Juvenile Systemic Sclerosis: About 9 Cases

Scleroderma is a rare disease with two primary forms: localized scleroderma (LS) and systemic sclerosis (SSc). Both are chronic conditions that can manifest in various patterns (subtypes) and are linked to extracutaneous involvement in pediatric patients. Juvenile SSc poses a higher risk of morbidity and mortality, with patients facing life-threatening complications such as lung, heart, and visceral organ fibrosis, and vasculopathy. In contrast, mortality is extremely rare in juvenile LS, but patients are susceptible to significant morbidity, leading to severe disfigurement and functional impairment. Treatment for scleroderma aims to control inflammation and address specific issues. An early diagnosis significantly enhances the overall outcome. This study conducts a retrospective descriptive analysis aiming to document the clinical manifestations, management approaches, and outcomes of systemic sclerosis in a cohort of nine children receiving treatment for juvenile systemic sclerosis at Pediatric B department of Mohammed VI University, Hospital Center in Marrakech, Morocco.

Research on hsa-miR-155-3p and hsa-miR-155-5p as biomarkers for systemic sclerosis and their role in regulating biological behavior

Objective: This study was to investigate the role of hsa-miR-155-3p and hsa-miR-155-5p as biomarkers and regulators of biological behavior in Systemic Sclerosis. Methods: A total of 10 SSc patients and 10 healthy controls were selected for the study. The expression levels of hsa-miR-155-3p and hsa-miR-155-5p in peripheral blood mononuclear cells of SSc patients and healthy controls were measured using RT-qPCR. The diagnostic value of these miRNAs was explored using Receiver Operating Characteristic curve analysis. Pearson or Spearman correlation analysis was performed to assess the correlation between miRNAs and clinical indicators in SSc patients. Potential target genes of hsa-miR-155-3p and hsa-miR-155-5p were predicted using miRDB, Targetscan, and miRDIP databases. GO functional annotation, KEGG pathway enrichment analysis, protein-protein interaction network construction, and selection of central genes were conducted. Results: The expression levels of hsa-miR-155-3p and hsa- miR-155-5p were significantly higher in PBMCs of SSc patients compared to healthy controls (P<0.001). The ROC curve analysis showed that hsa-miR-155-3p and hsa-miR-155-5p had a high diagnostic value for SSc (AUC=1, P<0.001). Correlation analysis revealed that hsa- miR-155-3p, hsa-miR-155-5p, and clinical indicators such as high-resolution CT, neutrophil percentage, lymphocyte percentage, and albumin to globulin ratio were correlated (P<0.05). The signaling pathways enriched with target genes of hsa-miR-155-3p and hsa-miR-155- 5p were closely associated with the occurrence and development of SSc fibrosis, immunity, and inflammation. Conclusions: hsa-miR-155-3p and hsa-miR-155-5p may be involved in regulating the occurrence and development of SSc fibrosis, immunity, and inflammation. They have the potential to serve as biomarkers for clinical diagnosis and treatment of SSc.

Gastrointestinal complications of systemic sclerosis

Systemic sclerosis is an autoimmune disease characterized by progressive skin thickening and tightness.Pulmonary interstitial fibrosis and kidney damage are the most important indicators for mortality;however,the gastrointestinal tract is the most commonly damaged system.Virtually all parts of the gastrointestinal(GI)tract can be involved,although the esophagus is the most frequently reported.The mechanisms that cause such extensive damage are generally unclear,but vascular changes,immunological abnormalities,excessive accumulation of collagen in the submucosa,smooth muscle atrophy and neuropathy may participate because these are the most common histological findings in biopsies and autopsies.Most patients with GI tract involvement complain about dyspepsia,nausea,vomiting,abdominal bloating/distension,and fecal incontinence.These symptoms are generally mild during the early stage of the disease and are likely ignored by physicians.As the disease becomes more advanced,however,patient quality of life is markedly influenced,whereby malnutrition and shortened survival are the usual consequences.The diagnosis for systemic sclerosis is based on manometry measurements and an endoscopy examination.Supportive and symptomatic treatment is the main therapeutic strategy;however,an early diagnosis is critical for successful management.

