The dichotomy of glucocorticosteroid treatment in immune-inflammatory rheumatic diseases: an evidence-based perspective and insights from clinical practice.

Objectives: Glucocorticosteroids (GCs) are the most used anti-inflammatory and immunosuppressive drugs due to their effectiveness in managing pain and disease modification in many immune-inflammatory rheumatic diseases (IRDs). However, their use is limited because of adverse effects (AEs). Material and methods: The authors analyzed recent studies, including randomized controlled trials (RCTs), observational, translational studies and systematic reviews, providing an in-depth viewpoint on the benefits and drawbacks of GC use in rheumatology. Results: Glucocorticosteroids are essential in managing life-threatening autoimmune diseases and a cornerstone in many IRDs given their swift onset of action, necessary in flares. Several RCTs and meta-analyses have demonstrated that when administered over a long time and on a low-dose basis, GC can slow the radiographic progression in early rheumatoid arthritis (RA) patients by at least 50%, satisfying the conventional definition of a disease-modifying anti-rheumatic drug (DMARD). In the context of RA treatment, the use of modified-release prednisone formulations at night may offer the option of respecting circadian rhythms of both inflammatory response and HPA activation, thereby enabling low-dose GC administration to mitigate nocturnal inflammation and prolonged morning fatigue and joint stiffness. Long-term GC use should be individualized based on patient characteristics and minimized due to their potential AEs. Their chronic use, especially at medium/high dosages, might cause irreversible organ damage due to the burden of metabolic systemic effects and increased risk of infections. Many international guidelines recommend tapering/withdrawal of GCs in sustained remission. Treat-to-target (T2T) strategies are critical in setting targets for disease activity and reducing/discontinuing GCs once control is achieved. Conclusions: Glucocorticosteroids' use in treating IRDs should be judicious, focused on minimizing use, tapering and discontinuing treatment, when possible, to improve long-term safety. Glucocorticosteroids remain part of many therapeutic regimens, particularly at low doses, and elderly RA patients, especially with associated chronic comorbidities, may benefit from long-term low-dose GC treatment. A personalized GC therapy is essential for optimal long-term outcomes.

Association between esophageal motor disorders and pulmonary involvement in patients affected by systemic sclerosis: a retrospective study.

Systemic sclerosis (SSc) is a rare autoimmune disease of the connective tissue that can affect multiple organs. The esophagus is the most affected gastrointestinal tract, while interstitial lung disease (ILD) is a main feature associated with SSc. The aim of the present study was to evaluate the association and prognostic implication between motor esophageal disorders and pulmonary involvement in SSc patients. We retrospectively assessed patients with SSc who underwent both the HRM with the new Chicago Classification 4.0 and pulmonary evaluation comprehensive of function tests and high-resolution computer tomography (HrCT) with the use of Warrick score. A total score ≥ 7 was considered predictive of ILD, while a score ≥ 10 in a HrCT acquired prospectively from baseline evaluation was considered to establish significant interstitial involvement. Forty-two patients were included. We found a score ≥ 7 in 11 patients with aperistalsis, in 6 subjects with IEM and in 6 patients with a normal manometry. Otherwise, a score < 7 was observed in 3 patients with aperistalsis, and in 2 and 14 patients with IEM and with a normal contractility, respectively. Higher scores were observed in subjects with absent contractility or ineffective esophageal motility than subjects with normal motility, indeed DCI and HrCT score were inversely correlated in linear and logarithmic regression analysis. Prospectively, lower baseline LESP and greater HrCT scores at follow-up evaluation were significantly correlated. This study shows an association between motor esophageal disorder and pulmonary involvement in SSc patients: more severe is the esophageal involvement, more critical is the pulmonary disease.

Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium.

