Search

Purpose: To determine whether Macklin effect (a linear collection of air contiguous to the bronchovascular sheath) on baseline CT imaging is an accurate predictor for subsequent pneumomediastinum (PMD)/pneumothorax (PNX) development in invasively ventilated patients with COVID-19-related acute respiratory distress syndrome (ARDS). Materials and methods: This is an observational, case-control study. From a prospectively acquired database, all consecutive invasively ventilated COVID-19 ARDS patients who underwent at least one baseline chest CT scan during the study time period (February 25th, 2020–December 31st, 2020) were identified; those who had tracheal lesion or already had PMD/PNX at the time of the first available chest imaging were excluded. Results: 37/173 (21.4%) patients enrolled had PMD/PNX; specifically, 20 (11.5%) had PMD, 10 (5.8%) PNX, 7 (4%) both. 33/37 patients with subsequent PMD/PNX had Macklin effect on baseline CT (89.2%, true positives) 8.5 days [range, 1–18] before the first actual radiological evidence of PMD/PNX. Conversely, 6/136 patients without PMD/PNX (4.4%, false positives) demonstrated Macklin effect (p < 0.001). Macklin effect yielded a sensitivity of 89.2% (95% confidence interval [CI]: 74.6–96.9), a specificity of 95.6% (95% CI: 90.6–98.4), a positive predictive value (PV) of 84.5% (95% CI: 71.3–92.3), a negative PV of 97.1% (95% CI: 74.6–96.9) and an accuracy of 94.2% (95% CI: 89.6–97.2) in predicting PMD/PNX (AUC:0.924). Conclusions: Macklin effect accurately predicts, 8.5 days in advance, PMD/PNX development in COVID-19 ARDS patients.

OBJECTIVE: The use of angiotensin II in invasively ventilated patients with coronavirus disease 2019 (COVID-19) is controversial. Its effect on organ function is unknown. DESIGN: Prospective observational study. SETTING: Intensive care unit (ICU) of a tertiary academic hospital in Milan, Italy. PARTICIPANTS: Adult patients receiving mechanical ventilation due to COVID-19. INTERVENTIONS: Use angiotensin II either as rescue vasopressor agent or as low dose vasopressor support. MAIN OUTCOME MEASURES: Patients treated before angiotensin II was available or treated in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of angiotensin II on organ function. RESULTS: We compared 46 patients receiving angiotensin II therapy with 53 controls. Compared with controls, angiotensin II increased the mean arterial pressure (median difference, 9.05 mmHg; 95% CI, 1.87–16.22; P = 0.013) and the Pao2/Fio2 ratio (median difference, 23.17; 95% CI, 3.46–42.88; P = 0.021), and decreased the odds ratio (OR) of liver dysfunction (OR, 0.32; 95% CI, 0.09–0.94). However, angiotensin II had no effect on lactate, urinary output, serum creatinine, C-reactive protein, platelet count, or thromboembolic complications. In patients with abnormal baseline serum creatinine, Bayesian modelling showed that angiotensin II carried a 95.7% probability of reducing the use of renal replacement therapy (RRT). CONCLUSIONS: In ventilated patients with COVID-19, angiotensin II therapy increased blood pressure and Pao2/Fio2 ratios, decreased the OR of liver dysfunction, and appeared to decrease the risk of RRT use in patients with abnormal baseline serum creatinine. However, all of these findings are hypothesis-generating only. TRIAL REGISTRATION: ClinicalTrials.gov NCT04318366.

Background Biobanks are imperative infrastructures, particularly during outbreaks, when there is an obligation to acquire and share knowledge as quick as possible to allow for implementation of science-based preventive, diagnostic, prognostic and therapeutic strategies. Methods We established a COVID-19 biobank with the aim of collecting high-quality and well-annotated human biospecimens, in the effort to understand the pathogenic mechanisms underlying COVID-19 and identify therapeutic targets (COVID-BioB, NCT04318366). Here we describe our experience and briefly review the characteristics of the biobanks for COVID-19 that have been so far established. Results A total of 46,677 samples have been collected from 913 participants (63.3% males, median [IQR] age 62.2 [51.2 - 74.0] years) since the beginning of the program. Most patients (66.9%) had been admitted to hospital for COVID-19, with a median length of stay of 15.0 (9.0 - 27.0) days. A minority of patients (13.3% of the total) had been admitted for other reasons and subsequently tested positive for SARS-CoV-2. The remainder were managed at home after being seen at the Emergency Department. Conclusions Having a solid research infrastructure already in place, along with flexibility and adaptability to new requirements, allowed for the quick building of a COVID-19 biobank that will help expand and share the knowledge of SARS-CoV-2.

In Europe, Italy and Lombardy, in autumn 2020, there was a steep increase in reported cases due to the second epidemic wave of SARS-Cov-2 infection. We aimed to evaluate the appropriateness of COVID-19 patients' admissions to the ED of the San Raffaele Hospital.We compared data between the inter-wave period (IWP, from 1st to 30th September) and the second wave period (WP, 1st October to 15th November) focusing on the ED presentation, discharge priority colour code and outcomes.Out of 977 admissions with a SARS-Cov-2 positive swab, 6% were in the IWP and 94% in the WP. Red, yellow and white code increased (these latter from 1.8% to 5.4%) as well as self-presented in yellow and white code. Discharges home increased from 1.8% to 5.4%, while hospitalizations decreased from 63% to 51%.We found a rise in white codes (among self-presented patients), indicating inappropriateness of admissions. The increase in discharges suggests that several patients did not require hospitalization.The pandemic brought out the fundamental role of primary care to manage patients with low-intensity needs. The important increase in ED admissions of COVID-19 patients caused a reduction of NO-COVID-19 patients, with possible inadequate treatment.

BackgroundRespiratory infections can be complicated by acute brain failure. We assessed delirium prevalence, predictors and outcomes in COVID-19 ED patients.MethodsThis was a retrospective observational study conducted at the San Raffaele ED (Italy). Patients age >18 years attending the ED between 26 February 2020 and 30 May 2020 and who had a positive molecular nasopharyngeal swab for SARS-CoV-2 were included. The Chart-Based Delirium Identification Instrument (CHART-DEL) was used to retrospectively assess delirium. Univariable and multivariable logistic regression analyses were used to evaluate delirium predictors. Univariable binary logistic regression analyses, linear regression analyses and Cox regression analyses were used to assess the association between delirium and clinical outcomes. Age-adjusted and sex-adjusted models were then run for the significant predictors of the univariable models.ResultsAmong the 826 included patients, 123 cases (14.9%) of delirium were retrospectively detected through the CHART-DEL method. Patients with delirium were older (76.9±13.15 vs 61.3±14.27 years, pConclusionsChart review frequently identified ED delirium in patients with COVID-19. Age, dementia, epilepsy and polypharmacy were significant predictors of ED delirium. Delirium was associated with an increased in-hospital mortality and with a reduced probability of being discharged home after hospitalisation. The findings of this single-centre retrospective study require validation in future studies.

