Kidney Biopsy and Immuno-Rheumatological Diseases: A Retrospective and Observational Study.

Renal involvement is a common occurrence in patients with immuno-rheumatological diseases (IRDs). Several instances of glomerulonephritis (GN) occur in the setting of IRD and complicate the clinical course of an underlying condition. The aim of this study was to observe the spectrum of nephropathies according to age, kidney function, history of IRD at the time of biopsy, and histopathological kidney diagnosis. We evaluated data relating to 699 consecutive kidney native biopsies (female 52.1%) with a median age of 48 years (IQR 34-62) performed in adult patients collected over 15 years. The study population was divided into three groups: patients with kidney histological findings correlated to underlying IRD (Group 1), patients with kidney histological findings not correlated to underlying IRD (Group 2), and patients with kidney histological findings compatible with "de novo" IRD (absent in personal medical history) (Group 3). Kidney involvement related to IRD was found in 25.2% of patients. Group 1 was mostly represented by lupus nephritis (76.6%), with a younger age than Group 3 (p < 0.001) and by a higher percentage of females than other groups (p < 0.001). Group 3 was the most represented by microscopic polyangiitis (50.8%) when compared with the other two groups (p < 0.001). Acute nephritic syndrome (p < 0.001), acute kidney injury (AKI), and abnormal urinalysis (p < 0.001) were more represented in Group 3 than the other groups. In conclusion, IRDs are characterized by different clinical presentations and heterogeneous histological findings. Kidney biopsy remains fundamental to achieving the correct diagnosis and starting targeted therapy.

Changes in renal microcirculation in patients with nephrotic and nephritic syndrome: The role of resistive index.

BACKGROUND: Renal Resistive Index (RRI) is an important and non-invasive parameter of renal damage and it is associated with abnormal microcirculation or to a parenchymal injury. The aim of our study was to compare the RRI in a cohort of patients with renal diseases categorized in three groups: nephrotic syndrome (NS), acute nephritic syndrome (ANS) and patients with urinary abnormalities (UA). METHODS: Four hundred eighty-two patients with median age of 48 years (IQR 34-62) with indications for kidney disease were included in the study. Biochemical analyses, clinical assessment with detection of NS, ANS and UA and comorbidities were reported. Renal Doppler ultrasound with RRI was evaluated in all patients at the time of enrolment. RESULTS: NS was present in 81 (16.8 %) patients while ANS in 81 (16.8 %) and UA in 228 (47.3 %) patients. Patients with ANS showed significant higher RRI compared to both patients with NS [0.71 (IQR 0.67-0.78) vs 0.68 (0.63-0.73), p < 0.001] and UA [0.71 (0.67-0.78) vs 0.65 (0.61-0.71), p < 0.001]; RRI was higher in NS patients than in patients with UA [0.68 (0.63-0.73) vs 0.65 (0.61-0.71), p < 0.001]. Patients with ANS had significantly lower median estimated glomerular filtration rate (eGFR) compared respectively to NS and UA patients [19.7 ml/min vs 54.8 ml/min and vs 72.3 ml/min, p < 0.001], while renal length was significantly higher in patients with NS compared to both patients with ANS and UA [111.88 mm vs 101.98 mm and vs 106.15, p < 0.001]. Patients with ANS had more frequently hematuria and RRI ≥ 0.70 (p < 0.001) compared to both patients with NS and patients with UA. The multiple regression analysis, weighted for age, showed that RRI inversely correlates with eGFR (ß coefficient = -0.430, p < 0.001). CONCLUSIONS: Higher and pathological RRI were found in ANS than NS and UA. Renal resistive index in ANS reflects changes in intrarenal perfusion and microvascular dysfunction related to disease characteristics.

Resistant Hypertension and Related Outcomes in a Cohort of Patients with Cardiorenal Multimorbidity Hospitalized in an Internal Medicine Ward.