Detection of Ⅴ,Ⅲ and Ⅰ Type Collagens of Dermal Tissues in Skin Lesions of Patients with Systemic Sclerosis and Its Implication

This study investigated the contents and distribution of collagen Ⅴ （Col Ⅴ） in skin lesions of the patients with systemic sclerosis （SSc） and its roles in the pathogenesis. The contents and distribution for α1 chain of collagen type Ⅰ, Ⅲ and V [α1 （Ⅰ）, α1 （Ⅲ） and α1 （Ⅴ）] in skin lesions of 36 patients with SSc （9 cases of mild fibrosis, 14 moderate, and 13 severe） were detected by using im- munohistochemical SP method. Six cases of normal skin tissues served as controls. The results showed that there was diffuse distribution for three kinds of collagens in dermis. The deep staining α1 （Ⅰ） and α1 （Ⅲ） masses or bands were seen in reticular layer, while α1 （Ⅴ） was distributed more ho- mogeneously. From control to weak, moderate and severe fibrosis stages, α1 （Ⅰ）, α1 （Ⅲ） and α1 （V） showed a gradually increased trend in skin lesions （P〈0.05）. α1 （Ⅴ） was obviously elevated in skin lesions at early stage and persisted in whole fibrotic process and risen in greater contents, while α1 （Ⅰ） and α1 （Ⅲ） were to go higher late and were apparently elevated at moderate and late stages. Com- pared with α1 （Ⅰ）, α1 （Ⅴ） took leading increase at early stage in skin lesions （P〈0.01）, and had more elevated contents than α1 （Ⅲ） at moderate and late stages. The fibrotic changes in dermal reticular layer occurred earlier than those in papillary layer, and the abnormalities of α1 （Ⅴ）/α1 （I） ratio ap- peared before α1 （Ⅲ）/α1 （Ⅰ） ratio. It was concluded that a lot of α1 （Ⅴ） began to deposit in greater contents prior to α1 （Ⅰ） and α1 （Ⅲ） at early stage in SSc and persisted in whole fibrotic process. The changes of α1 （Ⅴ） contents in reticular layer occurred earlier than those in papillary layer, and it sug- gested that the fibrosis in reticular layer appeared earlier.

Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients

AIM To investigate T-cell activation, the percentage of peripheral T regulatory cells(Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis(SSc).METHODS We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc(dc SSc, n = 13) or limited cutaneous SSc(lc SSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease-early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activationcapacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin(IL)-6, IL-10, tissue growth factor-β1(TGF-β1), and IL-17 A.RESULTS We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls(13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls(6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dc SSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects(5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls(18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lc SSc subset against controls(20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dc SSc and lc SSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dc SSc patients compared to controls(10.94% ± 1.65% vs 6.88% ± 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10(1.05-4.60) pg/m L vs 0.00 pg/m L, P < 0.001], TGF-β1(19.94 ± 3.35 ng/m L vs 10.03 ± 2.25 ng/m L, P = 0.02), IL-10(2.83 ± 0.44 pg/m L vs 0.68 ± 0.51 pg/m L, P = 0.008), and IL-17 A [6.30(2.50-15.60) pg/m L vs 0(0.00-0.05) pg/m L, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-β, IL-6 and IL-17 A in the lc SSc subset vs control subjects, as it follows: IL-10(3.32 ± 0.59 pg/m L vs 0.68 ± 0.51 pg/m L, P = 0.003), TGF-β1(22.82 ± 4.99 ng/m L vs 10.03 ± 2.25 ng/m L, P = 0.031), IL-6 [2.08(1.51-4.69) pg/m L vs 0.00 pg/m L, P < 0.001], and IL-17 A [14.50(8.55-41.65) pg/m L vs 0.00(0.00-0.05) pg/m L, P < 0.001]. Furthermore, circulating IL-17 A was higher in lc SSc as opposed to dc SSc subset(31.99 ± 13.29 pg/m L vs 7.14 ± 3.01 pg/m L, P = 0.008). Within the dc SSc subset, raised levels of IL-17 A and IL-6 were detected vs healthy controls: IL-17 A [2.60(0.45-9.80) pg/m L vs 0.00(0.00-0.05) pg/m L, P < 0.001], IL-6 [2.80(1.03-7.23) pg/m L vs 0.00 pg/m L, P < 0.001]. Regarding the stages of the disease, TGF-β1 serum levels were increased in early stage against late stage, independently from the SSc phenotype(30.03 ± 4.59 ng/m L vs 13.08 ± 4.50 ng/m L, P = 0.017).CONCLUSION It is likely that the altered percentage of Th17 and CD4+CD25-Fox P3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease.

