Elevated Plasma Levels of Growth Arrest Specific 6 (Gas6) Protein in Severe Obesity: Implications for Adipose Tissue and Inflammation.

BACKGROUND Preliminary data suggest an adipogenic role for growth arrest-specific 6 (Gas6), a pleiotropic molecule involved in inflammation, proliferation, and hemostasis through its Tyro3, Axl, and MerTK (TAM) receptors. This study compares Gas6 expression in plasma and visceral and subcutaneous adipose tissue in 42 adults with obesity (body mass index ≥40 kg/m²) and 32 normal-weight controls to elucidate its role in obesity and related metabolic alterations. MATERIAL AND METHODS Using a case-control design, we measured Gas6 levels in plasma via a validated sandwich enzyme-linked immunosorbent assay and in adipose tissues through quantitative polymerase chain reactio with specific probes. Medians and correlations were analyzed using Mann-Whitney and Spearman tests. A general linear model assessed the impact of covariates on the Gas6-anthropometric relationship, with statistical significance determined by P values. RESULTS Plasma Gas6 levels were significantly higher in the obese group than in controls (P=0.0006). While Gas6 mRNA expression did not significantly differ in subcutaneous adipose tissue between groups, it was notably higher in visceral than subcutaneous adipose tissue in controls (P<0.05). A significant correlation was found between plasma Gas6 levels and body mass index (P=0.001). CONCLUSIONS Gas6 plasma levels are elevated in morbid obesity, particularly in visceral adipose tissue, and are linked to altered glucose tolerance in female patients. These findings highlight the role of Gas6 in obesity-related metabolic complications and suggest avenues for further research and potential therapies.

A Pilot Study on Clinical Scores, Immune Cell Modulation, and Microbiota Composition in Allergic Patients with Rhinitis and Asthma Treated with a Probiotic Preparation.

BACKGROUND: Specific drugs and/or immunotherapies are widely used to treat allergies, but drug-induced adverse effects recently led to explore new additional strategies. We studied whether a probiotic preparation (iPROB®; Anallergo SpA, Florence, Italy) is effective in allergic patients and the mechanisms underlying clinical outcomes. METHODS: Eligible patients (n = 28), all suffering from allergic rhinitis with/without bronchial asthma, were consecutively recruited at the Allergology Medical Unit (Novara, Italy) and treated with this probiotic. From each patient, we collected blood and stool samples at the baseline, after 60 days of probiotic supplementation, and after 60 days from probiotic discontinuation. In each blood sample, the percentage of hematopoietic stem cells, eosinophils, and basophils was measured by FACS. To analyze stool microbiota composition, genomic DNA was extracted, bacterial 16S DNA libraries sequenced by Illumina platform (Miseq), and raw sequences processed. Generated data were statistically analyzed. RESULTS: Probiotic-treated patients showed a significant decrease in Average Rhinitis Total Symptom Score (d = -10.5714), and Visual Analog Scale (d = -2.00) clinical indices, as well as important improvements in quality of life. In whole blood, a significant reduction in the percentage of activated eosinophils and basophils was determined, and this effect persisted after specific cell stimulation. Consistently, the serum levels of IL-4 and IL-5 decreased after probiotic treatment, suggesting a reduction in the Th2 cytokine profile. In addition, microbiome genomic analysis (n = 6) showed an increase in microbiome biodiversity, which positively correlates with clinical and cellular data. CONCLUSION: Present study suggests that iPROB® preparation has clinical/biological properties to be a valid add-on supplementation in allergic patients with asthma and rhinitis.

Overlapping polyclonal lymphoproliferative disorders.

Multicentric Castleman disease (MCD) is a rare clinical entity characterized by a polyclonal lymphoid proliferation, leading to generalized lymphadenopathy, organomegaly and systemic symptoms. It has been reported in association with either other monoclonal or polyclonal lymphoid disorders, such as POEMS syndrome and immunoglobulin (Ig)G4-related disease. We present a patient showing a variant of MCD, sharing common features with POEMS syndrome and associated with the proliferation of IgG4-producing plasma cells.

First reported human case of meningitis by Staphylococcus condimenti.

