Liver Involvement in Patients with Systemic Sclerosis: Role of Transient Elastography in the Assessment of Hepatic Fibrosis and Steatosis.

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of the study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients fulfilling the 2013 ACR/EULAR classification criteria were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), activity index, videocapillaroscopy, echocardiography, and lung function data were analyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis. In addition, hepatic steatosis was evaluated by means of controlled attenuation parameter (CAP) findings. Specifically, CAP values ≥ 238 ≤ 259 dB/m were considered consistent with mild steatosis (S1), values ≥ 260 ≤ 290 dB/m were compatible with moderate steatosis (S2), and values ≥ 291 dB/m were indicative of severe steatosis (S3). Results The median age of patients was 51 years, with a median disease duration of 6 years. The median LS was 4.5 (2.9-8.3) kPa; 69.5% of patients had no evidence of fibrosis (F0); 27.1% displayed LS values between 5.2 and 7 kPa; and only 3.4% of patients had LS values > 7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164-343). Overall, 66.1% of patients did not show evidence of steatosis (CAP values < 238 dB/m); 15.2% showed values consistent with mild (S1) steatosis (CAP value ≥ 238 ≤ 259 dB/m); 13.5% had moderate (S2) steatosis (CAP value ≥ 260 ≤ 290 dB/m); and 5.1% were deemed to have severe steatosis (S3) due to CAP values ≥ 291 dB/m. Conclusions Although systemic sclerosis is associated with fibrosis of the skin and several organs, only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Therefore, fibrosis of the liver did not appear to be a significant concern in SSc patients, albeit moderate fibrosis could still be detected in a significant proportion of subjects. A prolonged follow-up may clarify whether liver fibrosis in SSc patients may still progress. Likewise, the prevalence of significant steatosis was low (5.1%) and depended on the same variables associated with fatty liver disease in the general population. TE was shown to be an easy and valuable method for detection and screening of hepatic fibrosis in SSc patients with no additional risk factors for liver disease and may be useful to assess the potential progression of liver fibrosis over time.

The Role of Neuropathy Screening Tools in Patients Affected by Fibromyalgia.

Fibromyalgia syndrome (sFM) is one of the most common causes of chronic pain. This study aimed to assess the presence of small and large fiber impairment in fibromyalgic patients by applying validated scores used in the screening for diabetic neuropathy. The endpoints for the study were the assessment of neuropathy prevalence in sFM patients using the NerveCheck Master (NCM), the Michigan Neuropathy Screening Instrument (MNSI), the Diabetic Neuropathy Symptom (DNS) and the Douleur Neuropathique 4 Questions (DN4). The sample was composed of 46 subjects: subjects with sFM (n = 23) and healthy controls (HC) (n = 23). The positivity rates in each group for DN4 were significantly different (p < 0.001), with a prevalence in symptomatic subjects of 56.3% (n = 9) among sFM individuals. A similar difference was also observed with the DNS total score (p < 0.001). NCM and MNSI did not disclose significant differences between the two groups. This finding seems to confirm the data regarding the prevalence of a neuropathic pain in sFM patients.

The Role of Lung Ultrasound in SARS-CoV-19 Pneumonia Management.

Purpose: We aimed to assess the role of lung ultrasound (LUS) in the diagnosis and prognosis of SARS-CoV-2 pneumonia, by comparing it with High Resolution Computed Tomography (HRCT). Patients and methods: All consecutive patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in COVID Centers were enrolled. LUS and HRCT were carried out on all patients by expert operators within 48−72 h of admission. A four-level scoring system computed in 12 regions of the chest was used to categorize the ultrasound imaging, from 0 (absence of visible alterations with ultrasound) to 3 (large consolidation and cobbled pleural line). Likewise, a semi-quantitative scoring system was used for HRCT to estimate pulmonary involvement, from 0 (no involvement) to 5 (>75% involvement for each lobe). The total CT score was the sum of the individual lobar scores and ranged from 0 to 25. LUS scans were evaluated according to a dedicated scoring system. CT scans were assessed for typical findings of COVID-19 pneumonia (bilateral, multi-lobar lung infiltration, posterior peripheral ground glass opacities). Oxygen requirement and mortality were also recorded. Results: Ninety-nine patients were included in the study (male 68.7%, median age 71). 40.4% of patients required a Venturi mask and 25.3% required non-invasive ventilation (C-PAP/Bi-level). The overall mortality rate was 21.2% (median hospitalization 30 days). The median ultrasound thoracic score was 28 (IQR 20−36). For the CT evaluation, the mean score was 12.63 (SD 5.72), with most of the patients having LUS scores of 2 (59.6%). The bivariate correlation analysis displayed statistically significant and high positive correlations between both the CT and composite LUS scores and ventilation, lactates, COVID-19 phenotype, tachycardia, dyspnea, and mortality. Moreover, the most relevant and clinically important inverse proportionality in terms of P/F, i.e., a decrease in P/F levels, was indicative of higher LUS/CT scores. Inverse proportionality P/F levels and LUS and TC scores were evaluated by univariate analysis, with a P/F−TC score correlation coefficient of −0.762, p < 0.001, and a P/F−LUS score correlation coefficient of −0.689, p < 0.001. Conclusions: LUS and HRCT show a synergistic role in the diagnosis and disease severity evaluation of COVID-19.