BACKGROUND: Nonthyroidal Illness Syndrome (NTIS) can be detected in many critical illnesses. Recently, we demonstrated that this condition is frequently observed in COVID-19 patients too and it is correlated with the severity the disease. However, the exact mechanism through which thyroid hormones influence the course of COVID-19, as well as that of many other critical illnesses, is not clear yet and treatment with T4, T3 or a combination of both is still controversial. Aim of this study was to analyze body composition in COVID-19 patients in search of possible correlation with the thyroid function. METHODS AND FINDINGS: We report here our experience performed in 74 critically ill COVID-19 patients hospitalized in the intensive care unit (ICU) of our University Hospital in Rome. In these patients, we evaluated the thyroid hormone function and body composition by Bioelectrical Impedance Analysis (BIA) during the acute phase of the disease at admission in the ICU. To examine the effects of thyroid function on BIA parameters we analyzed also 96 outpatients, affected by thyroid diseases in different functional conditions. We demonstrated that COVID-19 patients with low FT3 serum values exhibited increased values of the Total Body Water/Free Fat Mass (TBW/FFM) ratio. Patients with the lowest FT3 serum values had also the highest level of TBW/FFM ratio. This ratio is an indicator of the fraction of FFM as water and represents one of the best-known body-composition constants in mammals. We found an inverse correlation between FT3 serum values and this constant. Reduced FT3 serum values in COVID-19 patients were correlated with the increase in the total body water (TBW), the extracellular water (ECW) and the sodium/potassium exchangeable ratio (Nae:Ke), and with the reduction of the intracellular water (ICW). No specific correlation was observed in thyroid patients at different functional conditions between any BIA parameters and FT3 serum values, except for the patient with myxedema, that showed a picture similar to that seen in COVID-19 patients with NTIS. Since the Na+/K+ pump is a well-known T3 target, we measured the mRNA expression levels of the two genes coding for the two major isoforms of this pump. We demonstrated that COVID-19 patients with NTIS had lower levels of mRNA of both genes in the peripheral blood mononuclear cells (PBMC)s obtained from our patients during the acute phase of the disease. In addition, we retrieved data from transcriptome analysis, performed on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)s treated with T3 and we demonstrated that in these cells T3 is able to stimulate the expression of these two genes in a dose-dependent manner. CONCLUSIONS: In conclusion, we demonstrated that measurement of BIA parameters is a useful method to analyze water and salt retention in COVID-19 patients hospitalized in ICU and, in particular, in those that develop NTIS. Our results indicate that NTIS has peculiar similarities with myxedema seen in severe hypothyroid patients, albeit it occurs more rapidly. The Na+/K+ pump is a possible target of T3 action, involved in the pathogenesis of the anasarcatic condition observed in our COVID-19 patients with NTIS. Finally, measurement of BIA parameters may represent good endpoints to evaluate the benefit of future clinical interventional trials, based on the administration of T3 in patients with NTIS.

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients.

Background and aim: Vitamin D deficiency is frequently reported in patients with SARS-CoV-2 infection. The aim of this study was to correlate the 25OH-Vitamin D serum concentrations with clinical parameters of lung involvement, in elderly patients hospitalized for SARS-CoV-2 infection. Methods: Sixty-five consecutive COVID-19 patients (mean age 76 ± 13 years) and sixty-five sex- and age-matched control subjects (CNT) were analyzed. The following clinical parameters, including comorbidities, were collected at admission: type of pulmonary involvement, respiratory parameters (PaO2, SO2, PaCO2, PaO2/FiO2), laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein). Results: Significantly lower vitamin D serum levels were found in COVID-19 patients than in CNT (median 7.9 vs 16.3 ng/mL, p = 0.001). Interestingly, a statistically significant positive correlation was observed between vitamin D serum levels and PaO2 (p = 0.03), SO2 (p = 0.05), PaO2/FiO2 (p = 0.02), while a statistically significant negative correlation was found between vitamin D serum levels and D-dimer (p = 0.04), C-reactive protein (p = 0.04) and percentage of O2 in a venturi mask (p = 0.04). A negative correlation was also observed between vitamin D serum levels and severity of radiologic pulmonary involvement, evaluated by computed tomography: in particular, vitamin D was found significantly lower in COVID-19 patients with either multiple lung consolidations (p = 0.0001) or diffuse/severe interstitial lung involvement than in those with mild involvement (p = 0.05). Finally, significantly lower vitamin D serum levels were found in the elderly COVID-19 patients who died during hospitalization, compared to those who survived (median 3.0 vs 8.4 ng/mL, p = 0.046). Conclusions: This study confirms that 25OH-vitamin D serum deficiency is associated with more severe lung involvement, longer disease duration and risk of death, in elderly COVID-19 patients. The detection of low vitamin D levels also in younger COVID-19 patients with less comorbidities further suggests vitamin D deficiency as crucial risk factor at any age.

Trabecular Bone Score and Bone Quality in Systemic Lupus Erythematosus Patients.

