Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts.

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-ß activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-ß binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-ß-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-ß at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-ß stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-ß through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1ß gene expression was markedly decreased following A2AR antagonist treatment in TGF-ß-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.

Stratification of COVID-19 Patients with Moderate-to-Severe Hypoxemic Respiratory Failure for Response to High-Flow Nasal Cannula: A Retrospective Observational Study.

Background and Objectives: In patients with COVID-19, high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP) are widely applied as initial treatments for moderate-to-severe acute hypoxemic respiratory failure. The aim of the study was to assess which respiratory supports improve 28-day mortality and to identify a predictive index of treatment response. Materials and Methods: This is a single-center retrospective observational study including 159 consecutive adult patients with COVID-19 and moderate-to-severe hypoxemic acute respiratory failure. Results: A total of 159 patients (82 in the CPAP group and 77 in the HFNC group) were included in the study. Mortality within 28 days was significantly lower with HFNC compared to CPAP (16.8% vs. 50%), while ICU admission and tracheal intubation within 28 days were significantly higher with CPAP compared to HFNC treatment (32% vs. 13%). We identified an index for survival in HFNC by including three variables easily available at admission (LDH, age, and respiratory rate) and the PaO2/FiO2 ratio at 48 h. The index showed high discrimination for survival with an AUC of 0.88, a negative predictive value of 86%, and a positive predictive value of 95%. Conclusions: Treatment with HFNC appears to be associated with greater survival and fewer ICU admission than CPAP. LDH, respiratory rate, age, and PaO2/FiO2 at 48 h were independently associated with survival and an index based on these variables allows for the prediction of treatment success and the assessment of patient allocation to the appropriate intensity of care after 48 h. Further research is warranted to determine effects on other outcomes and to assess the performance of the index in larger cohorts.

New-Onset Atrial Fibrillation and Early Mortality Rate in COVID-19 Patients: Association with IL-6 Serum Levels and Respiratory Distress.

Background and objectives: COVID-19 is associated with an aberrant inflammatory response that may trigger new-onset cardiac arrhythmias. The aim of this study was to assess the mortality risk in hospitalized COVID-19 patients according to IL-6 serum levels and new-onset atrial fibrillation (AF) according to PaO2/FiO2 stratification. Materials and Methods: 175 COVID-19 patients (25 new-onset AF, 22 other types of AF and 128 no-AF) were included in this single-center, retrospective study; clinical and demographic data, vital signs, electrocardiograms and laboratory results were collected and analyzed. The primary outcome of the study was to evaluate the mortality rate in new-onset AF patients according to IL-6 serum levels and PaO2/FiO2 stratification. Results: The incidence of new-onset AF in the study population was 14.2%. Compared to the no-AF group, new-onset AF patients were older with a positive history of chronic kidney disease and heart failure, had higher IL-6, creatinine and urea serum levels whereas their platelet count was reduced. After PaO2/FiO2 stratification, 5-days mortality rate was higher in new-onset AF patients compared to patients with other types of AF and no-AF patients, and mortality risk increases 5.3 fold compared to no-AF (p = 0.0014) and 4.8 fold compared to other forms of AF (p = 0.03). Conclusions: New-onset AF is common in COVID-19 patients and is associated with increased IL-6 serum levels and early mortality. Further studies are needed to support the use of IL-6 as an early molecular target for COVID-19 patients to reduce their high rate of mortality.

Systemic sclerosis Progression INvestiGation (SPRING) Italian registry: demographic and clinico-serological features of the scleroderma spectrum.

OBJECTIVES: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). METHODS: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. RESULTS: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. CONCLUSIONS: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

Detecting Collagen Molecules at Picogram Level through Electric Field-Induced Accumulation.

The demand for sensors capable of measuring low-abundant collagen in human fluids has highly increased in recent years. Indeed, collagen is expected to be a biomarker for chronic diseases and could monitor their progression. Here we show detection of highly diluted samples of collagen at picogram level thanks to an innovative pyro-electrohydrodynamic jet (p-jet) system. Through the intense electric fields generated by the pyroelectric effect in a ferroelectric crystal, the collagen solution was concentrated on a small area of a slide that was appropriately functionalized to bind proteins. The collagen molecules were labeled by an appropriate fluorophore to show how the number of tiny droplets influences the limit of detection of the technique. The results show that the p-jet is extremely promising for overcoming the current detection limits of collagen-based products in human fluids, performing 10 times better than the enzyme-linked immunosorbent assay (ELISA) and thus paving the way for the early diagnosis of related chronic diseases.