It is unclear why activated platelets and platelet-derived microparticles (MPs) accumulate in the blood of patients with systemic sclerosis (SSc). This study was undertaken to investigate whether defective phagocytosis might contribute to MP accumulation in the blood of patients with SSc.Blood samples were obtained from a total of 81 subjects, including 25 patients with SSc and 26 patients with stable coronary artery disease (CAD). Thirty sex- and age-matched healthy volunteers served as controls. Studies were also conducted in NSG mice, in which the tail vein of the mice was injected with MPs, and samples of the lung parenchyma were obtained for analysis of the pulmonary microvasculature. Tissue samples from human subjects and from mice were assessed by flow cytometry and immunochemical analyses for determination of platelet-neutrophil interactions, phagocytosis, levels and distribution of P-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), and HMGB1 on platelets and MPs, and concentration of byproducts of neutrophil extracellular trap (NET) generation/catabolism.Activated P-selectin+ platelets and platelet-derived HMGB1+ MPs accumulated in the blood of SSc patients but not in the blood of healthy controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had fewer P-selectin+ platelets and a negligible number of MPs. The expression of the receptor for P-selectin, PSGL-1, in neutrophils from SSc patients was significantly decreased, raising the possibility that phagocytes in SSc do not recognize activated platelets, leading to a failure of phagocytosis and continued neutrophil release of MPs. As evidence of this process, activated platelets were not detected in the neutrophils from SSc patients, whereas they were consistently present in the neutrophils from patients with CAD. HMGB1+ MPs elicited generation of NETs, which were only detected in the plasma of SSc patients. In mice, P-selectin-PSGL-1 interaction resulted in platelet phagocytosis in vitro and influenced the ability of MPs to elicit NETs, endothelial activation, and migration of leukocytes through the pulmonary microvasculature.The clearance of activated platelets via PSGL-1 limits the undesirable effects of MP-elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis.

Objective To determine the incidence, predictors, and outcome of pneumothorax (PNX)/pneumomediastinum (PMD) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). Design Observational study. Setting Tertiary-care university hospital. Participants One hundred sixteen consecutive critically ill, invasively ventilated patients with COVID-19 ARDS. Interventions The authors collected demographic, mechanical ventilation, imaging, laboratory, and outcome data. Primary outcome was the incidence of PNX/PMD. Multiple logistic regression analyses were performed to identify predictors of PNX/PMD. Measurements and Main Results PNX/PMD occurred in a total of 28 patients (24.1%), with 22 patients developing PNX (19.0%) and 13 developing PMD (11.2%). Mean time to development of PNX/PMD was 14 ± 11 days from intubation. The authors found no significant difference in mechanical ventilation parameters between patients who developed PNX/PMD and those who did not. Mechanical ventilation parameters were within recommended limits for protective ventilation in both groups. Ninety-five percent of patients with PNX/PMD had the Macklin effect (linear collections of air contiguous to the bronchovascular sheaths) on a baseline computed tomography scan, and tended to have a higher lung involvement at intensive care unit (ICU) admission (Radiographic Assessment of Lung Edema score 32.2 ± 13.4 v 18.7 ± 9.8 in patients without PNX/PMD, p = 0.08). Time from symptom onset to intubation and time from total bilirubin on day two after ICU admission were the only independent predictors of PNX/PMD. Mortality was 60.7% in patients who developed PNX/PMD versus 38.6% in those who did not (p = 0.04). Conclusion PNX/PMD occurs frequently in COVID-19 patients with ARDS requiring mechanical ventilation, and is associated with increased mortality. Development of PNX/PMD seems to occur despite use of protective mechanical ventilation and has a radiologic predictor sign.

BackgroundDiagnosis of venous thromboembolism (VTE) requires chest CT angiography for pulmonary embolism and venous ultrasound for deep vein thrombosis. To reduce imaging, guidelines recommend D-dimer levels to rule-out VTE in patients with a low pre-test probability. The most widely used D-dimer cut-off is 500 ng/mL. This cut-off has low specificity, meaning many patients without disease require imaging.MethodsIn this retrospective chart review, we evaluated the diagnostic performance of the D-dimer/fibrinogen ratio (DFR) for identifying thromboembolism and compared it to the performance of two different D-dimer cut-offs (500 ng/mL and 1000 ng/mL) in patients who underwent a chest CT angiography or a venous ultrasound in the ED of San Raffaele Hospital, Italy, in 2017. Patients had a retrospective Wells score calculated after chart review, identifying both high-risk and low-risk pre-test probability patients for this study and low probability patients were further stratified into low-risk of deep vein thrombosis or pulmonary embolism.ResultsEnrolled patients included 92 with suspected pulmonary embolism and 154 with suspected deep vein thrombosis; of whom 67 (27%) were diagnosed with VTE. The most accurate cut-off for DFR in terms of discriminative power was 2.65. In the whole sample and in low-risk patients, this cut-off had the same sensitivity values of the 500 ng/mL D-dimer cut-off (97% (95% CI: 89.8% to 99.2%)), while slightly lower sensitivity values were found for the 1000 ng/mL D-dimer cut-off (95.5% (95% CI: 87.6% to 98.5%)). Specificity was higher for the 2.65 DFR cut-off (55.3% (95% CI: 48.0% to 62.4%)) in the whole sample compared with both 500 ng/mL D-dimer cut-off (22.9% (95% CI: 17.4% to 29.6%)) and 1000 ng/mL D-dimer cut-off (45.8% (95% CI: 38.7% to 53.1%)). Similar results were found in all subgroups.ConclusionA DFR, with a cut-off of 2.65, may improve the specificity for VTE patients when compared with D-dimer alone in high-risk VTE emergency medicine populations. This is exploratory information only, needing evaluation in prospective, multicentre studies, prior to consideration for use in routine clinical work.