INTRODUCTION: Resistant hypertension (RH) is characterized by the failure to reach a goal blood pressure despite the administration of three medications at maximally tolerated doses, one of which being a diuretic. RH can be observed in a variety of clinical conditions, such as heart failure and reduced renal function and may confer high cardiovascular risk. AIM: To evaluate the prevalence of RH and its association with clinical outcomes; the primary outcome was in-hospital mortality and the composite outcome was all-cause of mortality and morbidity in a cohort of patients with cardiorenal multimorbidity hospitalized in an internal medicine ward. METHODS: We conducted a retrospective analysis of consecutive hypertensive patients with cardiorenal multimorbidity. The composite outcome incorporated all-cause of in-hospital mortality and occurrence of sepsis, pulmonary embolism, acute coronary syndrome, stroke and renal replacement therapy. RESULTS: We collected data in 141 inpatients with a mean age of 77 years ± 10 (males 65.9 %), estimated glomerular filtration rate of 34 ± 18.6 ml/min with length of stay of 17 ± 12 days. The prevalence of RH was 52.4%. In-hospital mortality was observed in 24 patients (17%) and the composite outcome occurred in 87 patients (61.7%) and among these 74 (85.1%) were patients with RH. Free survival for composite outcome was significantly higher in patients without RH than patients with RH (log rank 7.52, p = 0.006). Resistant hypertension was a risk factor for composite outcome [HR 1.857(C.I. 1.170-2.946, p = 0.009)]. CONCLUSION: In patients with cardiorenal multimorbidity there is a high proportion of RH that represents a risk factor for composite outcome but not for in-hospital mortality.

In Systemic Sclerosis Patients, Peripheral Blood CD21low B Cells and Serum IL-4 and IL-21 Influence Joint Involvement.

Systemic sclerosis (SSc) patients have an increased frequency of CD21low B cells and of serum interleukin-4 (IL-4) and IL-21, each possible markers of joint involvement in inflammatory arthritis. The aim of this study was to investigate the possible influence of CD21low B cells, IL-4, and IL-21 on joint involvement in a cohort of 52 SSc patients. The DAS28-ESR was correlated with CD21low B cells (r = 0.452, p < 0.001), IL-4 (r = 0.478, p < 0.001), and IL-21 (r = 0.415, p < 0.001). SSc patients with a DAS28-ESR > 3.2 had more CD21low B cells (12.65% (IQR: 7.11-13.79) vs. 5.08% (IQR: 3.76-7.45), p < 0.01), higher IL-4 levels (132.98 pg/mL (IQR: 99.12-164.12) vs. 100.80 pg/mL (IQR: 62.78-121.13), p < 0.05), and higher IL-21 levels (200.77 pg/mL (IQR: 130.13-302.41) vs. 98.83 pg/mL (IQR: 35.70-231.55), p < 0.01) than patients with a DAS28-ESR ≤ 3.2. The logistic regression analysis models showed that the DAI (OR: 2.158 (95% CI: 1.120; 4.156), p < 0.05) and CD21low B cells (OR: 1.301 (95% CI: 1.099; 1.540), p < 0.01), the DAI (OR: 2.060 (95% CI: 1.082; 3.919), p < 0.05) and IL-4 level (OR: 1.026 (95% CI: 1.006; 1.045), p < 0.01), and the DAI (OR: 1.743 (95% CI: 1.022; 2.975), p < 0.05) and IL-21 level (OR: 1.006 (95% CI: 1.000; 1.011), p < 0.05) were independently associated with a DAS28-ESR > 3.2. An elevated CD21low B cell percentage, IL-4 level, and IL-21 level was associated with higher articular disease activity in patients, suggesting a possible role in the pathogenesis of SSc joint involvement.

Type 2 cytokines and scleroderma interstitial lung disease.

Interstitial lung disease (ILD) is a life-threatening complication of systemic sclerosis (SSc). Type 2 (Th2) cytokines play a pivotal role in airway disease. Study aim was to evaluate serum level of Th2 interleukin (IL) and chemokine in SSc-ILD. Serum levels of IL-4, IL-5, IL-11, IL-13, IL-21, IL-31 and CXCL-13 were measured by Bio-Plex Multiplex Immunoassays in 60 SSc patients and 20 healthy controls (HC). Pulmonary function tests with diffusion lung capacity for carbon monoxide (DLco) and high resolution computed tomography (HRCT) were performed in SSc patients. ILD is defined as fibrotic changes (ground glass, reticular and honeycombing), assessed by Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software, affecting at least 10% of the lungs. Serum levels of Th2 cytokines were higher in SSc patients than HC. A linear correlation was observed between ground glass and IL-13 (r = 0.342, p < 0.01), IL-21 (r = 0.345, p < 0.01), IL-31 (r = 0.473, p < 0.001), IL-4 (r = 0.863, p < 0.001), IL-5 (r = 0.249, p < 0.05) and peripheral blood eosinophils (r = 0.463, p < 0.001). We found a negative correlation between DLco and IL-4 (r = - 0.511, p < 0.001) and peripheral blood eosinophils (r = - 0.446, p < 0.001). In the logistic regression analysis, IL-4 is associated with DLco ≤ 60% of the predicted [OR 1.039 (CI 95%: 1.015-1.064), p < 0.001], whilst mRSS [OR 1.138 (CI 95%: 1.023-1.266), p < 0.05] and IL-4 [OR 1.017 (CI 95%: 1-1.034), p < 0.05] were associated with ILD. Th2 inflammation could play a key role in early phase of SSc-ILD.