Association between cortisol levels and pain threshold in systemic sclerosis and major depression.

Pain perception and threshold show complex interactions with the inflammatory, psychiatric and neuroendocrine stimuli. This study aims to test whether lower serum cortisol levels are associated with lower pain thresholds and higher degree of depression in systemic sclerosis (SSc) and major depression with atypical features (MD-AF) patients compared to controls. 180 female subjects (SSc = 60, MD-AF = 60, healthy controls = 60) participated in this observational, cross-sectional, parallel group study. Pressure pain threshold (PPT) was assessed in three anatomical sites: nail bed (NB), metacarpophalangeal joint (MCP) and quadriceps muscle (QDR). Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) scale and morning serum cortisol levels were collected. In SSc patients, quality of life was measured through the Health Assessment Questionnaire (HAQ-DI) and the scleroderma-specific visual analogue scales (scleroderma-VAS). Lower PPT scores (NB 4.42 ± 1.6; MCP 4.66 ± 1.4; QDR 4.79 ± 1.5) were observed in SSc patients compared to both MD-AF (NB 7.33 ± 2.2; MCP 6.01 ± 1.9; QDR 6.31 ± 1.6; p < 0.005) and controls (NB 9.57 ± 2; MCP 7.9 ± 2.1 and QDR 8.43 ± 2.1; p < 0.0001), while MD-AF patients had lower PPT scores compared to controls (p < 0.0001). SSc patients had also lower serum cortisol levels compared to MD-AF patients (8.78 vs 13.6 µg/dl; p < 0.05). A direct correlation was observed between serum cortisol and PPT scores both in SSc (r 2 for NB 0.29; for MCP 0.25; for QDR 0.27) and in MD-AF (r 2 for NB 0.34; for MCP 0.25; for QDR 0.47; p < 0.05), while depressive symptoms negatively correlated with serum cortisol (r 2 for NB 0.34; for MCP 0.17; for QDR 0.15) and in MD-AF (r 2 for NB 0.19; for MCP 0.31; for QDR 0.30; p < 0.05). Among SSc patients, those with serum cortisol levels below the normal range (n = 16) had higher BDI scores (15, 6-21 vs 9, 2-15; p < 0.005), lower PPTs (NB 4 ± 1.4 vs 4.9 ± 0.9; MCP 4.1 ± 0.8 vs 4.8 ± 0.9; QDR 4.1 ± 1.2 vs 5 ± 0.9; p < 0.005) and higher HAQ-DI (1.25, 0.25-2 vs 0.75, 0-1.25; p < 0.05) and scleroderma-VAS scores (VAS overall severity 7, 5.5-9.5 vs 4.5, 2.5-6; p < 0.05). The effect of cortisol serum levels upon pain mechanism, in chronic inflammatory conditions warrants longitudinal studies to detect treatable variations in pain thresholds, depressive symptoms and to improve quality of life.

Mastocytosis and systemic sclerosis: a clinical association.

BACKGROUND: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular alterations and autoimmune activation leading to widespread organ fibrosis. At the early stage of disease when organ involvement and extent of disease are emerging, mast cells may have some role, as implied by both symptoms and histologic evidence. CASE PRESENTATION: A female patient diagnosed with cutaneous mastocytosis experienced the onset of systemic sclerosis after 15 years followed by the switch of mastocytosis to the systemic phenotype. A literature review on the evidences related to mast-cells activation in systemic sclerosis is presented below. CONCLUSIONS: For clinicians, more attention must be paid to the potential association between systemic sclerosis and cancer. This case suggests that a proliferative disease in the mast cell compartment-though representing a rare association-may not be completely unexpected in SSc and perhaps excess mast cell activity can serve a pathogenic role in promoting fibrotic disease.

Practice pattern for the use of intravenous iloprost for the treatment of peripheral vasculopathy in systemic sclerosis: A case-control study from the Italian national multicenter "SPRING" (Systemic Sclerosis Progression InvestiGation) Registry.

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data. Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group). Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, "late" scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis. Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets.

Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats.

Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of α(v)ß(3) integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined.

Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis.