Cardiac manifestations in systemic sclerosis

Primary cardiac involvement, which develops as a direct consequence of systemic sclerosis(SSc), may manifest as myocardial damage, fibrosis of the conduction system, pericardial and, less frequently, as valvular disease. In addition, cardiac complications in SSc may develop as a secondary phenomenon due to pulmonary arterial hypertension and kidney pathology. The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of the diversity of cardiac manifestations, the presence of subclinical periods, the type of diagnostic tools applied, and the diversity of patient populations. When clinically manifested, cardiac involvement is thought to be an important prognostic factor. Profound microvascular disease is a pathognomonic feature of SSc, as both vasospasm and structural alterations are present. Such alterations are thought to predict macrovascular atherosclerosis over time. There are contradictory reports regarding the prevalence of atherosclerosis in SSc. According to some authors, the prevalence of atherosclerosis of the large epicardial coronary arteries is similar to that of the general population, in contrast with other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the level of inflammation in SSc is inferior. Thus, the atherosclerotic process may not be as aggressive and not easily detectable in smaller studies. Echocardiography(especially tissue Doppler imaging), single-photon emission computed tomography, magnetic resonance imaging and cardiac computed tomography are sensitive techniques for earlier detection of both structural and functional scleroderma-related cardiac pathologies. Screening for subclinical cardiac involvement via modern, sensitive tools provides an opportunity for early diagnosis and treatment, which is of crucial importance for a positive outcome.

Adipose-derived stem cells:Pathophysiologic implications vs therapeutic potential in systemic sclerosis

Adipose-derived stem cells(ADSCs)residing in the stromal vascular fraction(SVF)of white adipose tissue are recently emerging as an alternative tool for stem cell-based therapy in systemic sclerosis(SSc),a complex connective tissue disorder affecting the skin and internal organs with fibrotic and vascular lesions.Several preclinical and clinical studies have reported promising therapeutic effects of fat grafting and autologous SVF/ADSC-based local treatment for facial and hand cutaneous manifestations of SSc patients.However,currently available data indicate that ADSCs may represent a double-edged sword in SSc,as they may exhibit a pro-fibrotic and anti-adipogenic phenotype,possibly behaving as an additional pathogenic source of pro-fibrotic myofibroblasts through the adipocyte-to-myofibroblast transition process.Thus,in the perspective of a larger employ of SSc-ADSCs for further therapeutic applications,it is important to definitely unravel whether these cells present a comparable phenotype and similar immunosuppressive,anti-inflammatory,anti-fibrotic and pro-angiogenic properties in respect to healthy ADSCs.In light of the dual role that ADSCs seem to play in SSc,this review will provide a summary of the most recent insights into the preclinical and clinical studies employing SVF and ADSCs for the treatment of the disease and,at the same time,will focus on the main findings highlighting the possible involvement of these stem cells in SSc-related fibrosis pathogenesis.

Increased inspiratory esophagogastric junction pressure in systemic sclerosis:An add-on to antireflux barrier

AIM:To investigate crural diaphragm(CD)function in systemic sclerosis(SSc)using high-resolution manometryand standardized inspiratory maneuvers.METHODS:Eight SSc volunteers(average age,40.1years;one male)and 13 controls(average age,32.2years;six males)participated in the study.A highresolution manometry/impedance system measured the esophagus and esophagogastric junction(EGJ)pressure profile during swallows and two respiratory maneuvers:sinus arrhythmia maneuver(SAM;the average of six EGJ peak pressures during 5-s deep inhalations)and threshold maneuver(TM;the EGJ peak pressures during forced inhalation under 12 and 24 cm H2O loads).Inspiratory diaphragm lowering(IDL)was taken as the displacement of the EGJ high-pressure zone during the SAM.RESULTS:SSc patients had lower mean lower esophageal sphincter pressure than controls during normal breathing(19.7±2.8 mm Hg vs 32.2±2.7 mm Hg,P=0.007).Sinus arrhythmia maneuver pressure was higher in SSc patients than in controls(142.6±9.4 mm Hg vs 104.6±13.8 mm Hg,P=0.019).Sinus arrhythmia maneuver pressure normalized to IDL was also higher in SSc patients than in controls(83.8±13.4 mm Hg vs37.5±6.9 mm Hg,P=0.005).Threshold maneuver pressures normalized to IDL were also greater in SSc patients than in controls(TM 12 cm H2O:85.1±16.4mm Hg vs 43.9±6.3 mm Hg,P=0.039;TM 24 cm H2O:85.2±16.4 mm Hg vs 46.2±6.6 mm Hg,P=0.065).Inspiratory diaphragm lowering in SSc patients was less than in controls(2.1±0.3 cm vs 3±0.2 cm,P=0.011).CONCLUSION:SSc patients had increased inspiratory EGJ pressure.This is an add-on to EGJ pressure and indicates that the antireflux barrier can be trained.