Staphylococcus condimenti (S. condimenti) is a coagulase-negative bacterium, generally regarded as not pathogenic. Indeed, S. condimenti owes its name to having been isolated from starter cultures of fermented sausage, as well as from fish and soy sauces. To the best of our knowledge, only two cases of human infection caused by this bacterium have been reported. Here, we present a case of meningitis by S. condimenti in a 65-year-old woman who was brought to hospital after having been found unconscious at home. At her arrival, she had a Glasgow coma scale = 3, fever, and hypoxic-normocapnic respiratory failure. Examination of her cerebrospinal fluid showed a slightly increased white blood cell count, normal glucose and protein concentrations. Paired cultures on blood and liquor samples yielded S. condimenti. Targeted antibiotic treatment with ceftriaxone led to a complete recovery. This unique case expands our knowledge on S. condimenti as a pathogenic bacterium.

Relation among anti-rheumatic drug therapy, CD14(+)CD16(+) blood monocytes and disease activity markers (DAS28 and US7 scores) in rheumatoid arthritis: A pilot study.

Circulating human monocytes, a functionally and phenotypically heterogeneous population, are emerging as fundamental cell types in rheumatoid arthritis (RA). The aim of this pilot study was to assess the correlation, if any, among anti-rheumatic drug therapy, circulating CD14(+)CD16(+) monocytes and validated clinical scales (e.g., DAS28 score and ultrasonography US7 score) of disease severity in RA. Thirty consecutive RA patients, either naïve or under disease-modifying anti-rheumatic drugs (DMARDs) or biological therapy, and 10 age-matched healthy volunteers, were enrolled. Monocytes were prepared from heparinized blood samples; surface expression of CD14 and CD16 was determined by flow cytometry. RA patients presented a significantly higher percentage of CD14(+)CD16(+) monocytes, as compared to healthy subjects. There was a good correlation between DAS28 clinical score and the ultrasound composite score US7 (r=0.66), as well as between both scores and the percentage of CD14(+)CD16(+) monocytes (r=0.43 and 0.47, respectively). Naïve RA patients had the highest expression (19.2±3.2%) of CD14(+)CD16(+) monocytes and elevated DAS28 score; patients on DMARDs presented a 7-fold increased expression of CD14(+)CD16(+) monocytes, relatively to healthy volunteers (2.1±1.4%), and an intermediate disease severity. The RA patients treated with biological therapy had a low percentage of CD14(+)CD16(+) monocytes (5.1±3.6%; p<0.01 vs naïve and DMARDs groups), similar to the one detected in healthy controls, and reduced US7 and DAS28 scores. Interestingly, for the same DAS28 score, monocytes isolated from RA patients on biological therapy had a lower CD16 expression than patients on DMARDs. Therefore, CD14(+)CD16(+) circulating blood monocytes may represent an appropriate biomarker to assess RA disease activity along with DAS28 and US7 scores. Together, these three parameters may represent a better indicator for evaluating therapy efficacy.

Feasibility and usefulness of ultrasonography in idiopathic intracranial hypertension or secondary intracranial hypertension.

BACKGROUND: Transorbital sonography (TOS) has been proven to be able to non-invasively detect elevated intracranial pressure. In this condition TOS shows an increase in optic nerve sheath diameter (ONSD). It has been suggested that internal jugular vein valve insufficiency (IJVVI) may represent a factor contributing to the pathogenesis of idiopathic intracranial hypertension (IIH). The aim of this study was to investigate whether patients with IIH or secondary IH have higher ONSD values and higher frequency of IJVVI compared to subjects without IH. METHODS: Twenty-one patients with newly diagnosed IIH or secondary IH were prospectively evaluated and compared with 21 age, gender and BMI-matched controls. Experienced vascular sonographers used B-mode TOS to evaluate ONSD, optic nerve diameter (OND) and IJVVI. CSF opening pressures were also measured. RESULTS: ONSD values were significantly higher in patients (6.50 ± 0.67) than controls (5.73 ± 0.66; p < 0.0001). No differences were found in OND values between patients (2.99 ± 0.26) and controls (2.93 ± 0.41; p = 0.574). No correlation was demonstrated between ONSD and CSF opening pressure (r = 0,086) (p = 0.73). No difference in frequency of IJVVI between patients (11/42 valves, 26 %) and controls (9/42, 21 %) was observed (p = 0.777). CONCLUSIONS: Increased ONSD values detected by TOS support the diagnosis of IH. Our results do not support the hypothesis of a venous congestion as a potential factor contributing to the pathogenesis of IIH. TRIAL REGISTRATION: Not applicable. Observational, non-interventional study.