GLIM-diagnosed malnutrition predicts mortality and risk of hospitalization in systemic sclerosis: A retrospective study.

BACKGROUND: Malnutrition is a well-known risk factor for morbidity and mortality in many clinical settings and only few studies assessed the role of malnutrition on systemic sclerosis (SSc) patients' outcomes. The aim of this retrospective study was to evaluate the role of malnutrition as a predictive risk factor for mortality and/or hospitalization in SSc patients during a 4-year follow-up. METHODS: One hundred and one SSc patients were included in the study. Biochemical analyses, disease activity index, disease severity scale and anthropometric data were recorded at enrollment. Malnutrition was assessed by the Global Leadership Initiative on Malnutrition (GLIM) criteria. RESULTS: Malnutrition according to GLIM criteria was found in 22 patients (21.8%). During a 4-year follow-up, 20 (19.8%) SSc patients died or were hospitalized for all causes and 11 of them (55.0%) were malnourished. Kaplan-Meier curves showed that event free-survival for composite end-point of mortality and risk of hospitalization was significantly shorter in malnourished than in non-malnourished patients (p<0.001). The survival probability at 4 years was 0.885 (95% CI=0.818-0.959) in the non-malnourished group and 0.500 (95% CI=0.329-0.759) in the malnourished group (p<0.001). In multivariate analysis, malnutrition [HR=4.380 (95% CI=1.706-11.243), p = 0.002] was the most significant predictive risk factor for the composite end-point. Also, female gender [HR=0.157 (95% CI=0.055-0.449), p<0.001], age [HR=1.0450 (95% CI=1.011-1.090), p = 0.012] and disease severity scale [HR=1.269 (95% CI=1.089-1.479), p = 0.002] were predictive factors for the composite end-point. CONCLUSIONS: Malnutrition according to GLIM criteria represents a significant predictive risk factor for composite end-point of mortality and risk of hospitalization in SSc patients.

Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio and Cardiorenal Syndrome Type 2 in the Systemic Sclerosis EUSTAR Cohort.

OBJECTIVE: The aim of the study was to evaluate the association between the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) ratio and estimated glomerular filtration rate (eGFR) and their association with mortality in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS: Patients with systemic sclerosis (SSc) from the EUSTAR database with TAPSE, sPAP, and parameters required to calculate eGFR were included. Logistic regression and Cox regression analysis were performed to evaluate TAPSE/sPAP as a risk factor for chronic kidney disease (CKD) and overall survival. RESULTS: A total of 2,370 patients with SSc were included; 284 (12%) patients had CKD stage 3a-5. TAPSE/sPAP (odds ratio [OR] 0.479; 95% CI 0.310-0.743; P < 0.001), arterial hypertension (OR 3.118; 95% CI 2.173-4.475; P < 0.001), diastolic dysfunction (OR 1.670; 95% CI 1.148-2.428; P < 0.01), and N-terminal pro-B-type natriuretic peptide (OR 1.165; 95% CI 1.041-1.304; P < 0.01) were associated with CKD stage 3a-5. TAPSE/sPAP ≤0.32 mm/mm Hg (hazard ratio [HR] 3.589; 95% CI 2.236-5.761; P < 0.001), eGFR <60 mL/min per 1.73 m2 (HR 2.818; 95% CI 1.777-4.468; P < 0.001), and age (HR 1.782; 95% CI 1.348-2.356; P < 0.001) were the most significant predictive factors for all-cause mortality. A total of 276 patients with SSc had pulmonary hypertension (PH) confirmed by right heart catheterization, with 69 (25%) having CKD stage 3a-5. No difference was found in eGFR between patients with PH with reduced or normal cardiac index. CONCLUSION: Reduced TAPSE/sPAP ratio is independently associated with CKD. TAPSE/sPAP ratio ≤0.32 mm/mm Hg and eGFR <60 mL/min per 1.73 m2 are prognostic factors for all-cause mortality. In patients with SSc with PH, eGFR is independent by reduced cardiac output.

In acromegalic patients the serum levels of interleukin-33 and Resolvin D1 influence skin perfusion of hands: A pilot study.

