Remarkably, higher concentrations of Gal-1 were associated with the presence of telangiectasias (p = 0.015), and higher concentrations Gal-3 were associated with telangiectasias (p = 0.021), diarrhea (p = 0.039) and constipation (p = 0.038). Moreover, lower Gal-3 levels were associated with the presence of tendinous retractions (p = 0.005). Patients receiving calcium blockers (p = 0.048), methotrexate (p = 0.046) or any immunosuppressive treatment (p = 0.044) presented lower concentrations of Gal-3 compared to those not receiving such treatments. The presence of telangiectasia and the type of SSc maintained their statistical association with Gal-3 (β 0.25; p = 0.022 and β 0.26; p = 0.017, respectively) in multiple linear regression models. In conclusion, serum levels of Gal-3 are associated with clinical manifestations of SSc. Among them, the presence of telangiectasias could be explained by the central role of this lectin in the vascularization programs.

Muscle Damage in Systemic Sclerosis and CXCL10: The Potential Therapeutic Role of PDE5 Inhibition.

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc. In vitro, sildenafil dose-dependently reduced CXCL10 release by activated myocytes and impaired cytokine-induced Signal transducer and activator of transcription 1 (STAT1), Nuclear factor-κB (NFκB) and c-Jun N-terminal kinase (JNK) phosphorylation. This was also seen in cardiomyocytes. Sildenafil-induced CXCL10 inhibition at the systemic and human muscle cell level supports the hypothesis that PDE5i could be a potential therapeutic therapy to prevent and treat muscle damage in SSc.

Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66–16.11) vs. 13.56 (12.75–14.38) ng/mL, p < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25–75th percentiles), 10.0 (2.0–16.0) vs. 6.5 (3.25–8.75), p < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, p < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc.

Value of hematological parameters as biomarkers of disease manifestations and severity in systemic sclerosis

Aim of the workTo investigate the value of neutrophil- lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR), red blood cell distribution width (RDW), mean platelet volume (MPV) as biomarkers of disease severity and clinical manifestations in systemic sclerosis (SSc). Patients and methodsThis study included 35 SSc patients, together with 45 controls. Disease severity was assessed by Medsger severity score (MSS). NLR, PLR, MPV, RDW were measured by COULTER LH 750 assay analyzer. ResultsThe mean age of SSc patients and controls was 42.8 ± 12.6 and 40.8 ± 9.7 years respectively. MPV, RDW, NLR, PLR were significantly higher in patients compared to controls (p = 0.03, < 0.001, <0.001, 0.02). NLR, PLR were significantly higher in patients presenting with myositis (p = 0.002, 0.004), and proximal muscle weakness on MSS (p = 0.009, 0.02). NLR was significantly higher in patients with severe peripheral vascular ischemia (p = 0.02). RDW was significantly higher in patients with higher general MSS (p = 0.03) NLR, PLR were significantly positively correlated with severity of muscle weakness (p = 0.001, 0.004), RDW was significantly associated with general MSS (p = 0.002). NLR and PLR were the valuable predictors of muscle involvement (p = 0.003, 0.005) and severity of muscle weakness (p = 0.001, 0.003). ConclusionMPV, RDW, NLR, PLR were significantly higher in SSc patients suggesting their role as biomarkers reflecting the enduring inflammatory process in SSc. Increased NLR and PLR were related to muscular involvement, and severity of muscular weakness. Increased NLR predicted severity of peripheral vascular ischemia and elevated RDW predicted general severity, MPV did not predict severity or disease manifestations of SSc.

Demographic characteristics and clinical manifestations of systemic sclerosis in Benghazi, Libya

Background: Systemic sclerosis (SSc) is a rare, heterogeneous autoimmune disease characterized by skin fibrosis, vasculopathy, and internal organ involvement. This study aims to determine the frequency of clinical manifestations of SSc among Libyan patients in Benghazi. Patients and Methods: Thirty patients (28 females) attended the Rheumatology Clinic at Benghazi Medical Center between January 2016 and December 2019. They were diagnosed to have SSc according to American College of Rheumatology/European League Against Rheumatism 2013 revised classification criteria and were classified into diffuse cutaneous systemic sclerosis (dcSSc) and localized systemic sclerosis (lcSSc) disease subsets. Results: We reviewed the data of the 30 patients, including 28 (93.3%) females and 2 (6.7%) males (female: male ratio 14:1); the mean age at diagnosis was 40.5 ± 21.5 years (17–62 years). Twenty-four (80%) patients were diagnosed as dcSSc, whereas 6 (20%) were diagnosed as lcSSc. On diagnosis, patients with dcSSc were comparatively younger than those with lcSSc. The frequency of musculoskeletal manifestations and organ involvement was more frequent among patients with dcSSc (P = 0.001). All the thirty patients had rheumatoid factor and anti-nuclear antibody positivity. Anti-Scl-70 was only positive in the dcSSC subset in all patients of dcSSc only, whereas anti-centromere Ab was positive in all patients of lcSSc only. Conclusions: This is the first study to assess the clinical manifestations of SSc in the Libyan population. Our disease cohort showed similarity to what was published in other cohorts with regard to the age at the time of diagnosis, gender, and autoimmune profile.