Unveiling the Mystery of Adult-Onset Still's Disease: A Compelling Case Report.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, to some extent, a process of exclusion. AOSD has life-threating complications ranging from asymptomatic to severe, such as macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with cytokine storm production and monocyte/macrophage overactivation and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. For the treatment of MAS-HLH, the Histiocyte Society currently suggests high-dose corticosteroids, with the possible addition of cyclosporine A, anti-interleukin (IL)-1, or IL-6 biological drugs; the inclusion of etoposide is recommended for the most severe conditions. In all cases, a multidisciplinary collaboration involving the resources and expertise of several specialists (e.g., rheumatologist, infectiologist, critical care medicine specialist) is advised. Herein, we provide a detailed description of the clinical case of a previously healthy young woman in which MAS developed as a dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge; the condition was finally resolved by applying the HLH-94 protocol (i.e., etoposide in combination with dexamethasone).

Transcriptomic profile comparison of monocytes from rheumatoid arthritis patients in treatment with methotrexate, anti-TNFa, abatacept or tocilizumab.

It is well documented that patients affected by rheumatoid arthritis (RA) have distinct susceptibility to the different biologic DMARDs available on the market, probably because of the many facets of the disease. Monocytes are deeply involved in the pathogenesis of RA and we therefore evaluated and compared the transcriptomic profile of monocytes isolated from patients on treatment with methotrexate alone or in combination with tocilizumab, anti-TNFα or abatacept and from healthy donors. Whole-genome transcriptomics yielded a list of regulated genes by Rank Product statistics and DAVID was then used for functional annotation enrichment analysis. Last, data were validated by qRT-PCR. Abatacept, tocilizumab and anti-TNFa cohorts were separately compared with methotrexate, leading to the identification of 78, 6, and 436 differentially expressed genes, respectively. The upper-most ranked genes were related to inflammatory processes and immune responses. Such an approach draws the genomic profile of monocytes in treated RA patients and lays the basis for finding gene signature for tailored therapeutic choices.

SARS-CoV-2 infection risk is higher in vaccinated patients with inflammatory autoimmune diseases or liver transplantation treated with mycophenolate due to an impaired antiviral immune response: results of the extended follow up of the RIVALSA prospective cohort.

Background: A relevant proportion of immunocompromised patients did not reach a detectable seroconversion after a full primary vaccination cycle against SARS-CoV-2. The effect of different immunosuppressants and the potential risks for SARS-CoV-2 infection in these subjects is largely unknown. Methods: Patients from the Rivalsa prospective, observational cohort study with planned anti SARS-CoV-2 third dose mRNA vaccination between October and December 2021 were asked to participate to this follow-up study. Patients were asked about eventual confirmed positivity to SARS-CoV-2 infection within 6 months from the third dose and to undergo a blood draw to evaluate seroconversion status after the additional vaccine shot. Results: 19 out of 114 patients taking part in the survey developed a confirmed SARS-CoV-2 infection; we identified mycophenolate treatment as an independent predictor of an increased risk of infection even after the third vaccine dose (OR: 5.20, 95% CI: 1.70-20.00, p=0.0053). This result is in agreement with the in vitro evidence that MMF impairs both B and T lymphocytes driven immune responses (reduction both in memory B cells producing anti-spike antibodies and in proliferating CD4+ and CD8+ T cells). Conclusions: Immunocompromised patients need an additional vaccine administration to reach a detectable seroconversion, thus fostering a more personalized approach to their clinical management. Moreover, patients undergoing mycophenolate treatment show a specific increased infection risk, with respect to other immunosuppressants thus supporting a closer monitoring of their health status.