AIM: Acromegaly is a rare chronic disease, caused by the over-secretion of growth hormone (GH), that creates a pro-inflammatory state, but the exact mechanisms by which GH or insulin-like growth factor 1 (IGF-I) act on inflammatory cells are not fully understood. Aim of the study was to evaluate Interleukin-33 (IL33) and D-series resolvins 1 (RvD1) and the skin perfusion of hands in patients with acromegaly (AP) and healthy controls (HC). METHODS: IL33 and RvD1 have been assessed in 20 AP and 20 HC. Nailfold videocapillaroscopy (NVC) was performed and skin perfusion of hands was assessed by laser speckle contrast analysis (LASCA) in both populations. RESULTS: IL33 was significantly higher in AP compared to HC [73.08 pg/ml (IQR 47.11-100.80 pg/ml) vs 41.5 4 pg/ml (IQR 20.16-55.49 pg/ml), p < 0.05] and RvD1 was significantly lower in AP than HC [36.1 pg/ml (IQR 27.88-66.21 pg/ml) vs 60.01 pg/ml (IQR 46.88-74.69 pg/ml), p < 0.05]. At LASCA, peripheral blood perfusion (PBP) was significantly lower in AP compared to HC [56.66 pU (IQR 46.29-65.44 pU) vs 87 pU (IQR 80-98 pU), p < 0.001]. The median values of ROI1 and ROI3 were significantly lower in AP compared to HC [112.81 pU (IQR 83.36-121.69 pU) vs 131 pU (IQR 108-135 pU), p < 0.05] and [59.78 pU (IQR 46.84-79.75 pU) vs 85 pU (IQR 78-98 pU), p < 0.05], respectively. The proximal-distal gradient (PDG) was observed in 8 of 20 (40 %) AP. CONCLUSION: Serum IL33 is higher in AP compared to HC; conversely, RvD1 is lower in AP compared to HC. Reduction of PBP of hands was present in AP compared to HC, probably due to endothelial dysfunction.

Parasympathetic activity and total fibrotic kidney in autosomal-dominant polycystic kidney disease patients: a pilot study.

PURPOSE: Renin-angiotensin system hyperactivation in autosomal-dominant polycystic kidney disease (ADPKD) patients leads to early hypertension. Cystic enlargement probably causes parenchymal hypoxia, renin secretion, and endothelial dysfunction. Sympathetic and parasympathetic balance is altered in this condition, especially during the night, also affecting blood pressure circadian rhythm. Aim of this study was to evaluate sympathetic/parasympathetic balance using heart rate variability (HRV) parameters and find a correlation between HRV and renal damage progression, as total kidney volume enlargement, in ADPKD patients. METHODS: Sixteen adult ADPKD patients were enrolled in the study. Eleven patients (68.8%) were male, and the median age was 42 years (IQR 36-47.5). HRV parameters were calculated using 24 h-ECG Holter. A kidney magnetic resonance imaging (MRI) scan 3 Tesla was performed to evaluate total kidney volume (TKV) and total fibrotic volume (TFV). RESULTS: A statistically significant positive linear correlation was observed between length of kidneys and frequency domain parameters as low frequency (LF) (r = 0.595, p < 0.05) and LFday (r = 0.587, p < 0.05). Moreover, a statistically significant positive linear correlation exists between high frequency (HF) and TFV (r = 0.804, p < 0.01) or height-adjusted (ha) TFV (r = 0.801, p < 0.01). Finally, we found a statistically significant positive linear correlation between HFnight and TKV (r = 0.608, p < 0.05), ha-TKV (r = 0.685, p < 0.01), TFV (r = 0.594, p < 0.05), and ha-TFV (r = 0.615, p < 0.05). CONCLUSION: We suppose that the increase in TKV and TFV could lead to a parasympathetic tone hyperactivation, probably in response to hypoxic stress and vasoconstriction due to cystic enlargement.

Serum kynurenic acid is lower in systemic sclerosis patients with microvascular damage of hands.