Clinical pattern of systemic sclerosis in Central Ukraine. Association between clinical manifestations of systemic sclerosis and hypertension.

ObjectivesSystemic sclerosis (SSc) is a rare disease of connective tissue, manifestations of which may vary in different geographical areas. We aimed to describe the clinical portrait of patients with SSc in Dnipropetrovsk region and to investigate how initial clinical and laboratory characteristics are connected with the presence of hypertension in SSc onset.Material and methodsPatients were enrolled to this study from the registry of SSc patients, established in the Rheumatology Department, Mechnikov Dnipropetrovsk Regional Clinic, Dnipro. This registry contains histories of new cases of SSc from 1993 to 2014. Patients are followed-up and receive treatment according to EULAR and local standards. Diagnosis of SSc was based on ACR and EULAR Criteria for systemic Sclerosis. Two patients developed scleroderma renal crisis during follow-up. This report is a cross-sectional study. We analysed only data of the first visit to a rheumatologist.ResultsIn total 148 patients (median age [IQR] – 47 [40; 52] years) fulfilled the inclusion criteria. Male/female ratio was 1 : 20.1. The most frequent clinical signs were Raynaud’s phenomenon and arthritis. The prevalence of skin lesion in dcSSc patients was twice as high as in lcSSc patients. Pulmonary fibrosis occurred significantly more commonly in dcSSc patients. Hypertension occurred in 26–33% in both groups. Patients with hypertension at the SSc onset were seven years older than normotensive patients. More hypertensive patients were classified as lcSSc. Mean GFR was dramatically lower in hypertensive patients.ConclusionsThe most common clinical form in our study was diffuse cutaneous subset of SSc. Hypertension in patients with SSc may be associated with local cutaneous subset of SSc and renal impairment. The strongest predictors of clinical form of SSc are signs of fibrosis (skin lesion and pulmonary fibrosis) and inflammation (arthritis and elevated CRP).

Clinical Aspects of Overlap Syndrome - Case Report and Literature Review

We report a patient with overlap syndrome (systemic sclerosis (SSc) and polymyositis (PM)). The heterogeneous nature of systemic sclerosis may lead to a great diversity in the clinical presentation of the disease. With this case report we aim to demonstrate clinical manifestations of systemic sclerosis and polymyositis in an overlap-syndrome, with support from antibody profile and laboratory data.

Environmental Pollution by Benzene and PM10 and Clinical Manifestations of Systemic Sclerosis: A Correlation Study.

Atmospheric air pollution has been associated with a range of adverse health effects. The environment plays a causative role in the development of Systemic Sclerosis (SSc). The aim of the present study is to explore the association between particulate (PM10) and benzene (B) exposure in Italian patients with systemic sclerosis and their clinical characteristics of the disease. A correlation study was conducted by enrolling 88 patients who suffer from SSc at the Fondazione Policlinico “A. Gemelli” in Rome (Italy) in the period from January 2013 to January 2014. The average mean concentrations of B (in 11 monitoring sites) and PM10 (in 14 sites) were calculated using data from the Regional Environmental Protection Agency’s monitoring stations located throughout the Lazio region (Italy) and then correlated with the clinical characteristics of the SSc patients. Of the study sample, 92.5% were female. The mean age was 55 ± 12.9 years old and the mean disease duration from the onset of Raynaud’s phenomenon was 13.0 ± 9.4 years. The Spearman’s correlation showed that concentrations of B correlate directly with the skin score (R = 0.3; p ≤ 0.05) and inversely with Diffusing Lung Carbon Monoxide (DLCO) results (R = −0.36; p = 0.04). This study suggests a possible role of B in the development of diffuse skin disease and in a worse progression of the lung manifestations of SSc.

CD16-positive circulating monocytes and fibrotic manifestations of systemic sclerosis.