Transforming growth factor-β signaling in systemic sclerosis

Systemic sclerosis（SSc） is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific Immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β（TGF-β） has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β,a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.

Expression of MMP-9 and TIMP-1 in Lesions of Systemic Sclerosis and Its Implications

In order to investigate the role of MMP-9 and TIMP-1 in the pathogenesis of systemic sclerosis, the expression of MMP-9 and TIMP-1 was immunohistochemically detected in skin lesions of the patients with diffuse cutaneous systemic sclerosis, skin lesions of the patients with limited cutaneous systemic sclerosis, and skin tissues of normal subjects. The results showed that the expression of MMP-9 in lesions of diffuse cutaneous systemic sclerosis was significantly lower than that of normal skins （P〈0.05）. However, no significant difference in the level of MMP-9 in the limited cutaneous systemic sclerosis and normal skin was found. Meanwhile, the expression of TIMP-1 in lesions of diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis were significantly higher than that of normal skins （both P〈0.05）. It was suggested that the expression of MMP-9 and TIMP-1 might play an important role in the development of systemic sclerosis.

Investigation of stressful life events in patients with systemic sclerosis

Objective: To assess the occurrence of stressful life events in the year before the initiation of systemic sclerosis. Methods: A consecutive series of 40 patients with systemic sclerosis (mean age (56.3±11.9) years, mean disease duration (4.3±3.1) years; 32 females and 8 males), including 28 with diffuse cutaneous scleroderma and 12 with limited cutaneous scleroderma, were evaluated. A control group of 40 healthy subjects free of systemic sclerosis also was included. Socioeconomic status was inves- tigated and Paykel's interview for recent life events (a semi-structured research interview covering 64 life events) was conducted. Results: Patients with systemic sclerosis showed higher percentages of lower education (72.5%) and working class (82.5%), and reported more stressful life events (P<0.05), such as exits (P<0.05), undesirable events (P<0.01), and uncontrolled events (P<0.001), when compared with the control. More events that had an objective negative impact (P<0.001) were also reported in systemic sclerosis patients than in the control. These results are in accordance with a multifactorial model of pathogenesis in systemic sclerosis. Conclusion: We reported a strong relationship between stressful life events and the initiation of systemic sclerosis. Our findings are consistent with current understanding of the extensive links of behavioral responses to stress with neurophysiological and biochemical processes.

Gastrointestinal manifestations of systemic sclerosis:An updated review

Systemic sclerosis is an autoimmune disease characterized by vascular disease,fibrosis of the skin,and internal organ dysfunction.Gastrointestinal involvement is the most frequent complication of internal organs,impacting up to 90%of patients.Gastrointestinal involvement can affect any region of the gastrointestinal tract from the mouth to the anus,with a predominance of disorders being observed at the level of the upper digestive tract.The gastrointestinal involvement primarily involves the esophagus,small bowel,and rectum.The severity of gastrointestinal involvement affects quality of life and is a marker of worse prognosis and mortality in these patients.In this review,we describe the current findings regarding gastrointestinal involvement by this entity.

Is spleen circulation impaired in systemic sclerosis and what is the role of liver fibrosis?