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Hypovitaminosis D and response to cholecalciferol supplementation in patients with autoimmune and non-autoimmune rheumatic diseases.

Recent reports suggest a role of hypovitaminosis D in the pathogenesis of inflammatory autoimmune diseases (ARD); we investigated 25(OH)vitamin D plasma level before and after supplementation in ARD and NARD (non-ARD: osteoporosis and/or OA) patients. We retrospectively evaluated 572 consecutive clinical records of adult patients at immuno-rheumatology and rehabilitative units of our institution from January 2006 to October 2009. We excluded patients with vitamin D supplementation or renal failure, primary hyperparathyroidism, liver failure. We recorded 25(OH)vitamin D plasma concentration of 245 patients together with other clinical data. We then evaluated 25(OH)vitamin D plasma concentration of 100 (43 ARD and 57 NARD) patients previously included who underwent 750-1,000 UI/die 25(OH)vitamin D supplementation for at least 6 months. Appropriate statistical analysis was performed. The median 25(OH)vitamin D concentration was not significantly different between 119 ARD [33.4 (IQR 22.5-54.9) nmol/l] and 126 NARD patients 32.9 (IQR 18.7-50.2). In stepwise logistic regression, female sex (F:13.7), winter-spring season (F:5.6) and older age (F:5.3), but not ARD, predicted plasma 25(OH)vitamin D <75 nmol/l. Cholecalciferol supplementation increased 25(OH)vitamin D plasma concentration equally in both ARD and NARD; however, only 29/100 patients reached a plasma level ≥75 nmol/l without differences between ARD and NARD (χ(2) = n.s.). Hypovitaminosis D is common in rheumatic patients. Sex and age but not ARD are risk factors for this condition. 750-1,000 UI/die of cholecalciferol is not sufficient to normalize plasma level in these patients. Increase of plasma 25(OH)vitamin D after treatment is not influenced by the presence of an inflammatory autoimmune disease.

Clinical Relevance of Liver Involvement in the Clinical Course of Systemic Sclerosis.

Liver involvement in systemic sclerosis (SSc) is rare. We evaluated the prevalence of liver fibrosis and hepatic autoimmunity in SSc patients in a retrospective observational cohort (97 SSc or mixed connective tissue disease with sclerodermic manifestations patients undergoing transient elastography, evaluating liver stiffness (LS) and controlled attenuation parameter (CAP), due to clinical indications along with biochemistry assessments and major antibodies associated to liver autoimmunity). Among them, 11 had LS ≥ 7.5 kPa and 5 showed an LS compatible with cirrhosis (LS ≥ 12.5 kPa). Predictors of LS ≥ 7.5 fibrosis were alcohol consumption (>14 or >7 alcoholic units/week for men and women, respectively), waist circumference (>102 or >88 cm for men and women, respectively), elevated alkaline phosphatase, and anti-La and anti-mitochondrial antibody (AMA) positivity. Six patients had CAP values compatible with severe steatosis (≥280 dB/m). Waist circumference, body mass index and diabetes mellitus were significant predictors of steatosis. Out of 97 patients, 19 were positive for AMA, 4 for anti-Sp100, 1 for anti-Gp210 and 7 were diagnosed with primary biliary cholangitis. Among SSc patients, hepatic fibrosis biomarkers and AMA prevalence are relatively high, suggesting the opportunity of performing a transient elastography and a screening for hepatic autoimmunity at diagnosis and/or during disease progression.