Background: Systemic lupus erythematosus (SLE) patients run a higher risk of having low bone mass due to multifactorial events that include physical inactivity, persistent inflammation, low vitamin D levels, and glucocorticoid treatment. This study aimed at obtaining a comparison between bone involvement in SLE patients and healthy matched subjects (HS). Methods: A total of 40 SLE females (average age 54.1 ± 16.3 years) and 40 age-gender matched HS (average age 54.2 ± 15.9 years) were enrolled after having obtained informed written consent. Bone mineral density (BMD, g/cm2) of the lumbar spine (L1-L4) was analyzed by a dual-energy X-ray absorptiometry (DXA) scan (GE, Lunar Prodigy). The lumbar spine trabecular bone score (TBS) was derived for each spine DXA examination by the TBS index (TBS iNsight Medimaps). Results: The lumbar spine TBS score was statistically significantly lower in SLE patients than in HS (0.797 ± 0.825 vs. 1.398 ± 0.207, p < 0.001, as was BMD (p < 0.001) in all areas examined. Conclusions: SLE is associated with significant low bone mass as evidenced by DXA and TBS. This study emphasizes the importance of using DXA and TBS in the evaluation of the different aspects of bone architecture.

Lower urinary tract symptoms in systemic sclerosis: a detailed investigation.

OBJECTIVES: Urinary tract involvement is a seldom-reported manifestation of SSc that could compromise patients' quality of life. This study compares lower urinary tract symptoms (LUTS) in SSc patients and in healthy subjects and their association with clinical and diagnostic parameters. METHODS: LUTS were assessed through self-reported questionnaires in 42 SSc patients and 50 matched healthy subjects. Statistical analyses were performed to explore LUTS in the two populations and their association with SSc variables, including nailfold videocapillaroscopy patterns, SSc-related antibodies and DXA parameters. RESULTS: SSc patients showed significantly higher prevalence and severity of urinary incontinence (UI) and overactive bladder (OAB) than healthy controls (P < 0.005, P < 0.01). SSc was a strong predictor of LUTS, independent of demographic data, comorbidities and treatments (odds ratio 5.57, 95% CI 1.64-18.88). In SSc patients OAB positively correlated with sarcopenia (P < 0.001), and both OAB and UI significantly correlated with reduced BMD (P < 0.05, P = 0.001). UI positively correlated with Scl70 antibodies (P < 0.05) and ciclosporin treatment (P = 0.001) and negatively with RNA polymerase III antibodies (P < 0.05); OAB positively correlated with calcinosis (P < 0.005) and negatively with methotrexate treatment (P < 0.05). Nailfold videocapillaroscopy 'active' and 'late' patterns were predominant among SSc patients presenting urinary symptoms, although no statistical correlation was found. CONCLUSION: For the first time urinary tract involvement was found to be significantly higher in SSc patients than in healthy matched controls. In addition, sarcopenia, bone damage and calcinosis appeared significantly correlated with LUTS, suggesting a possible interplay.

Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review.

BACKGROUND AND AIM: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease; the clinical manifestations are correlated with continuum multiarticular synovitis, cartilage and bone damage, and defeat of joint function, that causes disability. Involvement of internal organs is also frequent. Between the inflammatory cells involved in RA, macrophages play a key role. These cells can polarize in different phenotype and mediate the immune/inflammatory reaction as well as the reparatory phase when possible. The properties of these cells are mediate by the body's environmental factors. In this systematic review, all English-speaking articles concerning the role of M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages in RA were systematically reviewed and categorized according to their polarized-function in RA, especially in the synovial tissue. Analyses of the endogenous molecules and the drugs that could modulate M1 and M2 activity in RA were achieved. METHODS: A sensitive search was developed in Pubmed, Web of Science, Ovid Med-Line, Embase Database and Science Direct Database (la both from Elsevier) to identify articles to increase the highlighting on the role of macrophages M1 and M2 in RA using the following terms: ((M1 AND M2) AND Rheumatoid Arthritis). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Relevant data were extracted and analyzed using a standardized template designed for this review. RESULTS: In total 39 resulting articles were selected and categorized according to description of M1/M2's role in RA. Data from humans, mice and rats were subcategorized, thus in every section were highlighted the contribute, in peripheral blood and synovial tissue, of both polarized macrophages; section for endogenous molecules and drugs that favor the switch from M1 to M2 macrophages were carried out. The most evinced relevant results, were that in RA blood and in the synovial tissue, there isn't a clear distinction phase with M1 or M2 macrophages (by membrane marker analysis); rather there is M1 and M2 subset disequilibrium and by deeply analyses of mRNA gene and cytokine produced, it emerged that a non-coherent expression inner marker match with membrane molecules, and also the tissue section can define the marker expressed. CONCLUSION: This systematic review emphasizes that the rigid classical subdivision of M1 and M2 macrophages, as well as the different samples' results comparison, might be questionable. In addition, it is suggested, when taking samples from RA patients, to carefully consider their therapies in order to analyze the M1 and M2 macrophages behavior without drug influence. In line with the advances in M1 and M2 knowledge, and the progression in the single-cell methodologies by identification of individual cell molecular markers, therapeutic approaches seem possible to favor the anti-inflammatory macrophage response in RA (e.g. M2 polarization).