BACKGROUND: Endothelial dysfunction occurs early in systemic sclerosis (SSc), leading to tissue hypoxia, vasoconstriction and fibrosis. It has been demonstrated that endothelial cells (ECs) are able to produce kynurenic acid (KYNA) in response to vascular inflammation, due to its anti-inflammatory and anti-oxidants activity. In SSc patients, blood perfusion of hands, assessed by laser speckle contrast analysis (LASCA), correlated negatively with the extent of the nailfold microvascular damage, scored according to nailfold videocapillaroscopy (NVC) classification. Aim of this study was to evaluate the difference of serum KYNA in SSc patients with different stages of microvascular damage. METHODS: Serum KYNA was assessed in 40 SSc patients at the enrolment. NVC was performed to evaluate capillaroscopic patterns (early, active and late). LASCA was performed to evaluate mean peripheral blood perfusion (PBP) of both hands and to evaluate the proximal-distal gradient (PDG). RESULTS: Median PDG was significantly lower in SSc patients with late NVC pattern compared to SSc patients with early and active NVC pattern [3.79 pU (IQR -8.55-18.16) vs 23.55 pU (IQR 14.92-43.80), p < 0.01]. Serum KYNA was significantly lower in SSc patients with late NVC pattern compared to SSc patient with early and active NVC pattern [45.19 ng/mL (IQR 42.70-54.74) vs 52.65 ng/mL (IQR 49.99-60.29), p < 0.05]. Moreover, SSc patients without PDG had significantly lower serum KYNA than in SSc patients with PDG [48.03 ng/mL (IQR 43.87-53.68) vs 59.27 ng/mL (IQR 49.15-71.00), p < 0.05]. CONCLUSION: KYNA is lower in SSc patients with late NCV pattern and without PDG. KYNA may be associated with early endothelial dysfunction.

Contrast-Induced Acute Kidney Injury and Endothelial Dysfunction: The Role of Vascular and Biochemical Parameters.

INTRODUCTION: Contrast-induced acute kidney injury (CIAKI) is one of the main causes of acute renal failure in hospitalized patients, following the administration of iodinated contrast medium used for CT scans and angiographic procedures. CIAKI determines a high cardiovascular risk and appears to be one of the most feared complications of coronary angiography, causing a notable worsening of the prognosis with high morbidity and mortality. AIM: To evaluate a possible association between the renal resistive index (RRI) and the development of CIAKI, as well as an association with the main subclinical markers of atherosclerosis and the main cardiovascular risk factors. MATERIALS AND METHODS: We enrolled 101 patients with an indication for coronary angiography. Patients underwent an assessment of renal function (serum nitrogen and basal creatinine, 48 and 72 h after administration of contrast medium), inflammation (C reactive protein (CRP), serum calcium and phosphorus, intact parathormone (iPTH), 25-hydroxyvitaminD (25-OH-VitD), serum uric acid (SUA), total cholesterol, serum triglycerides, serum glucose and insulin). All patients also carried out an evaluation of RRI, intima-media thickness (IMT), interventricular septum (IVS) and the ankle-brachial index (ABI). RESULTS: 101 patients (68 male), with a mean age of 73.0 ± 15.0 years, were enrolled for the study; 35 are affected by type 2 diabetes mellitus. A total of 19 cases of CIAKI were reported (19%), while among diabetic patients we reported an incidence of 23% (8 patients). In our study, patients with CIAKI had significantly higher RRI (p < 0.001) and IMT (p < 0.001) with respect to the patients who did not develop CIAKI. Furthermore, patients with CIAKI had significantly higher CRP (p < 0.001) and SUA (p < 0.006). CONCLUSIONS: We showed a significant difference in RRI, IMT, SUA and CRP values between the population developing CIAKI and patients without CIAKI. This data appears relevant considering that RRI and IMT are low-cost, non-invasive and easily reproducible markers of endothelial dysfunction and atherosclerosis.

The role of TAPSE/sPAP ratio in predicting pulmonary hypertension and mortality in the systemic sclerosis EUSTAR cohort.

OBJECTIVES: The study aim was to evaluate the predictive role of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for pulmonary hypertension (PH) diagnosis and mortality in the European Scleroderma Trials and Research (EUSTAR) cohort. METHODS: Eligible patients were systemic sclerosis (SSc) patients registered in the EUSTAR database with at least one visit recording TAPSE and sPAP data. Individual centres were required to provide TAPSE and sPAP data at 12 ± 3 months before right heart catheterization (RHC). Logistic regression analysis was applied to analyse the predictive ability of TAPSE/sPAP ratio for PH diagnosis. Cox regression analysis was performed to evaluate TAPSE/sPAP ratio as a predictive factor for all-cause mortality. RESULTS: 2555 SSc patients met the inclusion criteria for this study with 355 SSc patients having available RHC data at baseline. PH was confirmed by RHC in 195 SSc patients (54.9%). TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.251 (95% CI 0.084-0.753), p < 0.05] and FVC/DLCO [OR 2.568 (95% CI 1.227-5.375), p < 0.05] were significantly associated with PH diagnosis. In logistic regression analysis with echocardiographic parameters at 12 ± 3 months before RHC, TAPSE/sPAP ratio < 0.55 mm/mmHg [OR 0.265 (95% CI 0.102-0.685), p < 0.01] and FVC/DLCO [OR 2.529 (95% CI 1.358-4.711), p < 0.01] were associated with PH diagnosis. In multivariate Cox regression analysis, TAPSE/sPAP ratio ≤ 0.32 mm/mmHg [HR 0.310 (0.164-0.585), p < 0.001] was the most significant predictive factor for death. CONCLUSIONS: TAPSE/sPAP ratio < 0.55 mm/mmHg is a predictive risk factor for PH. TAPSE/sPAP ratio ≤ 0.32 mm/mmHg is a predictive risk marker for all-cause mortality.