Background: The use of angiotensin II (ANGII) in invasively ventilated COVID-19 patients is controversial. Its effect on markers of organ function is unknown.Methods: We used ANGII either as rescue vasopressor agent or as low dose vasopressor support. Patients treated before ANGII availability or in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of ANG on markers of organ function.Results: We compared 46 ANGII patients with 53 controls. Compared with controls, ANGII increased MAP (median difference, 9.05 mmHg [95% confidence interval, 1.87 to 16.22]; p = 0.013) and PaO2/FiO2 ratio (median difference, 23.17 [95% confidence interval, 3.46 to 42.88]; p = 0.021). ANGII had no effect on lactate, urinary output, serum creatinine, C-Reactive protein, platelet count, or thromboembolic complications. However, it significantly decreased the odd ratio of liver dysfunction (odds ratio: 0.32; 0.09 to 0.94) and, on Bayesian modelling, in patients with abnormal baseline serum creatinine, ANGII carried a 95.7% probability of decreasing renal replacement therapy use. Conclusions: In ventilated COVID-19 patients, ANGII therapy was associated with increased blood pressure and PaO2/FiO2 ratios, decreased odds ratio of liver dysfunction, and a high probability of decreasing renal replacement therapy use in patients with abnormal baseline serum creatinine.

The purpose of the study was to assess the prognostic performances, in terms of in-hospital mortality, of the quick sequential organ failure assessment (qSOFA) score and the systemic inflammatory response syndrome (SIRS) criteria applied to patients with suspected infection outside the ICU, and to critically reappraise the results and the clinical impact of the SEPSIS-3 study and of the subsequent trials. We performed bivariate meta-analysis, evaluation of the Bayesian post-test probabilities of death, and computation of the unidentified deaths for every 1000 screened cases (UDS1000). The use of qSOFA for screening instead of the SIRS implies a relevant increase in the UDS1000. However, this difference appears far smaller in the SEPSIS-3 study, largely due to an underestimation of SIRS sensitivity. The increment in the pre-test probability of death implied by a positive qSOFA is higher than that implied by a positivity of the SIRS. However, the included studies use highly variable definitions of "suspected sepsis" and carry very high levels of heterogeneity. SIRS overperforms qSOFA as a rule-out tool for mortality, while qSOFA shows a higher rule-in power. However, the evident lack of consistency across the published studies undermines the significance of both the meta-analytic approach and the reproducibility of the outcomes, and demands for a standardized definition of the target population.

Background Acute respiratory failure (ARF) is a common cause of presentation to the Emergency Department (ED). High flow nasal cannula (HFNC) has been introduced as an alternative way to administer oxygen. Objectives We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing HFNC with conventional oxygen therapy (COT) and noninvasive ventilation (NIV) exclusively in the ED setting. Methods Inclusion criteria were: RCTs on adults with ARF admitted to the ED, investigating HFNC vs. COT or other modes of ventilation. Trials that compared HFNC support outside the ED, were published as an abstract, or nonrandomized were excluded. Results Four RCTs comparing HFNC with COT and one HFNC to NIV met the criteria. Overall, 775 patients were included. The meta-analysis of the studies comparing HFNC and COT showed no differences in intubation requirement, treatment failure, hospitalization, or mortality. Intolerance was significantly higher with HFNC (risk ratio 6.81 95% confidence interval 1.18–39.19; p = 0.03). In the only available RCT comparing HFNC with NIV, no difference was found for intubation rate, treatment failure, tolerance, and dyspnea. Conclusions We did not find any benefit of HFNC compared with COT and NIV in terms of intubation requirement, treatment failure, hospitalization, and mortality; COT was better tolerated.

Background National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. Methods All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. Results Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56–75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5–11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60–99), with median PaO2/FiO2 ratio, 267 (IQR 184–314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4–16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. Conclusion In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.

Endothelial cell damage and platelet activation contribute to sustained vasculopathy, which is a key clinical characteristic of systemic sclerosis (SSc), also known as scleroderma. Microparticles released from activated platelets in the blood of SSc patients (SSc-microparticles) are abundant and express the damage-associated molecular pattern (DAMP) HMGB1. SSc-microparticles interacted with neutrophils in vitro and in immunocompromised mice and promoted neutrophil autophagy, which was characterized by mobilization of their granule content, enhanced proteolytic activity, prolonged survival, and generation of neutrophil extracellular traps (NETs). Neutrophils migrated within the mouse lung, with collagen accumulation in the interstitial space and the release of soluble E-selectin by the vascular endothelium. Microparticle-neutrophil interaction, neutrophil autophagy and survival, and generation of NETs abated in the presence of BoxA, a competitive inhibitor of HMGB1. Consistent with these results, neutrophils in the blood of SSc patients were autophagic and NET by-products were abundant. Our findings implicate neutrophils in SSc vasculopathy and suggest that platelet-derived, microparticle-associated HMGB1 may be a potential indicator of disease and target for novel therapeutics.

Background Takayasu arteritis(TA) is a large vessel vasculitis 1 . At disease presentation TA patients may present with inflammatory symptoms, sometimes associated with vascular pain. As arterial lesions ensue, more characteristic features may be found, such as limb claudication, decreased or absent pulses, vascular bruits, discrepancies in blood pressure 2 . Since initial symptoms are often non-specific, early detection of TA is challenging and patients at diagnosis frequently have established damage 3 Objectives To describe symptoms presentation and vascular involvement in a large cohort of Italian TA patients. To assess the diagnostic delay associated with symptoms and arteries involved at presentation Methods Data from 114 TA patients diagnosed according to ACR classification criteria at our tertiary centre were retrospectively collected. Signs and symptoms subsequently attributed to TA, age at first symptom onset, and age at diagnosis were analysed. The diagnostic delay was calculated. Arteries involved before the diagnosis were identified. Non-parametric statistic tests were used Results The cohort included mostly female patients(104;91.2%). Mean age at first symptom subsequently attributed to TA was 30.5 years(±13.1). Age at presentation of first TA related symptom was 18–40 years in 68 (59.6), 40 years in 26 (22.8%)patients. Mean age at diagnosis was 36 years(±12.7). Mean diagnostic delay was 65.6 months(±85.3). Diagnostic delay was >1 year in 75 patients(65.8%). The most frequent finding before diagnosis was raised inflammatory markers(82.4%), the least common pulmonary hypertension(2.8%). The features significantly associated with a diagnostic delay >1 year were arthralgias, hypertension, previous vascular surgery. The mean diagnostic delay(in months) was significantly higher in patients with raised inflammatory markers(8.4±4.9 vs 100.5±121.8,p=0.005), carotidynia(5.8±5.7 vs 34.2±32.9,p=0.034) and in patients who had upper limb claudication(11.0±13.2 vs 65.44±77.01,p=0.002). Data about arteries involved before diagnosis were available for 86 patients(75.4%). They were: subclavian in 43 (50%), carotid in 38 (44.2%), renal in 19 (22.1%), abdominal aorta in 18 (20.9%), ascending aorta in 15 (17.4%), axillary in 12 (14%), vertebral in 11 (12.8%), superior mesenteric in 10 (11.6%), thoracic aorta in 10 (11.6%), aortic arch in 9 (10.5%), celiac tripod in 9 (10.5%), brachiocephalic in 8 (9.3%), iliac in 8 (9.3%), coronary in 6 (7%), femoral in 6 (7%), pulmonary in 5 (5.8%), brachial in 3 (3.5%), popliteal in 2 (2.3%) patients. There was no significant difference in the arteries involved between patients diagnosed 1 year from symptoms onset. Mean diagnostic delay was not significantly different according to the arteries involved Conclusions In Italy TA diagnosis is burdened with an important diagnostic delay. In our cohort it seems that the presence of both specific and non-specific symptoms is associated with delayed recognition of TA. Moreover, the need for vascular surgery in young women should rise the concern about TA References [1] Weyand, C. M. & Goronzy, J. J. Medium- and large-vessel vasculitis. N. Engl. J. Med. 349, 160–9 (2003). [2] Kerr, G. S. et al. Takayasu arteritis. Ann. Intern. Med. 120, 919–29 (1994). [3] Numano, F., Okawara, M., Inomata, H. & Kobayashi, Y. Takayasu’s arteritis. Lancet356, 1023–1025 (2000). Disclosure of Interest A. Tomelleri: None declared, C. Campochiaro: None declared, S. Sartorelli: None declared, C. Sembenini: None declared, S. Franchini: None declared, F. Motta: None declared, D. Vanni: None declared, G. Cavalli: None declared, E. Baldissera: None declared, L. Dagna Grant/research support from: The Unit has received unrestricted educational grants from Abbvie, BMS, Celgene, Mundipharma, Novartis, MSD, Pfizer, Roche, and SOBI.