Interactions between microbiota, diet/nutrients and immune/inflammatory response in rheumatic diseases: focus on rheumatoid arthritis.

Rheumatic and musculoskeletal diseases (RMDs) are chronic systemic immune/inflammatory conditions characterized by the interaction between gene predisposition, autoimmunity and environmental factors. A growing scientific interest has focused on the role of diet in RMDs, suggesting its significant contribution to the pathogenesis and prognosis of these diseases. It is now clear that diet can directly modulate the immune response by providing a wide range of nutrients, which interfere with multiple pathways at both the gastro-intestinal and systemic level. Moreover, diet critically shapes the human gut microbiota, which is recognized to have a central role in the modulation of the immune response and in RMD pathogenesis. We hereby provide an in-depth analysis on the role of the microbiota in RMDs and on nutritional intervention as an integral part of a multidisciplinary approach. Particular attention will be given to the Mediterranean diet, as the only diet proven to support substantial benefits in RMD management.

Aminaphtone Efficacy in Primary and Secondary Raynaud's Phenomenon: A Feasibility Study.

OBJECTIVES: The aim of this six-month open feasibility study was to evaluate skin blood perfusion and clinical symptom changes during aminaphtone treatment in patients with either primary or secondary Raynaud's phenomenon to systemic sclerosis. METHODS: Ninety-two patients referring for Raynaud's phenomenon have been enrolled in November during routine clinical assessment, after informed consent. Aminaphtone was administered 75 mg twice daily in addition to current treatments to forty-six patients. Skin blood perfusion was measured by Laser Speckle Contrast Analysis (LASCA) at the level of fingertips, periungual areas, dorsum and palm of hands, and face at baseline (W0), after one (W1), four (W4), twelve (W12) and twenty-four (W24) weeks of treatment. Raynaud's condition score (RCS) and both frequency and duration of Raynaud's attacks were assessed at the same time. RESULTS: Compared with the control group, despite colder period of the year, aminaphtone treated patients showed a progressive statistically significant increase of blood perfusion, as well as a decrease of RCS, frequency of Raynaud's attacks/day and their duration, from W0 to W12 in all skin areas. From W12 to W24 no further increase of blood perfusion was observed. The results were similar in both primary and secondary Raynaud's phenomenon patients. Five weeks after aminaphtone discontinuation blood perfusion values were significantly higher than those at baseline in the majority of skin areas. CONCLUSION: This study demonstrates that aminaphtone treatment increases skin blood perfusion and improves Raynaud's phenomenon clinical symptoms, with sustained efficacy up to 6 months, even in patients with systemic sclerosis. A randomized, blind, controlled, clinical trial including a larger number of subjects is advisable to confirm these early results.

Correlation between bone quality and microvascular damage in systemic sclerosis patients.

Objectives: SSc patients are recognized as presenting an increased risk of altered bone mass. The aim of this study was to assess the bone quality, by trabecular bone score (TBS), in SSc patients in correlation with different levels of microvascular damage, as evaluated by nailfold videocapillaroscopy (NVC), and to compare the results regarding bone quality with RA patients and healthy subjects (CNT). Methods: Eighty-four SSc patients, 98 RA patients and 60 CNT, were studied. BMD (g/cm2) of the lumbar spine (L1-L4) was analysed by DXA scan. Lumbar spine bone quality was derived from each spine DXA examination using the TBS analysis. NVC patterns were analysed. Results: A total of 56/84 SSc patients (66%) as well as 78/98 RA patients (80%) showed bone loss at DXA and BMD was found to be significantly lower than in the CNT (P < 0.001). Similarly, lumbar spine TBS was found to be significantly lower in SSc and RA patients than in CNT (P < 0.001). TBS values were found to be lower in SSc with a late NVC pattern, compared with the active or early pattern (late vs active and early pattern, P < 0.001). There was no statistically significant difference in the mean lumbar spine TBS between SSc and RA patients (P = 0.238). Conclusion: The data obtained showed significantly lower bone quality (lower TBS and BMD) in SSc and RA patients compared with CNT. The bone quality seemed lower in SSc patients with more altered microvasculature (late NVC pattern).