Increased Levels of ICOS and ICOSL Are Associated to Pulmonary Arterial Hypertension in Patients Affected by Connective Tissue Diseases.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening complication of connective tissue diseases (CTD); in this study, we aimed at investigating the potential role of inducible co-stimulator (ICOS) and its ligand (ICOS-L) as biomarkers of PH in CTD. MATERIALS AND METHODS: We recruited 109 patients: 84 CTD patients, 13 patients with CTD complicated by pulmonary arterial hypertension (PAH), and 12 subjects with PAH alone. All recruited patients underwent a complete clinical and instrumental assessment along with quantitative measurement of serum ICOS and ICOS-L. RESULTS: Independently of the underlying cause, patients with PAH were older and had a lower glomerular filtration rate. Interestingly, patients with both CTD-related and CTD-unrelated PAH had higher ICOS and ICOS-L serum concentrations than CTD patients (0.0001 for both). When compared to CTD patients, those affected by CTD-PAH showed higher ICOS (440 (240-600) vs. 170 (105-275) pg/mL, p = 0.0001) and ICOS-L serum concentrations (6000 (4300-7000) vs. 2450 (1500-4100) pg/mL; p = 0.0001). In a logistic regression, ICOS and ICOS-L were associated with a diagnosis of PAH, independently from age, gender, and renal function. The corresponding receiver operating characteristic (ROC) curves demonstrated a good diagnostic performance for both ICOS and ICOS-L. CONCLUSIONS: ICOS and ICOS-L are increased in patients with PAH, irrespectively from the underlying cause, and represent promising candidate biomarkers for the diagnostic screening for PAH among CTDs patients.

Ongoing Mycophenolate Treatment Impairs Anti-SARS-CoV-2 Vaccination Response in Patients Affected by Chronic Inflammatory Autoimmune Diseases or Liver Transplantation Recipients: Results of the RIVALSA Prospective Cohort.

Vaccines are the most effective means to prevent the potentially deadly effects of SARS-CoV-2 infection, but not all vaccinated individuals gain the same degree of protection. Patients undergoing chronic immunosuppressive therapy due to autoimmune diseases or liver transplants, for example, may show impaired anti-SARS-CoV-2 antibody response after vaccination. We performed a prospective observational study with parallel arms, aiming to (a) evaluate seroconversion after anti-SARS-CoV-2 mRNA vaccine administration in different subgroups of patients receiving immunosuppressive treatment for rheumatological or autoimmune diseases or to prevent organ rejection after liver transplantation and (b) identify negative predictors of IgG anti-SARS-CoV-2 development. Out of 437 eligible patients, 183 individuals were enrolled at the Rheumatology and Hepatology Tertiary Units of "Maggiore della Carità" University Hospital in Novara: of those, 52 were healthy subjects, while among the remaining 131 patients, 30 had a diagnosis of spondyloarthritis, 25 had autoimmune hepatitis, 10 were liver transplantation recipients, 23 suffered from connective tissue diseases (including 10 cases that overlapped with other diseases), 40 were treated for rheumatoid arthritis, and 5 had vasculitis. Moreover, all patients were receiving chronic immunosuppressive therapy. The immunogenicity of mRNA COVID-19 vaccines was evaluated by measuring IgG anti-SARS-CoV-2 antibody titers before vaccination and after 10, 30, and 90 days since the first dose administration. Of the selected cohort of patients, 24.0% did not develop any detectable anti-SARS-CoV-2 IgG after a complete mRNA-based two doses primary vaccination cycle. At univariate analysis, independent predictors of an absent antibody response to vaccine were a history of liver transplantation (OR 11.5, 95% CI 2.5−53.7, p = 0.0018), the presence of a comorbid active neoplasia (OR 26.4, 95% CI 2.8−252.4, p = 0.0045), and an ongoing immunosuppressive treatment with mycophenolate (MMF) (OR 14.0, 95% CI 3.6−54.9, p = 0.0002) or with calcineurin inhibitors (OR 17.5, 95% CI 3.1−99.0, p = 0.0012). At multivariate analysis, only treatment with MMF (OR 24.8, 95% CI 5.9−103.2, p < 0.0001) and active neoplasia (OR 33.2, 95% CI 5.4−204.1, p = 0.0002) were independent predictors of seroconversion failure. These findings suggest that MMF dose reduction or suspension may be required to optimize vaccine response in these patients.

Cardiopulmonary Exercise Testing Is an Accurate Tool for the Diagnosis of Pulmonary Arterial Hypertension in Scleroderma Related Diseases.