AIM:To investigate the spleen vascular involvement and the presence of liver fibrosis in a population of subjects with established systemic sclerosis(SSc).METHODS:In a cross-sectional fashion,17 patients with SSc were compared with 18 patients suffering from hepatitis C virus(HCV) -related liver cirrhosis,grade A and B Child-Pugh classification.Eighteen non elderly subjects,apparently healthy,were used as the control group.Splenic artery resistivity index(SARI) at doppler ultraSound,transient elastography of liver and nailfold capillaroscopy were the main outcomes.RESULTS:Transient elastography values of SSc patients were similar to those of controls;5.2±1.1 vs 4.5 ±1,(P=0.07).Median Alanine amino transferase(ALT) concentrations of cirrhotic patients were greater than those of controls and SSc patients,i.e.66.5(36-89) U/L vs 29(22-34) U/L and 31(22-41) U/L,respectively,(P =0.005).SARI determinations in cirrhotic patients,although significantly higher than those found in controls and SSc patients,showed some degree of overlap with SSc patients,i.e.0.59 vs 0.52 and 0.57,respectively,(P =0.04).Mean systolic blood pressure was significantly higher in SSc patients than in cirrhotics and controls,i.e.142 mmHg vs 128.2 mmHg and 127 mmHg,respectively,(P=0.005).Mean diastolic blood pressure behaved in a similar fashion,i.e.84 mmHg vs 72.2 mmHg and 76.9 mmHg(P=0.005).Nailfold Capillaroscopy grades and diastolic blood pressure values correlated well with SARI results.CONCLUSION:An enhanced resistivity of the splenic artery was found in patients suffering from SSc;they did not have evidence of splenomegaly as well as no liver fibrosis or any other form of liver damage.

Associations with Organ Involvement and Autoantibodies in Systemic Sclerosis: Results from the Canadian Scleroderma Research Group (CSRG)

Objective: Serum from SSc patients was analyzed centrally to determine ANA patterns and extractable nuclear antigens (ENAs) between lcSSc and dcSSc and associations with organ involvement. Methods: 1145 SSc patients had ANA and ENA analyzed by indirect immunofluorescence on HEp-2 substrate at a screening serum dilution of 1/160. Most ENA antibodies [Sm. U1-RNP, Ro52, SS-A/Ro60, topoisomeraseI (Topo1), SS-B/La, chromatin, ribosomal P and Jo1] were measured by laser bead immunoassay;and RNA polymerase III (RNAP) by ELISA. Results: ANA was positive in 95% (same in lcSSc, and dcSSc). Centromere pattern was present in 34%, speckled 22%, nucleolar 18%, homogeneous and speckled (H&S) 16%, multiple nuclear dots 6%. Anti-centromere Ab (ACA) occurred in 46% of lcSSc and 11% of dcSSc (P = 0.0001). ENAs that differed between lcSSc and dcSSc subsets were Topo1 (OR 2.4, P = 0.0001) and RNAP (OR 5.6, P 0.0001) more common in dcSSc. Overall, 15% had positive Topo1;usually with a H&S pattern (67%);Topo1 was associated with ILD on CXR (OR 2.3;95% CI 1.5 - 3.5) and HRCT (OR 3.8;95% CI 1.8 - 8.2). RNAP occurred in 18.5% (35.4% in dcSSc vs. 8.9% in lcSSc). Scleroderma renal crisis (SRC) was 13 times more likely if RNAP positive;P = 0.0001. ACA was only weakly associated with sPAP > 50 mmHg (OR 1.8;95%CI 1.1 - 3.0). Conclusion: ANA homogeneous pattern alone is rare in SSc;ACA was significantly more common in lcSSc. Many ENAs are equal in lcSSc and dcSSc except RNAP and Topo1. RNAP has the highest OR of SRC. Topo1 is less strongly associated with ILD. Abstract word count: 249, Body word count 1246, Figures 2, Tables 2. Key Messages: 1) 95% of SSc has a positive ANA and ANA patterns in SSc include centromere, nucleolar, and homogeneous and speckled together;2) Most ENAs are equal in both dcSSc and lcSSc except anti RNA polymerase III and topoisomerase I;3) RNA polymerase III has the highest association (odds ratio) with scleroderma renal crisis, topoisomerase I is associated with interstitial lung disease;whereas anticentromere was not associated with elevated pulmonary arterial pressures on echocardiogram.