Serum Immunoglobulin G (IgG) Subclasses in a Cohort of Systemic Sclerosis Patients.

OBJECTIVES: To assess serum immunoglobulin G (IgG) subclasses in a cohort of systemic sclerosis (SSc) patients and to evaluate the influence of IgG subclasses in the main complications of the disease. METHODS: The serum level of IgG subclasses was evaluated in 67 SSc patients and 48 healthy controls (HC), matched for sex and age. Serum samples were collected and measured IgG1-4 subclasses by turbidimetry. RESULTS: SSc patients had lower median total IgG [9.88 g/l (IQR 8.18-11.42 g/l) vs. 12.09 g/l (IQR 10.24-13.54 g/l), p < 0.001], IgG1 [5.09 g/l (IQR 4.25-6.38 g/l) vs. 6.03 g/l (IQR 5.39-7.90 g/l), p < 0.001], and IgG3 [0.59 g/l (IQR 0.40-0.77 g/l) vs. 0.80 g/l (IQR 0.46-1 g/l), p < 0.05] serum levels compared to HC. The logistic regression analysis showed IgG3 as the only variable associated with the diffusing capacity of the lung for carbon monoxide (DLco) ≤60% of the predicted [OR 9.734 (CI 95%: 1.312-72.221), p < 0.05] and modified Rodnan skin score (mRSS) [OR 1.124 (CI 95%: 1.019-1.240), p < 0.05], anti-topoisomerase I [OR 0.060 (CI 95%: 0.007-0.535), p < 0.05], and IgG3 [OR 14.062 (CI 95%: 1.352-146.229), p < 0.05] as variables associated with radiological interstitial lung disease (ILD). CONCLUSION: SSc patients have reduced levels of total IgG and an altered IgG subclass distribution compared to HC. Moreover, SSc patients show different serum IgG subclasses profiles according to the main involvement of the disease.

Serum-soluble ST2 and systemic sclerosis arthropathy.

Interleukin (IL)33 and its receptor ST2 have been involved in the pathogenesis of several conditions, including arthritis. The aim of the study was to evaluate the association between IL33 or soluble ST2 (sST2) serum levels and systemic sclerosis (SSc) articular involvement. IL33 and sST2 serum levels were measured in 64 SSc patients and 24 HC matched for sex and age. Articular involvement assessed by using Disease Activity Score 28 based on erythrocyte sedimentation rate (DAS28-ESR), presence of tendon friction rubs (TFRs) and finger-to-palm (FTP) distance. sST2 serum levels were significantly higher in SSc patients with DAS28-ESR > 3.2 than in SSc patients with DAS28-ESR⩽3.2 [9726.1 (IQR 7746.5 - 14,953.5) pg/mL vs 7611.7 (IQR 5162.6 -11,036.7) pg/mL; p < 0.05]. sST2 serum levels were significantly higher in SSc patients with TFRs compared to SSc patients without TFRs [9726.1 (IQR 7746.5 - 14,953.5) pg/mL vs 7426.4 (IQR 5145.9 - 10,593.5) pg/mL; p < 0.01] and in SSc patients with FTP ≥ 1 cm compared to SSc patients with FTP < 1 cm [9683.7 (IQR 8067.2 - 16,387.6) pg/mL vs 7679.1 (IQR 5246.1 - 11,472.2) pg/mL; p < 0.05]. No significant association was observed between IL33 and DAS28-ESR, TFRs and FTP. A slightly positive linear correlation was found between sST2 and Disease Activity Index (r = 0.294, p < 0.05) and Disease Severity Scale (r = 0.265, p < 0.05). sST2 serum levels were positively correlated with DAS28-ESR (r = 0.371, p < 0.01). Elevated sST2 serum levels were associated with higher articular disease activity, TFRs and hand dysfunction, suggesting that sST2 might have a role in the pathogenesis of SSc articular involvement. Key Points • In SSc patients elevated serum levels of sST2 were associated with higher articular disease activity • High serum levels of sST2 were reported in SSc patients with TFRs and hand dysfunction • sST2 might have a role in the pathogenesis of SSc articular involvement.