The early diagnosis of pulmonary arterial hypertension (PAH) is a major determinant of prognosis in patients affected by connective tissue diseases (CTDs) complicated by PAH. In the present paper we investigated the diagnostic accuracy of cardiopulmonary exercise testing (CPET) in this specific setting. We recorded clinical and laboratory data of 131 patients who underwent a CPET at a pulmonary hypertension clinic. Out of them, 112 (85.5%) had a diagnosis of CTDs; 8 (6.1%) received a diagnosis of CTDs-PAH and 11 (8.4%) were affected PH of different etiology. Among CPET parameters the following parameters showed the best diagnostic performance for PAH: peak volume of oxygen uptake (VO2; AUC: 0.845, CI95% 0.767-0.904), ratio between ventilation and volume of exhaled carbon dioxide (VE/VCO2 slope; AUC: 0.888, CI95%: 0.817-0.938) and end-tidal partial pressures (PetCO2; AUC: 0.792, CI95%: 0.709-0.861). These parameters were comparable among CTDs-PAH and PH of different etiology. The diagnostic performance was even improved by creating a composite score which included all the three parameters identified. In conclusion, CPET is a very promising tool for the stratification of risk of PAH among CTDs patients; the use of composite measures may improve diagnostic performance.

Role of Osteopontin as a Potential Biomarker of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis and Other Connective Tissue Diseases (CTDs).

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTD). Its early diagnosis is essential to start effective treatment. In the present paper, we aimed to evaluate the role of plasma osteopontin (OPN) as a candidate biomarker of PAH in a cohort of CTD patients. OPN is a pleiotropic protein involved in inflammation and fibrogenesis and, therefore, potentially promising in this specific clinical context. We performed a cross-sectional observational study on a cohort of 113 CTD patients (females N = 101, 89.4%) affected by systemic sclerosis N = 88 (77.9%), mixed connective tissue disease N = 10 (8.8%), overlap syndrome N = 10 (8.8%) or undifferentiated connective tissue disease N = 5 (4.4%). CTD-PAH patients showed significantly higher OPN plasma values than patients with CTD alone (241.0 (188.8-387.2) vs. 200.7 (133.5-281.6) ng/mL; p = 0.03). Although OPN levels were directly correlated with age and inversely with glomerular filtration rate, they remained associated with PAH at multivariate analysis. In conclusion, OPN was significantly associated with PAH among patients with CTD, suggesting it may have a role as a non-invasive disease biomarker of PAH.

Role of positron emission tomography in the assessment of disease burden and risk of relapse in patients affected by giant cell arteritis.

Giant cell arteritis (GCA) is characterized by two subsets: cranial GCA and large-vessel GCA (LV-GCA); positron emission tomography (PET) is an essential tool in the diagnosis of LV-GCA. In this study, we aimed to investigate its potential prognostic value in the stratification of relapse risk. We retrospectively revised all the clinical records of patients who received a diagnosis of GCA at an immuno-rheumatology clinic of a University Hospital along 6 years and who underwent to a PET-CT examination at diagnosis. Clinical, laboratory, and imaging data were collected. Relapses were recorded. The study population included 19 patients (10 females, 52.6%; median age 74.0 [65.5-76.0] years), 12 with typical cranial GCA (63%) and 7 (37%) with LV-GCA. Based on PET findings, a diagnosis of aortitis was made in 15/19 patients, including 8/12 patients with a classical cranial GCA (58%). Along a median follow-up of 15 months [4.5-26.5], 4 relapses were observed. All relapsers were male; indeed, the difference in gender distribution was the only variable reaching statistical difference between relapsers and non-relapsers. Specifically, aortitis was not more frequent among relapsers. Our study confirms PET as a valid tool in the identification of LV-GCA with no cranial involvement. We failed to demonstrate a role for PET in the prognostic stratification of GCA, while male gender is suggested as a potential risk factor for GCA relapse.Key Points• A significant proportion of patients with GCA presents with non-cranial disease, the identification of which requires imaging studies, among which PET is particularly useful.• Aortitis might be detected also in patients with the classical, cranial GCA type but does not seem to have prognostic implications, at least in terms of relapse risk.• Male gender is suggested as a risk factor for relapse in GCA.