Advances in nailfold capillaroscopic analysis in systemic sclerosis.

Systemic sclerosis is an autoimmune connective tissue disease characterized by early and persistent microvascular impairment which leads to functional and organic manifestations, with progressive fibrosis of the skin and internal organs. Morphological and functional assessment of the peripheral microvasculature is a must, not only for diagnosis but also for the prognosis and therapeutical follow-up of systemic sclerosis patients, as reported in recent studies. Nailfold videocapillaroscopy is the validated technique for the study of scleroderma microangiopathy as it is able to detect peripheral microvascular morphology and both classify and score the capillary abnormalities into different microangiopathy patterns ('Early', 'Active' and 'Late'). Indeed, the possibility to early diagnose and follow the microvascular changes and the safety of the technique have made nailfold videocapillaroscopy a mandatory tool for patient evaluation and included its assessment in the new systemic sclerosis classification criteria. Important links between nailfold videocapillaroscopy patterns and systemic sclerosis clinical manifestations have been described.

Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients.

Adult-onset Still's disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi's criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

Effects of macitentan and its active metabolite on cultured human systemic sclerosis and control skin fibroblasts.

OBJECTIVE: To investigate the effects of the endothelin 1 (ET-1) receptor antagonists (ETRA) macitentan, its active metabolite ACT-132577, and bosentan on myofibroblast activation and extracellular matrix production induced by ET-1 in cultured systemic sclerosis (SSc) and control skin fibroblasts. METHODS: Fibroblasts were obtained from skin biopsies of 6 patients with SSc and 5 healthy subjects. Some cultured cells were untreated or treated with macitentan, ACT-132577, or bosentan alone (10 µM). Other cultured cells were treated with ET-1 alone (100 nM) or with ETRA, and after 1 h, also with ET-1. After 48 h of treatment, myofibroblast activation was investigated to evaluate the α-smooth muscle actin (α-SMA) expression by immunofluorescence; type I collagen (COL-1) and fibronectin (FN) were investigated by immunocytochemistry, Western blotting, and quantitative real-time PCR (qRT-PCR). Statistical analysis was performed by the nonparametric Mann-Whitney U test. RESULTS: In cultured SSc skin fibroblasts, only the treatment with macitentan significantly reduced the basal level of α-SMA expression (p = 0.03 vs untreated cells). Macitentan also significantly reduced the basal level of COL-1 synthesis, similarly to bosentan (p < 0.05 vs untreated cells). Macitentan or ACT-132577 antagonized the ability of ET-1 to further induce α-SMA expression (p = 0.03), COL-1, and FN synthesis (p = 0.03, p = 0.005); bosentan showed similar effects. These results obtained by immunofluorescence and immunocytochemistry were confirmed by Western blotting and qRT-PCR. The downregulatory effects exerted by ETRA were observed also in cultured human control skin fibroblasts. CONCLUSION: Macitentan and ACT-132577 seem to downregulate in vitro the profibrotic myofibroblast phenotype induced by ET-1 in cultured human SSc skin fibroblasts.

Utilization of small changes in serum creatinine with clinical risk factors to assess the risk of AKI in critically lll adults.

BACKGROUND AND OBJECTIVES: Disease biomarkers require appropriate clinical context to be used effectively. Combining clinical risk factors, in addition to small changes in serum creatinine, has been proposed to improve the assessment of AKI. This notion was developed in order to identify the risk of AKI early in a patient's clinical course. We set out to assess the performance of this combination approach. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A secondary analysis of data from a prospective multicenter intensive care unit cohort study (September 2009 to April 2010) was performed. Patients at high risk using this combination approach were defined as an early increase in serum creatinine of 0.1-0.4 mg/dl, depending on number of clinical factors predisposing to AKI. AKI was defined and staged using the Acute Kidney Injury Network criteria. The primary outcome was evolution to severe AKI (Acute Kidney Injury Network stages 2 and 3) within 7 days in the intensive care unit. RESULTS: Of 506 patients, 214 (42.2%) patients had early creatinine elevation and were deemed at high risk for AKI. This group was more likely to subsequently develop the primary endpoint (16.4% versus 1.0% [not at high risk], P<0.001). The sensitivity of this grouping for severe AKI was 92%, the specificity was 62%, the positive predictive value was 16%, and the negative predictive value was 99%. After adjustment for Sequential Organ Failure Assessment score, serum creatinine, and hazard tier for AKI, early creatinine elevation remained an independent predictor for severe AKI (adjusted relative risk, 12.86; 95% confidence interval, 3.52 to 46.97). Addition of early creatinine elevation to the best clinical model improved prediction of the primary outcome (area under the receiver operating characteristic curve increased from 0.75 to 0.83, P<0.001). CONCLUSION: Critically ill patients at high AKI risk, based on the combination of clinical factors and early creatinine elevation, are significantly more likely to develop severe AKI. As initially hypothesized, the high-risk combination group methodology can be used to identify patients at low risk for severe AKI in whom AKI biomarker testing may be expected to have low yield. The high risk combination group methodology could potentially allow clinicians to optimize biomarker use.