Electrical storm in systemic sclerosis: Inside the electroanatomic substrate

We report the case of a 63-year-old woman affected by a severe form of systemic scleroderma with pul-monary involvement(interstitial fibrosis diagnosed by biopsy and moderate pulmonary hypertension) and cardiac involvement(paroxysmal atrial fibrillation, right atrial flutter treated by catheter ablation, ventricular tachyarrhythmias, previous dual chamber implantable cardioverter defibrillator implant). Because of recurrent electrical storms refractory to iv antiarrhythmic drugs the patient was referred to our institution to undergo catheter ablation. During electrophysiological proce-dure a 3D shell of cardiac anatomy was created with intracardiac echocardiography pointing out a significant right ventricular dilatation with a complex aneurysmal lesion characterized by thin walls and irregular multiple trabeculae. A substrate-guided strategy of catheter ab-lation was accomplished leading to a complete electri-cal isolation of the aneurism and to the abolishment of all abnormal electrical activities. The use of advanced strategies of imaging together with electroanatomical mapping added important information to the complex arrhythmogenic substrate and improved efficacy and safety.

Exploring the treatment of Systemic Sclerosis with Danggui (Angelica sinensis, AS)-Sini Decoction using GEO combined with Network pharmacology and Molecular docking

Background:To explore the relevant targets of the Chinese herbal medicine compound Danggui-Sini Decoction(DGSND)for the treatment of systemic sclerosis(SSc).Method:We used TCMSP to enlist ingredients and Swiss Target Prediction for targets fishing,and the protein names by UniProt for organized as gene symbol.Strawberry Perl was used to integrate the active ingredients and the drugs action target of DGSND,with Cytoscape 3.9.0 software to construct"Active ingredient-Drug target"network.Then,GEO database,GeneCards database,TTDdatabase,DisGENent database and MalaCards database for SSc-related disease target prediction,and then analyzed the active drug targets of DGSND and SSc-related targets of Danggui-Sini Decoction treat SSc.Then,the above results we combined with STRING database to visualize the Protein-protein interaction(PPI)network for the core targets of SSc,and performed Gene ontology(GO)functional analysis and Kyoto Encyclopedia of Genomics(KEGG)signaling pathway enrichment analysis for SSc-related targets treated with DGSND Result:DGSND contains 223 active ingredients including Sitogluside,Benzoylpaeoniflorin,(-)-Asarinin Palbinone,Glycyro,4'DMEP etc.which acts on Signal transducer and activator of transcription 3(STAT3),Tumor Necrosis Factor(TNF),Vascular endothelial growth factor(VEGFA),Nuclear factor kappa-B(NFκB1),Interleukin(IL1β,IL17),Mitogen-activated protein kinase(MAPK)and Janus Kinase(JAK)and many other genes totaling 176,mainly involved in 4 more biological processes 3 molecular functions and 3 cellular components.Conclusion:DGSND is primarily used to treat SSc by regulating calcium homeostasis,inflammatory signaling pathways and neural cell repair and apoptosis-related pathways within the body.

Pulmonary rehabilitation outcome of exercise-induced oxygen desaturation in systemic sclerosis with interstitial lung disease

While exercise capacity in systemic sclerosis with interstitial lung disease could be improved by exercise training, the training outcome of exercise-induced oxygen desaturation has not been examined. The aim of this study was to investigate the effect of pulmonary rehabilitation on exercise-induced oxygen desaturation during the six-minute walk test and to detect the factors affecting outcome retrospectively. Patients showing impaired exercise capacity (≤80% of predicted) and/or exercise-induced oxygen desaturation (≤-4% in SpO2) at the end of the six-minute walk test underwent routine walking exercise. Sixteen patients with stable systemic sclerosis completed exercise training for 55 days on average. The mean six-minute walk distance improved from 467 m to 502 m (P = 0.0012). The improvement in distance was negatively related to baseline distance (R2 = 0.28, P = 0.037), but was not related to parameters from pulmonary function tests and echocardiograms. Oxygen saturation was normal at rest, but was decreased in fifteen patients at the end of the test. Exercise-induced oxygen desaturation was positively related to the diffusion capacity of the lungs for carbon monoxide at baseline (R2 = 0.33, P = 0.026);however, it was not related to any cardiopulmonary parameters after intervention. Seven of sixteen patients ameliorated exercise-induced oxygen desaturation or showed no oxygen desaturation after exercise training, while others deteriorated. No cardiopulmonary parameters affected the training outcome of exercise-induced oxygen desaturation. Exercise train ing was beneficial in improving exercise tolerance, but training effects and mechanisms on exercise-induced oxygen desaturation still need more studies to be explained.