Background Periostin(PN), a matricellular protein, serves as a regulator of wound healing and fibrosis. PN-/- mice develop lower degrees of fibrosis when exposed to bleomycin(BLM), suggesting a possible role in the pathogenesis of Systemic Sclerosis(SSc)1. PN serum levels are increased in SSc and seem to be associated with skin disease severity2. Objectives To evaluate the role of serum PN as a biomarker of SSc severity, and to determine PN tissue expression in SSc patients. Methods PN serum levels were assessed by ELISA in 48 patients: 3 primary Raynaud’s, 12 early SSc, 11 SSc without organ involvement, 22 SSc with organ involvement. All SSc patients met 2013 ACR/EULAR criteria. PN serum levels were evaluated in 28 sex-/age-matched healthy-controls(HCs). Data regarding disease subtypes and organ involvement were correlated. PN skin expression was determined by immunohistochemistry on paired involved and uninvolved skin biopsy samples in 10 patients(4 lcSSc and 6 dcSSc) in combination with a-SMA, CD68, CD3, CD4, CD8, CD163, CD20 and CD131. Results PN serum levels were higher in SSc patients compared to HCs(32.7±8.0 vs 27.7±7.3 ng/ml, p Conclusions In our cohort PN serum levels are elevated in SSc patients but they do not correlate with disease features. Its postulated role as a severity biomarker needs to be further elucidated. The different immunohistochemical expression of PN in uninvolved skin from dcSSc and lcSSc patients suggests a possible pathogenic role in the progressive inflammation-driven fibrosis that characterise diffuse cutaneous involvement. References [1] Yang L, et al. Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma. PLoSOne2012. [2] Yamaguchi Y, et al. Serum Periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis. Br J Dermatol2013. Disclosure of Interest None declared

To describe the efficacy and safety of different biological agents in a large cohort of 20 patients with adult-onset Still's disease (AOSD).We retrospectively evaluated 20 patients with severe or refractory AOSD treated with at least one biological agent (anakinra, etanercept, tocilizumab, and adalimumab), followed up for at least 12 months at our Institution. We collected and analysed data on the disease course, treatment outcome, and adverse effects, and compared our data with other published series.The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. In eight patients the biological agent that was first administered proved ineffective, and a switch to a different biologic was necessary. In three patients a third biologic was necessary to achieve disease control. The biologics eventually determined a clinical response in all patients. Patients with systemic disease showed better responses than patients with chronic articular disease (p0.05). Biological agents allowed either the withdrawal or the tapering of corticosteroid therapy (p0.0001) and of disease-modifying anti-rheumatic agents (DMARDs; p0.05). Three patients experienced herpes zoster reactivation.This is the longest follow-up of a cohort of AOSD patients treated with biological agents. Our data show that biologics are safe and generally effective in the long-term management of AOSD, particularly in cases with systemic disease, and suggest that a clinical response can be obtained in almost all AOSD patients, although a switch to drugs with a different mechanism of action may be necessary.

Background Persistent oxidative stress and unrelenting vascular inflammation are hallmarks of Systemic Sclerosis (SSc). Platelet-derived microparticles (PD-uP) that express a bioactive redox-dependent moiety, HMGB1 accumulate in the peripheral blood of patients with SSc. Objectives To verify whether PD-uP might represent a biomarker of SSc clinical involvement and whether their biological actions is regulated by environmental redox. Methods Fifty-four patients with SSc were enrolled so far. Twenty healthy controls (HC) matched for sex and age were studied in parallel. PD-uP were characterized and quantified by flow cytometry. Leukocyte features, including expression and distribution of myeloperoxidase (MPO), were assessed by flow cytometry and confocal microscopy. PD-uP ability to regulate neutrophil activation and proteolytic action was assessed in vitro in defined redox conditions and in vivo upon intravenous (i.v.) injection in immunocompromised NSG mice, and traced at various times based on recognition of the human platelet antigen CD61. Action on fibroblasts derived from SSc patients and HC are being assessed using biochemical and functional assays. Results PD-uP are present in the blood of SSc patients. Their concentration is significantly higher than in the blood of HC (p Conclusions HMGB1 expression on PD-up of SSc patients could help identify functionally relevant population of microparticles, involved in neutrophil activation/function and possibly valuable as a novel biomarker of vascular remodeling. References Sabbadini MG et al, Lupus, 1999. Filippi et al., Lancet Neurol 2013. Rocca MA et al., Brain Struct Funct, 2016. Disclosure of Interest None declared

We report the work-up, diagnosis, and management of a 43-year-old woman affected by a limited cutaneous systemic sclerosis (SSc) who developed an unexpected acute virus-negative lymphocytic myocard...