OBJECTIVE: The antifibrotic effect of simvastatin has been demonstrated in human lung fibroblasts. This study aimed to measure the effects of simvastatin in the development of pulmonary and cutaneous fibrosis in a murine model of SSc and to explore the mechanisms of these effects. METHODS: Chronic oxidant stress SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: treatment with HOCl, HOCl plus simvastatin or vehicle alone. Statin treatment was initiated 30 min after HOCl s.c. injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histological methods. Immunohistochemical staining for α-smooth muscle actin in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of VEGF, extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homologue gene family (Rho) and TGF-ß were analysed by western blot. RESULTS: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. Simvastatin treatment prevented both skin thickness and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by simvastatin in the skin and in the lung. Increased cutaneous and pulmonary expression of VEGF, ERK, Ras and Rho in mice treated with HOCl was significantly lower in mice treated with HOCl plus simvastatin. CONCLUSION: Simvastatin reduces the development of pulmonary fibrosis, potentially modulating adverse lung remodelling, as shown by the reduced deposition of collagen in alveolar septae. Simvastatin also reduces skin thickness in this model.

Role of 2D strain in the early identification of left ventricular dysfunction and in the risk stratification of systemic sclerosis patients.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by diffuse fibrosis involving several organs, including heart. Aim of our study was to analyze left ventricular (LV) myocardial deformation, by use of 2D strain, in asymptomatic SSc patients with normal LV ejection fraction. METHODS: We enrolled 29 SSc patients (28 female, 65±4 years) and 30 controls (23 female, 64±2 years). Echocardiographic study with tissue Doppler imaging (TDI) and 2D strain analysis was performed; moreover, patients were submitted to a two-year follow-up for the occurrence of cardiovascular events. RESULTS: Standard echocardiographic parameters and TDI velocities were comparable between groups. LV longitudinal (LS) and circumferential (CS) strains were lower in patients than in controls (-13.1±4.8 vs -22.6±4.1, p < 0.001; -15.3±6.2 vs -20.4±5.6, p = 0.001), whereas radial strain (RS) was comparable between groups; moreover, a significant correlation of LS and CS with serum levels of Scl-70 antibodies was found (r = 0.74, p = 0.001; r = 0.53, p = 0.025). In addition, patients with cardiovascular events during follow-up showed a greater impairment of LS and CS (-10.3±2.5 vs -14.4±4.1, p = 0.015; -14.2±3.1 vs -20.1±1.6, p = 0.048) and higher values of Scl-70 antibodies serum levels (p = 0.047). CONCLUSION: The impairment of LV function, often subclinical, worsens prognosis of SSc patients, leading to increased risk of cardiovascular complications. 2D strain, allowing the early detection of LV abnormalities and the identification of patients at greater cardiovascular risk, may be a useful tool in order to provide a more accurate management of SSc patients.

Echocardiography in Coronavirus Disease 2019 Era: A Single Tool for Diagnosis and Prognosis.

Coronavirus disease 2019 (COVID-19) is characterized by multi-organ involvement, including respiratory and cardiac events. Echocardiography is widely considered the first-choice tool for the evaluation of cardiac structures and function because of its reproducibility, feasibility, easy to use at bedside, and for good cost-effectiveness. The aim of our literature review is to define the utility of echocardiography in the prediction of prognosis and mortality in COVID-19 patients with mild to critical respiratory illness, with or without known cardiovascular disease. Moreover, we focused our attention on classical echocardiographic parameters and the use of speckle tracking to predict the evolution of respiratory involvement. Finally, we tried to explore the possible relationship between pulmonary disease and cardiac manifestations.

Natural Course of COVID-19 and Independent Predictors of Mortality.

BACKGROUND: During the SARS-CoV-2 pandemic, several biomarkers were shown to be helpful in determining the prognosis of COVID-19 patients. The aim of our study was to evaluate the prognostic value of N-terminal pro-Brain Natriuretic Peptide (NT-pro-BNP) in a cohort of patients with COVID-19. METHODS: One-hundred and seven patients admitted to the Covid Hospital of Messina University between June 2022 and January 2023 were enrolled in our study. The demographic, clinical, biochemical, instrumental, and therapeutic parameters were recorded. The primary outcome was in-hospital mortality. A comparison between patients who recovered and were discharged and those who died during the hospitalization was performed. The independent parameters associated with in-hospital death were assessed by multivariable analysis and a stepwise regression logistic model. RESULTS: A total of 27 events with an in-hospital mortality rate of 25.2% occurred during our study. Those who died during hospitalization were older, with lower GCS and PaO2/FiO2 ratio, elevated D-dimer values, INR, creatinine values and shorter PT (prothrombin time). They had an increased frequency of diagnosis of heart failure (p < 0.0001) and higher NT-pro-BNP values. A multivariate logistic regression analysis showed that higher NT-pro-BNP values and lower PT and PaO2/FiO2 at admission were independent predictors of mortality during hospitalization. CONCLUSIONS: This study shows that NT-pro-BNP levels, PT, and PaO2/FiO2 ratio are independently associated with in-hospital mortality in subjects with COVID-19 pneumonia. Further longitudinal studies are warranted to confirm the results of this study.