Laser speckle contrast analysis: a new method to evaluate peripheral blood perfusion in systemic sclerosis patients.

OBJECTIVE: The aim of this pilot study was to assess peripheral blood perfusion (PBP) by a new technique, the laser speckle contrast analysis (LASCA), in systemic sclerosis (SSc) patients showing different patterns of nailfold microangiopathy. Correlations between LASCA and single laser Doppler flowmetry (LDF) analysis were also checked. METHODS: Sixty-one SSc patients and 61 healthy subjects were enrolled. PBP was evaluated using LASCA and LDF. Scleroderma patterns and microangiopathy evolution score (MES) were assessed by nailfold videocapillaroscopy (NVC). RESULTS: As detected by LASCA and LDF, PBP was lower in SSc patients than in healthy subjects (p<0.0001), showing SSc patients with the 'Early', 'Active' or 'Late' NVC pattern a progressively lower PBP (p=0.04 and p=0.002, respectively). There was a negative correlation between PBP and MES values (p=0.006 and p=0.002 for LASCA and LDF, respectively). A positive correlation was detected between LASCA and LDF values, in all subjects (p<0.0001). However, LASCA evaluates larger skin areas, is significantly less time consuming, is more accepted by patients and shows lower intra-operator variability than LDF. CONCLUSIONS: LASCA detected lower PBP in SSc patients than in healthy subjects, and for the first time, LASCA perfusion values were found correlated with progression of NVC patterns of microangiopathy.

Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study.

INTRODUCTION: Use of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last-resort treatment for extensively drug-resistant infections caused by gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics. METHODS: The cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome. RESULTS: The 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores ≥43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone. CONCLUSIONS: In severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic shock and with the severity of the patients as reflected by the SAPS II score.

RIFLE-based data collection/management system applied to a prospective cohort multicenter Italian study on the epidemiology of acute kidney injury in the intensive care unit.

The epidemiology of acute kidney injury (AKI) has been difficult to explore in the past, due to different definitions across various studies. Nevertheless, this is a very important topic today in light of the high morbidity and mortality of critically ill patients presenting renal dysfunction during their stay in the intensive care unit (ICU). The case mix has changed over the years, and AKI is a common problem in critically ill patients often requiring renal replacement therapy (RRT). The RIFLE and AKIN initiatives have provided a unifying definition for AKI, making possible large retrospective studies in different countries. The present study aims at validating a unified web-based data collection and data management tool based on the most recent AKI definition/classification system. The interactive database is designed to elucidate the epidemiology of AKI in a critically ill population. As a test, we performed a prospective observational multicenter study designed to prospectively evaluate all incident admissions in ten ICUs in Italy and the relevant epidemiology of AKI. Thus, a simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive incident patients into the study; 25 patients with end-stage renal disease were excluded, leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 (IQR 3-14) days. Of 576 patients, 246 patients (42.7%) had AKI within 24 h of ICU admission, while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-AKI patients (p < 0.001). 48 patients (8.3%) were treated with RRT in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. AKI patients were started on RRT a median of 1 (IQR 0-4) day after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) days. AKI patients had a higher crude ICU mortality (28.8 vs. 8.1%, non-AKI; p < 0.001) and longer ICU length of stay (median 7 vs. 3 days, non-AKI; p < 0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. 225 (59.4% of AKI patients) had complete recovery of renal function, with a serum creatinine at time of ICU discharge which was ≤120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. The study supports the use of RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients, where the level of severity is correlated with mortality and length of stay. The tool developed for data collection was user-friendly and easy to implement. Some of its features, including a RIFLE class alert system, may help the treating physician to systematically collect AKI data in the ICU and possibly may guide specific decisions on the institution of RRT.