Objective.The aim of our study was to evaluate the safety and the efficacy of tocilizumab (TCZ) for refractory Takayasu arteritis (TA).Methods.We retrospectively assessed the outcome of blocking interleukin (IL)-6 with TCZ in 7 consecutive patients with refractory TA using a combination of clinical and imaging assessment.Results.During a median followup visit at 14 months, 4 patients taking TCZ [including 2 nonresponders to tumor necrosis factor (TNF) inhibitors] achieved clinical response, suggesting a nonredundant role for IL-6 in TA. Inflammatory markers normalized in all patients treated with TCZ. However, vascular progression occurred in 4 patients, suggesting the involvement of other inflammatory pathways and confirming the limitations of erythrocyte sedimentation rate and C-reactive protein for disease activity assessment while taking TCZ. Three patients experienced adverse events and 2 suspended TCZ.Conclusion.TCZ may be effective in a subset of patients with refractory TA, even in cases of unresponsiveness to TNF inhibitors. Inflammatory markers are not valid markers of TA activity on TCZ. Further studies are needed to confirm these preliminary observations.

The impact of maternal systemic autoimmune diseases on pregnancy outcome is not unequivocally defined. We analysed the pregnancy outcome of 221 pregnancies from 181 autoimmune patients, consecutively followed in a single Italian reference centre from 2001 to 2009. All patients were prospectively followed with monthly visits. Pregnancy outcome was compared with the previous obstetrical history. The patient population comprised five groups: primary antiphospholipid syndrome (PAPS, 39 pregnancies), antiphospholipid syndrome associated with a rheumatic disease (APS/RD, 17 pregnancies), other RD (92 pregnancies), isolated autoantibodies (autoAbs) in the absence of a definite autoimmune disease (aAbs, 38 pregnancies) and reactive arthritis or spondyloarthropathies (35 pregnancies). Of these patients, 50.6% had previous pregnancy complications with an anamnestic live-birth rate of 43.4%. In these patients, complications dropped to 28.2% (44/156). This percentage was very similar to that observed in the 221 pregnancies (29.9%, 66/221) with a live-birth rate of 87.3%. Mean neonatal weight was 3018 ± 611 g; mean gestational age at delivery was 38.17 ± 2.79 weeks. Thus, 10.4% of pregnancies resulted in preterm delivery and 10.9% newborns had low weight at delivery. APS/RD patients had the worse outcome: 17.6% resulted in miscarriage, 14.3% resulted in growth restriction and 50% resulted in preterm delivery. This result was mainly due to patients with APS/systemic lupus erythematosus (SLE) that had the lowest gestational age at delivery (30.8 ± 3.56 weeks) and the lowest newborn weight (1499 ± 931 g). Results confirm that a strict follow-up and targeted treatments significantly improve pregnancy outcomes in autoimmune patients with PAPS, SLE and isolated autoAbs. The pregnancy outcome in patients with APS/SLE remains unsatisfactory.

Objective Systemic sclerosis (SSc; scleroderma) is characterized by a unique widespread vascular involvement that can lead to severe digital ischemia, pulmonary arterial hypertension (PAH), or other organ dysfunction. Microthrombotic events and procoagulation factors such as anti–β2-glycoprotein I (anti-β2GPI) or anticardiolipin antibodies (aCL) may be implicated in the development of these manifestations. This study was undertaken to investigate whether anti-β2GPI and aCL are correlated with macrovascular disease, including ischemic digital loss and PAH, in SSc patients. Methods Seventy-five SSc patients with a history of ischemic digital loss and 75 matched SSc controls were evaluated. Anticentromere antibodies (ACAs), anti-β2GPI, and aCL were measured, and clinical associations were determined using conditional and simple logistic regression models. Results Positivity for anti-β2GPI was significantly more frequent in SSc patients with digital loss than in patients without digital loss (P = 0.017), with the IgA isotype of anti-β2GPI showing the strongest association (odds ratio [OR] 4.0). There was no significant difference in aCL frequency between patients with digital loss and control patients. After adjustment for demographic characteristics, disease type, smoking, and ACA, anti-β2GPI positivity was significantly associated with active digital ischemia (OR 9.4), echocardiographically evident PAH (OR 4.8), and mortality (OR 2.9). ACA positivity was associated with history of digital loss (OR 3.28), but not with PAH or mortality. History of digital loss was strongly associated with increased mortality (OR 12.5). Conclusion Anti-β2GPI is significantly associated with macrovascular disease in SSc and independently predicts mortality. It is unclear whether it has a pathogenetic role or simply reveals the presence of underlying endothelial injury. The use of anti-β2GPI as a biomarker of vascular disease in SSc should be further explored.

We evaluated serum levels of CXCL12 in patients with severe sepsis/septic shock and controls.We enrolled 27 patients admitted to our emergency department with severe sepsis/septic shock and 20 healthy controls. Complete blood count, serum levels of CXCL12, C-reactive protein, lactate, Charlson comorbidity index, sequential organ failure score on hospital admission, and inhospital mortality were evaluated at baseline (T0) and after 24 hours (T24).Mean serum levels of CXCL12 were higher in patients with severe sepsis/septic shock than in healthy subjects (3121 vs 1991 pg/mL; P.001). We also found that patient who survived had lower serum levels of CXCL12 than those who died (2630 vs 3957 pg/mL; P.001) but still higher than controls (2630 vs 1991 pg/mL; P = .001) on admission. CXCL12 serum levels were higher in patients with serum lactate greater than 4 mmol/L.Our data suggest a possible role for CXCL12 as a prognostic marker in severe sepsis/septic shock and give background evidence for larger trials to evaluate the pathophysiologic and clinical role of CXCL12 in sepsis, with respect to other markers of inflammation and hypoxia.

BACKGROUND This observational study was designed to evaluate the prevalence of coronary microvascular dysfunction (CMD) in asymptomatic patients affected by systemic sclerosis (SSc), stratifying the results according to the limited (lcSSc) and the diffuse (dcSSc) forms of the disease. METHODS AND RESULTS We enrolled 19 consecutive asymptomatic patients with dcSSc (n=7) or lcSSc (n=12). In all subjects, coronary flow reserve (CFR) was assessed by measuring diastolic coronary flow velocities in the left anterior descending artery by pulsed wave Doppler at baseline and after dipyridamole infusion (0.84 mg·kg(-1)·6 min(-1)). Wall motion score index was evaluated at baseline and during stress. We enrolled 20 healthy subjects as controls. Mean CFR was 1.96±0.62 in patients and 2.69±0.47 in controls (P