Tailoring biologic therapy for real-world rheumatoid arthritis patients.

Introduction: The cornerstone of rheumatoid arthritis (RA) therapy relies on the treat-to-target strategy, which aims at dampening inflammation as soon as possible in order to achieve persistent low disease activity or, ideally, remission, according to validated disease activity measures. Traditional disease-modifying antirheumatic drugs (DMARDs) may be chosen in monotherapy or in combination as first-line therapy; in case of an unsatisfactory response after a 3-6-month trial, biologic therapy may be commenced.Areas covered: Real-life RA patients may present with concomitant comorbidities/complications or be in peculiar physiological states which raise more than one question as to which biotherapy may be more well suited considering the whole clinical picture. Therefore, a thorough literature search was performed to identify the most appropriate biologic therapy in each setting considered in this review.Expert opinion: Here we provide suggestions for the use of biologic drugs having a predictable better outcome in specific real-world conditions, so as to ideally profile the patient to the best of the current knowledge.

Autonomic nervous system dysfunction correlates with microvascular damage in systemic sclerosis patients.

Objectives: Cardiac autonomic neuropathy is among the known cardiovascular complications of systemic sclerosis and may affect the whole prognosis of the disease. The aim of our study was to assess cardiac autonomic neuropathy prevalence in our cohort of systemic sclerosis patients and compare its main features with clinical and epidemiological data, particularly with the severity of microvascular damage, as detected by nailfold videocapillaroscopy. Methods: Twenty-six patients with definite systemic sclerosis were consecutively enrolled at our outpatient rheumatology clinic. All patients underwent physical examination, nailfold videocapillaroscopy, and autonomic neuropathy diagnostic tests (orthostatic hypotension test, deep breathing test, lying-to-standing, and Valsalva maneuvers). Results: Cardiac autonomic neuropathy prevalence was 50% (13 cases). On univariate analysis, cardiac autonomic neuropathy was shown to be significantly associated with an active pattern on nailfold videocapillaroscopy (odds ratio 5.86, 95% confidence interval 1.59-9.24; p = 0.032), whereas anti-Scl-70 positivity (odds ratio, 0.24; 95% confidence interval, 0.03-2.12; p = 0.049) and C-reactive protein (odds ratio, 19.32; 95% confidence interval, 1.79-56.71; p = 0.036) reached only a borderline statistical association. The time-dependent Cox multivariate regression model showed cardiac autonomic neuropathy development to be independently associated with an active pattern on nailfold videocapillaroscopy (odds ratio, 7.19; 95% confidence interval, 1.87-8.96; p = 0.042) and anti-Scl-70 positivity (odds ratio, 5.92; 95% confidence interval, 1.06-18.43; p = 0.048). Conclusions: Severe microvascular damage, as detected by nailfold videocapillaroscopy, may suggest the coexistence of autonomic dysfunction and should be considered as a red flag for the identification of patients particularly at risk of cardiac morbidity and mortality.

Choosing the most appropriate biologic therapy for Crohn's disease according to concomitant extra-intestinal manifestations, comorbidities, or physiologic conditions.

Introduction: approximately half of Crohn's disease (CD) patients suffer from concomitant extra-intestinal manifestations (EIMs). Moreover, CD patients may suffer from comorbidities or have physiologic characteristics that may influence the outcome of a biologic treatment. Previous guidelines, published when only TNF-α antagonists were available as biological agents, addressed only management of CD patients with the most common EIMs.Areas covered: Because of the recent introduction of new biologics for the treatment of Crohn's disease as well as increased awareness about comorbidities potentially able to affect the impact of biological drugs, here we provide an update on management considering old and new biologics with proven efficacy on both Crohn's disease and associated conditions, in order to ideally profile the patient to the best of the current knowledge.Expert Opinion: While waiting for identification and validation of widely available and reliable biomarkers able to predict which biologic may yield the best response in the individual IBD patient (rigorous precision medicine), the choice of biologic agents in CD patients in order to achieve the best outcome still lies on a thorough assessment of patient-related characteristics as well as deep knowledge of the properties and place in therapy of each biologic drug.