Acute Renal Failure during Progressive Systemic Sclerosis in the Regional University Teaching Hospital of Brest-La Cavale Blanche (France)

Systemic scleroderma is a rare disease in which visceral manifestations occur, particularly peripheral vascular, digestive, cardiopulmonary and renal. It is pathology with a predilection for women. The present clinical case is that of a man with the renal complications of scleroderma and the difficulties of the treatment even in the developed countries like France. In the present case, the management of this disease required a high dose of corticosteroid therapy and extra-renal purification. Early detection of complications through a minimal clinical examination supplemented with paraclinic tests has proved necessary.

Epidemiology of Cancer in Systemic Sclerosis—Systematic Review and Meta-Analysis of Cancer Incidence, Predictors and Mortality

Objectives: The study was conducted to improve our understanding of the epidemiology of cancer in systemic sclerosis (SSc) by evaluating the incidence, prevalence, relative risk of overall and site-specific malignancies, predictors and cancer-attributable mortality. Methods: MEDLINE, CINAHL, EMBASE and Cochrane Library (inception-May 2012) were searched. Estimates were combined using a random effects model. Consistency was evaluated using the I2 statistic. Results: 4876 citations were searched to identify 60 articles. The average incidence of malignancy in SSc was 14 cases/1000 person-years;the prevalence ranged between 4%-22%. Cancer was the leading cause of non-SSc related deaths with a mean of 38%. Overall SIR for all-site malignancy risk was 1.85 (95%CI 1.52, 2.25;I276%). There was a greater risk of lung (SIR 4.69, 95%CI 2.84, 7.75;I293%) and haematological (SIR 2.58, CI 95% 1.75, 3.81;I20%) malignancies, including non-Hodgkin’s lymphoma (SIR 2.55, 95%CI 1.40, 4.67;I20%). SSc patients were at a higher risk of leukemia (SIR 2.79, 95%CI 1.22, 6.37;I20%), malignant melanoma (SIR 2.92, 95%CI 1.76, 4.83;I235%), liver (SIR 4.75, 95%CI 3.09, 7.31;I20%), cervical (SIR 2.28, 95%CI 1.26, 4.09;I254%) and oropharyngeal (SIR 5.0, 95%CI 2.18, 11.47;I258%) cancers. Risk factors include a-RNAP I/III seropositivity, male sex, and late onset SSc. Smoking and longstanding interstitial lung disease increase the risk of lung cancer;Barrett’s esophagus and a positive family history of breast cancer, respectively, increase the risk of esophageal adenocarcinoma and breast cancer. Conclusions: SSc patients have a two-fold increase in all-site malignancy, and greater risk of lung and haematological malignancies that contribute significantly to mortality. Vigilance should be considered in SSc patients with risk factors for cancer.

Pulmonary arterial hypertension associated with systemic sclerosis: Current diagnostic approach and therapeutic strategies

Pulmonary arterial hypertension(PAH) represents a devastating vascular complication of systemic sclerosis(SSc) and is found in 10%-15% of cases carrying a severe prognosis. PAH has a dramatic impact on the clinical course and overall survival, being the single most common cause of death in patients with this entity. The clinical course and aggressive progression of PAH has led clinicians to perform annual screening for it, since early detection and diagnosis are the cornerstone of a prompt therapeutic intervention. The diagnosis of PAH can be challenging to clinicians, particularly in its early stages, since in the context of SSc, the multiple causes of dyspnea need to be assessed. Doppler echocardiography represents the best initial screening tool, however, right heart catheterization remains the gold standard and definitive diagnostic means. Remarkable advances have been achieved in elucidating the pathogenesis of PAH in the past two decades, leading to the development of disease-specific targeted therapies: prostacyclin analogues, endothelin receptor antagonists and inhibitors of five phosphodiesterase pathways. However, the clinical response to these therapies in SSc-associated PAH has not been as great as the one seen with idiopathic PAH. This review also focuses on the diagnosis and novel therapies that are currently available for PAH, as well as potential future therapeutic developments based on newly acquired knowledge of diverse pathogenic mechanisms.