The objective of this study is to assess the association of clinical manifestations of systemic sclerosis (SSc) with the absolute count of circulating blood monocyte subpopulations according to their membrane expression of CD16. Forty-eight consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in this cross-sectional study. CD16+ monocyte absolute count was defined by flow cytometry and confronted to the clinical characteristics of SSc patients. Twenty-three healthy donors (HD) were randomly selected for comparison. SSc patients had an increased number of total circulating blood monocytes compared to HD (p<0.001). The CD16- subpopulation absolute count was increased in SSc patients compared to HD (p<0.001) but was similar in limited SSc (lSSc) and diffuse SSc (dSSc). On the contrary, the CD16+ population absolute count was increased in dSSc compared to both HD and lSSc patients (dSSc 0.071Giga/L (±0.034) vs HD 0.039Giga/L (±0.030), p<0.01, and dSSc 0.071Giga/L (±0.034) vs lSSc 0.048Giga/L (±0.024), p<0.05). The CD16+ monocyte subpopulation absolute count was significantly correlated with the severity of skin fibrosis evaluated by the modified Rodnan skin score (p<0.001). The CD16+ monocyte subpopulation was also associated with pulmonary fibrosis (p<0.05), with the severity of the restrictive ventilatory defect evaluated by total lung capacity (p<0.05) and with the pulmonary function impairment reflected by diffusing capacity of the lungs for carbon monoxyde measures (p<0.01). These results suggest that CD16+ monocytes are associated with the main fibrotic manifestations of SSc and their role in the pathogenesis of fibrosis in this autoimmune disorder should therefore be further considered.

Association between Clinical Manifestations of Systemic Sclerosis and Esophageal Dysmotility Assessed by High-Resolution Manometry

Purpose To characterize esophageal involvement according to high-resolution manometry (HRM) findings using the 3rd version of the Chicago Classification, in a French population of patients fulfilling the ACR/EULAR 2013 classification criteria for systemic sclerosis (SSc). Methods Thirty-six patients were consecutively included in this cross-sectional non-interventional study and had HRM performed in Rennes University hospital. Demographic and clinical characteristics, SSc history and interstitial lung disease (ILD) on CT-scan were assessed, and compared with esophageal motility. Results Sixty-one percent of SSc patients had ineffective peristalsis (55.6% failed peristalsis and 5.6% weak peristalsis), 33.3% had hypotensive esophagogastric junction pressure, 75% did not have a physiologic contraction following multiple rapid swallow (MRS), and 44.4% had an abnormal peristaltic reserve. One patient had type 1 achalasia and another one had Jackhammer esophagus. Failed peristalsis was associated with pyrosis (odds ratio [OR] 7.28, 95% confidence interval [CI] 1.51-35.21, p = 0.009), a higher modified Rodnan skin score (MRSS) (without failed peristalsis: 4.68 ± 2.95 vs. with failed peristalsis: 10.68 ± 9.23; p&lt;0.05), the presence of telangiectasia (OR 7, 95% CI 1.59-30.8, p = 0.007), and low diffusing capacity of the lung for carbon monoxide (DLCO) (p = 0.013). Food in the esophagus and esophageal dilation on CT-scan were associated with failed contractions on HRM (respectively, OR 6.85, 95% CI 1.12-40.82, p = 0.05, and OR 14.67, CI 2.4-88.5, p = 0.002). Conclusions This study confirms that failed peristalsis is frequent in SSc and associated with other organ involvement. We found a concordance between HRM results and CT-scan findings regarding esophageal involvement.

Ethnic Differences in Autoantibody Diversity and Hierarchy: More Clues from a US Cohort of Patients with Systemic Sclerosis.

To determine the autoantibody repertoire and clinical associations in a multiethnic cohort of American patients with systemic sclerosis (SSc). There were 1000 patients with SSc (196 Hispanic, 228 African American, 555 white, and 21 other) who were screened for antinuclear antibodies (ANA), including anticentromere antibodies (ACA) by indirect immunofluorescence assay, antitopoisomerase-1 (topo-1/Scl-70) by immunodiffusion, and anti-RNA polymerase III (RNAP III) by ELISA. Sera from 160 patients with mainly nucleolar and/or speckled ANA pattern, but negative for ACA, Scl-70, and RNAP III, were further characterized by immunoprecipitation for SSc-specific antibodies. The prevalence of antibodies against RNAP III, Th/To, and PM/Scl did not differ significantly among the ethnic groups. The frequency of anti-Scl-70 was lowest in whites (18.0%) compared with 24.0% and 26.8% in Hispanics and African Americans (p = 0.01), respectively. Compared with African American patients, Hispanic and white subjects had a higher frequency of ACA (p < 0.0001) and lower frequency of U3-RNP (p < 0.0001). U3-RNP antibodies were uniquely higher in African American patients, independent of clinical subset, while Th/To autoantibodies were associated with limited cutaneous SSc in white subjects. Overall, Hispanic and African American patients had an earlier age of onset and a predominance of diffuse cutaneous SSc compared with their white counterparts. SSc-specific antibodies may predict disease subset; however, the hierarchy of their prevalence differs across ethnic groups. This study provides the most extensive analysis to date on the relevance of autoantibodies in the diagnosis and clinical manifestations of SSc in Hispanic American patients.