Heart involvement confers a poor prognosis in patients affected by systemic sclerosis (SSc). Nevertheless, the prevalence of heart involvement in these patients is not fully known. In this study we analyzed the most frequent manifestations of heart involvement at rest in a cohort of patients with SSc, comparing their prevalence in patients with the limited form (lcSSc) and in patients with the diffuse form (dcSSc) of the disease, taking also into account the duration of the disease.We thoroughly evaluated with electrocardiographic and echocardiographic examinations 174 patients affected by SSc who were followed at our hospital between 2001 and 2011. They were divided according to the disease subtype (dcSSc vs lcSSc) and information about the disease duration was available for 121 of them (calculated from the onset of the Raynaud's phenomenon).Patients with dcSSc had a greater prevalence of heart involvement at rest when evaluated within 5 and 10 years after the onset of the Raynaud's phenomenon (p=0.0051 within 5 years and p=0.035 within 10 years). Indeed, patients with dcSSc had a greater prevalence of atrioventricular conduction abnormalities within 20 years after the onset of the Raynaud's phenomenon (p=0.03 within 10 years and p=0.04 within 20 years) and a greater prevalence of valvular abnormalities within 5 years (p=0.04). In dcSSc there was a greater prevalence of rhythm disturbances in patients with a disease duration ≤20 or20 years (p=0.04 within 20 years and p=0.04 after 20 years), but not in those with a disease duration ≤5 and ≤10 years. Left ventricular hypertrophy had a greater prevalence in dcSSc after 20 years of disease duration (p=0.02).Cardiac manifestation occurs earlier and more frequently in patients affected by dcSSc than in patients with lcSSc.

The link between platelet activation and vascular injury in Systemic Sclerosis (SSc) is poorly characterized. Here we report that platelet activation results in i) the translocation from the cytoplasm to the surface of HMGB1, a prototypical DAMP signal associated with tissue regeneration and ii) the release of platelet derived microparticles (PDμP) expressing HMGB1. Decreased HMGB1 content (334.6 ± 21.2 vs 587.1 ± 11.1 AUF, P < 0.001) and HMGB1 translocation to the outer leaflet of the plasma membrane (17.8 ± 3.5 vs 4.5 ± 0.5%, P < 0.001) characterize circulating platelets of SSc patients (n = 29) when compared with age-matched healthy controls (HC, n = 20). Conversely, a significantly higher fraction of PDμP in the blood of SSc patients, but not of HC, consistently expose (HMGB1 (MFI 62.8 ± 3.95 vs 4.3 ± 0.7). Platelet HMGB1 depletion is significantly associated in SSc patients with degranulation and with expression of P-selectin and of tissue factor as well as with fibrinogen binding to their plasma membrane. These findings indicate that platelets represent a source of HMGB1, an ancestral signal of necrosis, in the vasculature of SSc patients, possible contributing to persistent microvascular injury and endothelial cell activation.

We study the Renyi entropy of the one-dimensional XYZ spin-1/2 chain in the entirety of its phase diagram. The model has several quantum critical lines corresponding to rotated XXZ chains in their paramagnetic phase, and four tri-critical points where these phases join. Two of these points are described by a conformal field theory and close to them the entropy scales as the logarithm of its mass gap. The other two points are not conformal and the entropy has a peculiar singular behavior in their neighbors, characteristic of an essential singularity. At these non-conformal points the model undergoes a discontinuous transition, with a level crossing in the ground state and a quadratic excitation spectrum. We propose the entropy as an efficient tool to determine the discontinuous or continuous nature of a phase transition also in more complicated models.

Purpose: Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guerin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guerin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guerin. Materials and Methods: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guerin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. Results: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. Conclusions: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guerin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.

Objective To evaluate the efficacy of antiinflammatory agents, steroids, immunosuppressants, and biologic agents in patients with adult-onset Still's disease (AOSD) who have either chronic articular disease or nonchronic disease. Methods Forty-five patients with AOSD were seen and followed up for at least 2 years at our institution, from 1991 to 2008. The majority of patients were treated with several therapeutic regimens; a total of 152 efficacy trials were administered. Data regarding the type of medication, the dosage used, and the outcome of these trials were collected and analyzed. Results Our data showed that the efficacy of monotherapy with a nonsteroidal antiinflammatory drug was very low (16%) and confirmed good efficacy of steroid therapy (63%), particularly in patients without chronic articular disease (78%). Patients whose disease did not respond to steroid therapy at the time of disease onset were at risk of the subsequent development of chronic arthritis. Disease-modifying antirheumatic drug (DMARD) monotherapy was successful in controlling steroid-resistant or steroid-dependent disease in 60% of patients. Methotrexate and cyclosporine showed the best response rates. The combination of high-dose steroids and cyclosporine was administered to successfully control some acute life-threatening complications. Only 6 patients had disease that was both steroid resistant and DMARD resistant. Treatment with biologic agents eventually led to satisfactory control of disease manifestations in 5 (83%) of these 6 patients. Conclusion Steroids were less effective in patients with chronic articular disease than in those with nonchronic disease. The administration of DMARDs early after disease onset could be beneficial in patients with steroid-resistant disease who are at risk of the development of chronic articular disease. Biologic agents proved to be highly effective in both steroid-resistant and DMARD-resistant AOSD.

Background No data is available on the long-term clinical outcome of Adult-Onset Still9s Disease (AOSD) patients treated with biological drugs, nor on the efficacy and safety of switching biologics in the management of refractory cases. 1 Objectives To evaluate the efficacy and safety of switching biological agents in a large, monocentric cohort of 20 patients with refractory AOSD. Methods Twenty Italian AOSD patients treated with biological agents were followed-up at our Institution for at least 24 months. For each case we retrospectively evaluated the disease course, the efficacy of treatment, and the potential adverse effects. Efficacy was evaluated as “Complete response” (CR: absence of articular and systemic manifestations, normalization of inflammatory indexes, >50% reduction in the corticosteroid dosage); “Partial response” (PR: clinical improvement without normalization of inflammatory markers, nor >50% reduction in the dose of steroids); or “Treatment failure” (TF: persistence/worsening of disease manifestations, persistent elevation of inflammatory markers, or need for an increased dose of corticosteroids despite 2 months of treatment). Results The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. Five patients were switched to a different biologic because of lack of efficacy. In 3 patients, a third biologic was necessary to achieve disease control. Biologics eventually determined a clinical response in all patients. Anakinra was used in all 20 patients; etanercept, tocilizumab and adalimumab was used in 6, 4, and 1 patient, respectively. Sixteen patients responded to anakinra (80%; CR 70%; PR 10%). Four patients (20%) did not respond to anakinra, and of these three responded to tocilizumab, and one responded to adalimumab. Etanercept was used unsuccessfully in six patients. Patients with systemic manifestations showed better responses than patients with chronic articular disease ( p . Overall, biologic agents determined a significant reduction in the dose of the associated therapy with corticosteroids (p ) and DMARDs (p . Three patients experienced herpes zoster reactivation. Conclusions Biological agents represent a pivotal therapeutic resource for AOSD patients refractory to conventional treatment. Although the biologic drug of choice may prove ineffective, switching between biologics ultimately resulted in a clinical response in all patients without significant adverse effects, hence the importance of pursuing a tailored treatment approach. Although IL-1 blockade with anakinra represents the mainstay of treatment, IL-6 blockade may be more effective in patients with chronic articular involvement. Both anakinra and tocilizumab were more effective than TNF-α blockers. Patients with SD are more likely to respond favorably to biologics than patients with CAD. Different pathogenic mechanisms underlying SD and CAD, or the development of irreversible articular damage in CAD, may account for the differences in response to treatment. References Al-Homood IA. Biologic treatments for adult-onset Still9s disease. Rheumatology 2013. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2153