In systemic sclerosis TAPSE/sPAP ratio is correlated with ventilatory efficiency and exercise capacity assessed by CPET.

OBJECTIVES: The aim of the study was to evaluate the correlation between cardiopulmonary exercise testing (CPET) parameters and right ventricular echocardiographic parameters for pulmonary arterial hypertension screening in a cohort of systemic sclerosis (SSc) patients. Methods forty SSc patients were examined using CPET and resting transthoracic echocardiography. CPET parameters analyzed were minute ventilation/carbon dioxide production (VE/VCO2) slope and maximum oxygen uptake (VO2 max); echocardiographic parameters were systolic pulmonary artery pressure (sPAP), tricuspid annular plane systolic excursion (TAPSE), and TAPSE/sPAP ratio. Results a positive correlation was observed between VE/VCO2 slope and age (r = 0.415, p < 0.01) and sPAP (r = 0.461, p < 0.01), conversely, a negative correlation was found between VE/VCO2 slope and TASPE/sPAP ratio (r = - 0.521, p = 0.001). VO2 max showed an inverse correlation with age (r = - 0.367, p < 0.05) and sPAP (r = - 0.387, p < 0.05) and a positive correlation with TAPSE/sPAP ratio (r = 0.521, p < 0.01). On stepwise linear regression analysis, VE/VCO2 slope was significantly correlated with TAPSE/sPAP ratio (ß coefficient = - 0.570; p < 0.0001), as well as VO2 max was significantly correlated with TAPSE/sPAP ratio (ß coefficient = 0.518; p = 0.001). Conclusion in SSc patients, TAPSE/sPAP ratio is the echocardiographic parameter of RV function which showed the best correlation with ventilatory efficiency and exercise capacity.

Interleukin-33 and soluble suppression of tumorigenicity 2 in scleroderma cardiac involvement.

Interleukin (IL)-33 is part of the IL-1 family of cytokines and soluble suppression of tumorigenicity 2 (sST2) is part of the family of IL-1 receptors. In systemic sclerosis (SSc), IL-33 and sST2 are involved in cardiac manifestations such as diastolic dysfunction (DD), autonomic dysfunction (AD) and right ventricular-pulmonary arterial coupling assessed by tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP). Serum levels of IL33 and sST2 were assessed in 50 SSc patients and 14 healthy controls (HC). Clinical assessment, echocardiography and heart rate variability (HRV) analysis were performed in SSc patients. Serum levels of IL-33 and sST2 were significantly higher in SSc patients than HC. A linear positive correlation between modified Rodnan skin score and IL33 was observed. Serum values of sST2 were higher in SSc patients with DD than in patients without DD [15403 pg/ml (12,208-19,941) vs 8556 pg/ml (6820-11,036), p < 0.001]. sST2 showed a negative correlation with standard deviation of normal-to-normal RR intervals (SDNN) (r = - 0.281, p < 0.05) and positive correlation with low frequency/high frequency (LF/HF) (r = 0,349, p < 0.01). Negative linear correlation exists between sST2 and TAPSE/sPAP (r = - 0.398, p < 0.01). Serum levels of IL-33 and sST2 are higher in SSc patients than HC. Serum levels of sST2 are a potential marker of DD, AD and right ventricular-pulmonary arterial coupling.

Phase angle, nutritional status, and mortality in systemic sclerosis: An exploratory pilot study.