Role of Gas6 and TAM Receptors in the Identification of Cardiopulmonary Involvement in Systemic Sclerosis and Scleroderma Spectrum Disorders.

BACKGROUND: Few biomarkers are available for early identification of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) in systemic sclerosis (SS) and scleroderma spectrum disorders (SSD). AIMS: To evaluate Gas6, sAxl, and sMer as biomarkers for cardiopulmonary complications of SS and SSD. METHODS: In a cross-sectional observational study, we recruited 125 consecutive patients, affected by SS and SSD and referred to a tertiary-level pulmonary hypertension outpatient clinic. All patients underwent a comprehensive evaluation for identification of PAH and ILD. Gas6, sMer, and sAxl concentrations were measured with ELISA protocols, and concentrations were compared according to PAH or ILD. RESULTS: Nineteen subjects had pulmonary hypertension (PH) (14 PAH), and 39 had ILD (6 severe). Plasma sMer was increased in PAH (18.6 ng/ml IQR [11.7-20.3]) with respect to the absence (12.4 [8.0-15.8]) or other form of pulmonary hypertension (9.6 [7.4-12.5]; K-W variance p < 0.04). Conversely, Gas6 and sAxl levels were slightly increased in mild ILD (25.8 ng/ml [19.5-32.1] and 24.6 [20.1-32.5]) and reduced in severe ILD (16.6 [15.0-22.1] and 15.5 [14.9-22.4]) in comparison to no evidence of ILD (23.4 [18.8-28.1] and 21.6 [18.1-28.4]; K-W, p ≤ 0.05). Plasma sMer ≥ 19 ng/ml has 50% sensitivity and 92% specificity in PAH identification (area under the ROC curve (AUC) 0.697, p < 0.03). Values of Gas6 ≤ 24.5 ng/ml and of sAxl ≤ 15.5 ng/ml have 100% and 67% sensitivity and 47% and 86% specificity, respectively, in identifying severe ILD (Gas6 AUC 0.787, p < 0.001; sAxl AUC 0.705, p < 0.05). CONCLUSIONS: The assay of Gas6 sAxl and sMer may be useful to help in the identification of PAH and ILD in SS and SSD patients. The Gas6/TAM system seems to be relevant in cardiopulmonary complications of SS and SSD and merits further investigations.

Red Cell Distribution Width and Platelet Count as Biomarkers of Pulmonary Arterial Hypertension in Patients with Connective Tissue Disorders.

INTRODUCTION/OBJECTIVE: In the present paper, we aimed to test the value of the red cell distribution width (RDW) coefficient of variation as a candidate biomarker for pulmonary arterial hypertension (PAH) in patients with connective tissue disorders (CTD), correlating it with the degree of cardiopulmonary impairment in these patients. METHODS: The study population included N = 141 patients with CTD and N = 59 patients affected by pulmonary hypertension of other etiologies, all referred to the Pulmonary Hypertension Clinic of the Cardiology Division of an Academic Hospital in Northern Italy for evaluation (including right catheterization). Clinical, instrumental, and laboratory data were collected and related to RDW and other full blood count indexes. RESULTS: Twenty out of 141 CTD patients (14%) received a diagnosis of PAH. In comparison to those without PAH, CTD patients with PAH displayed a larger RDW (14.9% (13.5-17.2) vs. 13.8% (13.1-15.0); p = 0.02) and a lower platelet count (205 (177-240) × 109/l vs. 244 (197.5-304.2) × 109/l; p = 0.005). Moreover, with respect to CTD patients without PAH, RDW was significantly larger also in PH of other etiologies. In contrast, the platelet count was significantly lower only in CTD-related PAH, with a value > 276 × 109/l being 100% sensitive in ruling out PAH. Finally, RDW, but not the platelet count, was related directly to systolic pulmonary arterial pressure (r = 0.381; p = 0.0008) and right ventricle diameter (r = 0.283; p = 0.015) and inversely to diffusing capacity of the lung for carbon monoxide (r = -0.325; p = 0.014). CONCLUSION: RDW is a promising candidate biomarker for the screening and the prognostic stratification of PAH in CTD patients.