Background Adult-onset Still’s disease (AOSD) is an inflammatory condition of unknown origin.We previously reported that non-steroidal anti-inflammatory drugs, steroids and immunosuppressive drugs such as methotrexate (MTX) and cyclosporin (CsA) successfully control the disease in 60% of patients (pts).(1)Growing evidences support the use of biologic agents such as anakinra,tocilizumab-(TCZ) and TNF-alpha blocking agents in refractory forms of AOSD.(2,3) Objectives To assess the long-term efficacy and safety of biologic agents in pts with AOSD in terms of systemic features, disease markers and dose reduction of the immunosuppressive and steroid drugs. Methods Sixteen Italian pts with refractory AOSD were treated with anakinra,TCZ,etanercept or adalimumab.Complete response (CR) was defined as the absence of joint swelling,systemic symptoms,normal acute phase reactants and steroid dose reduction by 50% or more for at least 2 months.Clear improvement without normalization of acute phase reactants and steroid dose reduction by less then 50% were considered partial response (PR).Treatment failure was defined as persistent or worsening of systemic manifestation and acute phase reactants despite ongoing treatment for at least 2 months. Results Sixteen pts with AOSD treated with biologic agents were followed-up at our institution from 1998 to 2012.The mean age (range) at the diagnosis was 33.1 years (16-55), disease duration was 6.6 years (2–12) and the mean follow-up time after the beginning of biologic agents was 42.5 months (8–80).All pts were treated with anakinra; 10 pts (63%) achieved CR, 2 pts (12%) achieved PR and 4 pts (25%) did not respond.Among non responders, 2 pts were treated with etanercept without benefit: thus, one received TCZ with PR, and one adalimumab with CR.The remaining 2 non responder pts are now starting TCZ.Steroid treatment was discontinued in 9 pts (56%) that achieved CR; in the remaining 7 pts (44%), the steroid dose was decreased by 25 to 94%. Three pts (19%) resumed immunosuppressive agents, 5 pts (30%) maintained MTX at the initial dose, 6 pts (38%) reduced MTX by 50% to 63% and 2 pts (13%) reduced CsA by 37 to 50%.Mild reactions to injections were the most frequent adverse events although herpes zoster infection developed in 2 pts treated with anakinra and in 1 treated with TCZ. Conclusions The present study describes the longest follow-up assessing the long-term efficacy and tolerability of biologic agents in refractory AOSD.In particular, anakinra was effective in the majority of AOSD affected pts, except in 2 pts in which adalimumab and TCZ provided CR and PR respectively.Treatment with biologic agents, either ensuring a CR or a PR, prompted a significant reduction in the overall dose of steroid and immunosuppressive drugs. References Franchini S,et al. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still’s disease. Arthritis Rheum 2010;62:2530-5. Lequerre T,et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008;67:302-8. Sakai R,et al. Successful treatment of adult-onset Still’s disease with tocilizumab monotherapy: two case reports and literature review. Clin Rheumatol 2012 Disclosure of Interest None Declared

Background Takayasu arteritis (TA) is a rare chronic-relapsing granulomatous vasculitis involving primarily the aorta and its major branches 1 . TA is associated with considerable morbidity and mortality 2 . Therapy is based on corticosteroids (CS) but steroid-sparing immunosuppressive drugs are required in most patients to minimize CS adverse events and to control progressive vascular disease 1 . However, about 25% of patients relapse when CS are tapered 3 . In this setting, previous works showed that anti-TNF (aTNF) drugs may be useful, with a response rate of about 60-70% 4,5 . Objectives To evaluate safety and efficacy of aTNF drugs in the treatment of refractory TA. Methods We retrospectively studied 15 TA patients treated with aTNF drugs between 2004 and 2011 at a single academic Italian center. All patients satisfied ACR criteria for TA classification. Results 15 female patients (mean age at the beginning of aTNF therapy 36 years) with active relapsing TA were studied. All had been treated with at least one immunosuppressive drug and CS. Mean follow-up (FU) was 46 months (range 11-56). Mean duration of CS therapy was 37 months before aTNF. 13 patients received infliximab, 5 adalimumab and 1 golimumab. Mean prednisone (PDN) daily dose could be reduced from 17,8 mg to 7,9 mg at the end of FU (p0,036). None of the patients could be weaned off PDN. A reduction in both ESR and CRP was observed (respectively from 39 to 26 mm/h and from 19.5 to 7.1 mg/l, p 0,011 and 0,003). At the end of FU 27% of patients showed active disease according to NIH criteria 3 . Vascular involvement was assessed by angio-MR in 14 cases and by echography in only one subject: the mean number of lesions per patient reduced from 9,9 to 7,7 (p0,002). At vascular sites not previously treated with a revascularisation procedure (native lesions) 53% of lesions improved and only 11% showed progressive worsening, while revascularised lesions showed progressive worsening in 67% of vascular sites (even in patients whose other native vascular lesions improved). Partial response (i.e. PDN daily dose reduction ≥50%) was obtained in 5 cases; complete sustained response (i.e. absence of imaging progression and features of active disease while on PDN daily dose ≤7.5 mg for at least 6 months) in 8. No serious side effects, including infection, were observed during FU and none of the patients discontinued aTNF therapy due to adverse events. Conclusions According to previous studies 4,5 , we confirmed that aTNF drugs could be considered as an effective and safe steroid sparing option for refractory TA. However, even if we observed a significant improvement of native vascular lesions, we documented a very low efficacy in preventing revascularisation failure, suggesting that the pathophysiology of revascularised lesions and native lesions could differ. References Mason JC. Takayasu arteritis-advances in diagnosis and management. Nat Rev Rheumatol 2010;6:406-15 Maksimowicz MKK et al. Takayasu arteritis: what is the long term prognosis? Rheum Dis Clin N Am 2007;33:777-86 Kerr GS et al. Takayasu arteritis. Ann Int Med 1994;120:919-29 Hoffman GS et al. Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum. 2004;50:2296-304 Molloy ES et al. Anti-TNF therapy in patients with refractory Takayasu arteritis: long-term follow-up. Ann Rheum Dis 2008;67:1567-69 Disclosure of Interest None Declared