OBJECTIVES: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by microvascular damage and fibrosis of the skin and internal organs. Among SSc complications, changes in nutritional status have a negative effect on quality of life and predispose patients to malnutrition. The aim of this exploratory pilot study was to examine whether bioelectrical impedance analysis-derived phase angle (PhA) is a parameter of nutritional status and a marker of mortality in patients with SSc. METHODS: Consecutive adult patients with SSc were included in the study. Biochemical analyses, anthropometric data, and bioelectrical impedance analysis assessments were recorded at the time of enrollment. The Malnutrition Universal Screening Tool (MUST) and Global Leadership Initiative on Malnutrition (GLIM) were applied to assess nutritional status. RESULTS: A total of 104 patients with SSc (88 women; median age: 55 y [interquartile range (IQR), 45.5- 66 y]) were enrolled. In patients with SSc and high malnutrition risk according to MUST, mean values of PhA were significantly lower than those of patients with SSc and low malnutrition risk (4° [IQR, 3.7°-4.4°] vs 4.6° [IQR, 4.2°-5.1°]; P = 0.004). Patients with SSc and malnutrition according to the GLIM criteria showed significantly lower PhA than patients with SSc but without malnutrition (3.8° [IQR, 3.5°-4.3°] vs 4.6° [IQR, 4.2°-5.1°]; P < 0.0001). Kaplan-Meier curves demonstrated that overall survival was significantly shorter (34.57 mo [±13.35] vs 48 mo [±0]; P = 0.001) in patients with SSc and PhA <3.75°. In the multivariate analysis, only PhA was a predictive factor for death (hazard ratio: 0.283; 95% confidence interval, 0.083-0.965; P = 0.044). CONCLUSIONS: The data obtained suggest that lower PhA values in patients with SSc are associated with an increased malnutrition risk with MUST, malnutrition with GLIM, and increased mortality. Additional studies are necessary to confirm these preliminary results.

Role of kinurenic acid in the systemic sclerosis renal involvement.

Systemic sclerosis (SSc) subclinical renal vasculopathy is characterized by progressive increase of intrarenal stiffness and reduction of parenchymal thickness due to post ischemic fibrosis secondary to the renal Raynaud phenomenon. Aims of this study were to evaluate kinurenic acid (KYNA) serum level in SSc patients and healthy controls (HC) and to assess the role of KYNA in SSc subclinical nephropathy. Serum level of KYNA was evaluated in 52 SSc patients and 20 HC, matched for sex and age. Renal function was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate glomerular filtration rate (eGFR) and renal doppler ultrasound was performed to evaluate kidneys' morphology and indices of intrarenal stiffness. The parameters registered were renal longitudinal length, atrophy index (AI), renal sinus, parenchymal thickness, renal resistive index (RRI), pulsatile index (PI) and systolic/diastolic ratio (S/D). SSc patients had lower median value of KYNA than HC [54.43 ng/ml (IQR 44.44-63.64) vs 61.94 ng/ml (IQR 55.23-88.75), p < 0.001]. SSc patients with AI ≥ 0.70 had lower KYNA than SSc patients with AI < 0.70 [47.85 ng/ml (IQR 41.16-59.91) vs 55.5 ng/ml (IQR 49.99-67.33), p < 0.05] and a slightly significant negative linear correlation was found between KYNA and AI (r = - 0.249, p < 0.05). SSc patient with RRI ≥ 0.70 had higher KYNA than SSc patients with RRI < 0.70 [58.25 ng/ml (IQR 50.49-69.68) vs 50.07 ng/ml (IQR 42.70-56.31), p < 0.05] and a significant positive correlation was found between KYNA and RRI (r = 0.318, p < 0.05). KYNA may be used as a marker to evaluate the renal involvement in SSc patients.

Nephroangiosclerosis not related to hypertension: A matter to resolve in the era of precision medicine.

Nephroangiosclerosis (NAS) associated with hypertension continues to be one of the most causes of end stage renal diseases in Europe, but it is still poorly studied. The prevalence of NAS shows a large variability due to the difference among different countries regarding clinical presentations and the indication to perform renal biopsy. The study aimed to investigate the prevalence in biopsy-proven NAS patients and the association with hypertension and/or glomerulonephritis (GN). We included all patients referred for native kidney biopsy between 2003-2021 at Policlinic Umberto I of Rome. From 837 patients who underwent renal biopsy NAS was diagnosed in 80 (10.5%) patients. Serum creatinine was significantly higher in NAS [2.07 mg/dl (IQR 1.13-5.2) vs 1.1 mg/dl (IQR 0.8-2.1), p < 0.001] compared to patients without NAS. Hypertension was present in 45% of patients with NAS. Proteinuria was significantly higher in patients with mild-moderate NAS compared to patients with severe NAS [2.6 g/die (IQR 1-5) vs 1.5 g/die (IQR 0.86-2.3), p < 0.05]. We did not find any significant differences, including histological features, between NAS patients with hypertension and NAS patients without hypertension (p > 0.05). IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy were the most frequent GN associated. In conclusion no specific histological features are reported in NAS with and without hypertension. More information on the phenotype, clinical presentation and markers are needed to improve histological and clinical diagnostics.