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology.

OBJECTIVE: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. METHODS: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. RESULTS: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). CONCLUSION: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum.

Impact of the COVID-19 Pandemic on Chronic Neurological Disorders: Focus on Patients with Dementia.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) represents a public health problem worldwide. COVID-19 triggers a maladaptive cytokine release commonly referred to as cytokine storm syndrome with increased production of proinflammatory cytokines, which also appears to contribute to chronic neuroinflammation and neurodegenerative disorders' appearance, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease. In this context, SARS-CoV-2 might enter the central nervous system through binding with the angiotensin converting enzyme 2 receptors which are highly expressed in glial cells and neurons. For this reason, an association between COVID-19, its dependent cytokine storm, and the development and/or progression of neurodegenerative disorders might be evaluated. Therefore, the aim of this review was to assess the impact of COVID-19 on neurodegenerative disorders, focusing on the possible increased mortality risk and/or deterioration of the clinical course of pre-existing chronic neurological diseases in patients with dementia.

Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease.

Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD.

Corrigendum: Activation of A2A receptor by PDRN reduces neuronal damage and stimulates WNT/ß-catenin driven neurogenesis in spinal cord injury.

[This corrects the article DOI: 10.3389/fphar.2018.00506.].

Optimizing the Outcomes of Percutaneous Coronary Intervention in Patients with Chronic Kidney Disease.

Percutaneous coronary intervention (PCI) is one of the most common procedures performed in medicine. However, its net benefit among patients with chronic kidney disease (CKD) is less well established than in the general population. The prevalence of patients suffering from both CAD and CKD is high, and is likely to increase in the coming years. Planning the adequate management of this group of patients is crucial to improve their outcome after PCI. This starts with proper preparation before the procedure, the use of all available means to reduce contrast during the procedure, and the implementation of modern strategies such as radial access and drug-eluting stents. At the end of the procedure, personalized antithrombotic therapy for the patient's specific characteristics is advisable to account for the elevated ischemic and bleeding risk of these patients.

Autologous Haematopoietic Stem Cell Transplantation and Systemic Sclerosis: Focus on Interstitial Lung Disease.

Autologous hematopoietic stem cells transplantation (AHSCT) has been employed as treatment for severe systemic sclerosis (SSc) with high risk of organ failure. In the last 25 years overall survival and treatment-related mortality have improved, in accordance with a better patient selection and mobilization and conditioning protocols. This review analyzes the evidence from the last 5 years for AHSCT-treated SSc patients, considering in particular the outcomes related to interstitial lung disease. There are increasing data supporting the use of AHSCT in selected patients with rapidly progressive SSc. However, some unmet needs remain, such as an accurate patient selection, pre-transplantation analysis to identify subclinical conditions precluding the transplantation, and the alternatives for post-transplant ILD recurrence.

IL-13 and IL-33 Serum Levels Are Increased in Systemic Sclerosis Patients With Interstitial Lung Disease.

OBJECTIVE: Systemic sclerosis (SSc) mortality is extremely variable in its internal organ involvement. Pulmonary fibrosis occurs in up to 30% of the cases. Animal models provide evidence that IL-33 is able to induce both cutaneous and pulmonary fibrosis via increased IL-13 and in SSc patients the levels of IL-33 correlate with skin fibrosis. Our aim was to test whether both IL-33 and IL-13 are higher in patients with diffuse SSc and interstitial lung disease (SSc-ILD) compared to SSc patients without ILD and healthy controls. METHODS: Serum levels of IL-13 and IL-33 were measured in 30 SSc patients with diffuse disease and 30 healthy controls by enzyme-linked immunosorbent assay. The extent of pulmonary fibrosis was assessed according to HRCT Warrick score. Pulmonary function tests included lung diffusion capacity for carbon monoxide, forced vital capacity and total lung capacity. RESULTS: Both IL-13 and IL-33 levels were increased in SSc patients compared to controls and significantly associated each other. DLco, FVC and TLC scores were inversely associated with IL-33 and IL-13 levels. Both IL-33 and IL-13 levels were significantly associated with the Warrick severity score and higher in the group of SSc patients with reduced pulmonary function compared to SSc patients with normal pulmonary function tests. CONCLUSION: The IL-13/IL-33 axis needs to be further explored in longitudinal studies of SSc-ILD patients to assess its validity as a biomarker and future treatment target, as does downstream mediator ST2.