PURPOSE To evaluate the safety/efficacy of topical infliximab, an anti-TNF-α monoclonal antibody, in a mouse model of ocular surface scarring. METHODS Twenty alkali burn mice were treated with infliximab (10 mg/mL) topically 6 times a day, while 20 alkali burn mice received saline for 7 days. Corneal opacity, epithelial wound healing, and ocular phimosis were examined at the slit-lamp. Tear production was quantified with phenol red thread test. Immunofluorescence for infliximab penetration, TNF-α localization, CD45+ cell infiltration, PAS, and Masson's trichrome staining were evaluated on ocular globes and eyelids. TNF-α and IL-1β expression levels were measured on treated murine corneas and eyelids. Finally, quantification of corneal CD31+ blood vessels and LYVE1+ lymphatic vessels were evaluated on 10 additional alkali burn mice receiving either infliximab or saline, after 14 days. RESULTS Topical infliximab penetrated the cornea and the conjunctiva and was not toxic (negative fluorescein stain). Its molecular target, TNF-α, was detected in the cornea after injury. Infliximab significantly reduced corneal perforation, opacity index, phimosis, leukocyte infiltration, and fibrosis in the eyelids. It also significantly prevented goblet cell infiltration in epithelial cornea and loss in the conjunctiva (P < 0.05), improved tear secretion and epithelial healing (P < 0.05). Finally, it significantly reduced both corneal hem- (P < 0.05) and lymphangiogenesis (P < 0.01). CONCLUSIONS Infliximab penetrates the cornea and is safe to the ocular surface in an animal model of ocular surface scarring. We suggest that topical application of infliximab may be a useful treatment in ocular caustications.

"BACKGROUND:. . Because pentraxin-3 (PTX3) is produced by immune and vascular cells in response to proinflammatory signals, it may be a useful biomarker for defining disease activity in patients with Takayasu arteritis.. OBJECTIVE:. . To compare PTX3 levels in patients who have Takayasu arteritis with those in healthy and infected controls, and to compare accuracy of PTX3 levels with that of C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) for distinguishing active and inactive disease.. DESIGN:. . Cross-sectional, noninterventional study conducted between September 2005 and October 2008.. SETTING:. . Immunology and rheumatology clinic at a university hospital in Italy.. PATIENTS:. . 57 consecutive patients with Takayasu arteritis and known disease activity, 57 healthy blood donor controls, and 15 patients with acute infection.. MEASUREMENTS:. . Disease activity by clinical criteria; plasma PTX3 and CRP levels and ESR.. RESULTS:. . 27 patients had active Takayasu arteritis; 30 had inactive disease. Levels of PTX3 were higher in patients with active disease (median, >2.14 ng\/mL [range, 0.57 to 48.18 ng\/mL]) than in those with inactive disease (median, 0.63 ng\/mL [range, 0.00 to 1.64 ng\/mL]) and were higher than in healthy patients (median, 0.11 ng\/mL [range, 0 to 1.20 ng\/mL]) or those with acute infection (median, 0.26 ng\/mL [range, 0 to 0.75 ng\/mL]). A plasma PTX3 level greater than 1 ng\/mL was more accurate than normal thresholds of CRP or ESR for distinguishing active from inactive disease.. LIMITATION:. . The study excluded patients with unknown or equivocal disease status.. CONCLUSION:. . Plasma levels of PTX3 could help distinguish active from inactive Takayasu arteritis but should not be adopted for clinical use until the findings are confirmed in a broader spectrum of patients whose disease activity is unknown or equivocal before testing." Background: Because pentraxin-3 (PTX3) is produced by immune and vascular cells in response to proinflammatory signals, it may be a useful biomarker for defining disease activity in patients with Takayasu arteritis. Objective: To compare PTX3 levels in patients who have Takayasu arteritis with those in healthy and infected controls, and to compare accuracy of PTX3 levels with that of C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) for distinguishing active and inactive disease. Design: Cross-sectional, noninterventional study conducted between September 2005 and October 2008. Setting: Immunology and rheumatology clinic at a university hospital in Italy. Patients: 57 consecutive patients with Takayasu arteritis and known disease activity, 57 healthy blood donor controls, and 15 patients with acute infection. Measurements: Disease activity by clinical criteria; plasma PTX3 and CRP levels and ESR. Results: 27 patients had active Takayasu arteritis; 30 had inactive disease. Levels of PTX3 were higher in patients with active disease(median, >2.14 ng/mL [range, 0.57 to 48.18 ng/mL]) than in those with inactive disease (median, 0.63 ng/mL [range, 0.00 to 1.64 ng/mL]) and were higher than in healthy patients (median, 0.11 ng/mL [range, 0 to 1.20 ng/mL]) or those with acute infection (median, 0.26 ng/mL [range, 0 to 0.75 ng/mL]). A plasma PTX3 level greater than 1 ng/mL was more accurate than normal thresholds of CRP or ESR for distinguishing active from inactive disease. Limitation: The study excluded patients with unknown or equivocal disease status. Conclusion: Plasma levels of PTX3 could help distinguish active from inactive Takayasu arteritis but should not be adopted for clinical use until the findings are confirmed in a broader spectrum of patients whose disease activity is unknown or equivocal before testing.

Background: Lung damage leading to gas-exchange deficit and sepsis leading to systemic hypoperfusion are well-known features of severe pneumonia. Although frequently described in COVID-19, their prognostic impact in COVID-19-related pneumonia vs COVID-19-urelated pneumonia has never been compared. This study assesses fundamental gas-exchange and hemodynamic parameters and explores their prognostic impact in COVID-19 pneumonia and non-COVID-19 pneumonia. Methods: We prospectively evaluated arterial pO2/FiO2, alveolar to arterial O2 gradient, shock index, and serum lactate in 126 COVID-19 pneumonia patients, aged 18- 65, presenting to the emergency department with acute, non-hypercapnic respiratory failure. As a control group we identified 1:1 age-, sex-, and pO2/FiO2-matched COVID-19-urelated pneumonia patients. Univariate and multivariable predictors of 30-day survival were identified in both groups. Results: COVID-19 patients showed lower arterial serum lactate concentration (p