Uncommon immune-mediated extrahepatic manifestations of HCV infection.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has been associated with myriad extrahepatic manifestations, often resulting from aberrant immune responses. Among the most common immune-mediated manifestations of HCV infection, mixed cryoglobulinemia is the best known extra-hepatic complication. Areas covered: Here we review less common extrahepatic manifestations of HCV infection, with ascertained or presumed immune pathogenesis and the role of the new all oral direct-acting antiviral agents. Rheumatologic, dermatologic, ophthalmologic, renal, pulmonary, hematologic, cardiovascular, and neuropsychiatric manifestations of HCV infection have been considered. Expert commentary: Pathogenesis of HCV-induced aberrant immune responses resulting in peculiar clinical manifestations is not restricted to a single mechanism. A sound approach would therefore consider implementation of an etiologic treatment, through use of antiviral medications, to stop upstream in the pathogenic process all the immune mechanisms leading to hepatic and extrahepatic abnormalities. With the recent introduction of interferon-free, direct antiviral agents, capable of warranting cure for nearly all HCV-infected patients subjected to therapy, both common and uncommon extrahepatic manifestations of chronic hepatitis C are expected to no longer constitute a matter of comorbidity in the course of HCV infection.

The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score.

BACKGROUND: Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc. METHODS: Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination. RESULTS: The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p < 0.0001), and it was the only one among the NVC variables that gave a significant contribution in a logistic model where the ESSG score represented the dependent variable. ROC curve analysis confirmed that the NEMO score had the best performance in measuring DA. The AUC of the NEMO score was significantly greater than the AUCs obtained by plotting the sensitivity and specificity of the number of GCs and the mean nCs (p < 0.0001 in all cases). The NEMO score values that showed the best sensitivity-specificity balance in capturing patients with a relevant DA level were slightly higher in the Naples cohort than in the Milan cohort. CONCLUSIONS: This study confirms that the presence of a certain number of MHEs and MTs in NVC may be considered a strong warning signal of a current phase of DA in patients with SSc.

Reductive activation of HCFC-123 by methaemalbumin.

Hydrochlorofluorocarbon 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), a close structural analogue of the hepatotoxic anaesthetic halotane and a replacement for some ozone-depleting chlorofluorocarbons, is metabolized by liver cytochrome P450 (P450), both in vitro and in vivo. P450 activates HCFC-123, both oxidatively and reductively, to reactive species which attack P450 itself and also damage other targets leading to hepatotoxicity. Previous work in our laboratory has shown that some haloalkanes, including halomethanes CCl4, CCl3Br, CHCl4 and CH2Cl2 as well as halothane, are activated by different haemoproteins to reactive metabolites resulting in the protein's suicidal inactivation. Among these is methaemalbumin (MHA), a synthetic complex of haem with human albumin often used as a model for various natural haemoproteins, such as P450. The aim of this study was to use MHA as a model to investigate the mechanism of P450 inactivation by HCFC-123. We found that MHA can reductively activate HCFC-123 to reactive species resulting in the loss of its haem group. During anaerobic incubation of MHA with 10 mM HCFC-123, a typical reduced difference spectrum was observed with a 470-nm peak that increased with time, indicating an interaction between HCFC-123 or HCFC-123 metabolites and haem. In similar anaerobic incubations, a significant loss of haem was measured using both the pyridine-haemochromogen technique and an ion-pairing reverse-phase HPLC method (37 and 30%, respectively). The loss of haem was time-, but not dose-dependent. No statistically significant loss of protoporphyrin IX, as measured by a fluorescence technique, or of the absolute haem spectrum produced in presence of CO (CO-haem complex) was observed up to 10 mM HCFC-123. Finally, a small but statistically significant inorganic fluoride production was measured in the presence of 20 mM HCFC-123 using an F(-)-specific electrode. Taken together, these results indicate that incubation of the non-enzymatic P450 model MHA with HCFC-123 under anaerobic conditions leads to reductive activation of the substrate, resulting in the modification of haem, as was previously shown to occur for halothane. The haem modification is due to interaction of the prosthetic haem group of MHA with HCFC-123 metabolites. These data confirm the results of previous work with rat liver microsomal P450 and confirm suicidal destruction of haem to be the mechanism responsible for the HCFC-123-dependent loss of the enzyme's content and catalytic function.