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The spectrum of kidney involvement in systemic sclerosis (SSc) includes scleroderma renal crisis, widely recognized as the most severe renal-vascular complication, but also several forms of chronic renal vasculopathy and reduced renal function are complications of scleroderma. Scleroderma renal crisis, myeloperoxidase-antineutrophil cytoplasmic antibody associated glomerulonephritis, penicillamine-associated renal disease, abnormal urinalysis, alteration of vascular endothelial markers, scleroderma associated-vasculopathy with abnormal renal resistance indices and cardiorenal syndromes type 5 were also reported in SSc patients. A frequent form of renal involvement in SSc patients is a subclinical renal vasculopathy, characterized by vascular damage and normal renal function. Indeed, asymptomatic renal changes, expressed by increase of intrarenal stiffness, are often non-progressive in SSc patients but can lead to a reduction in renal functional reserve. The purpose of this review is to provide an assessment of kidney involvement in SSc, from SRC to subclinical renal vasculopathy., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2022 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: Systemic sclerosis (SSc) patients are at risk for a severe disease course during SARS-CoV-2 infection either due to comorbidities or immunosuppression. The availability of SARS-CoV-2 vaccines is crucial for the prevention of this hard-to-treat illness. The aim of this study is to assess the humoral response after mRNA vaccination against SARS-CoV-2 in SSc patients., Method: Seropositivity rate and serum IgG levels were evaluated 1 month (t1) and 3 months (t3) after the second dose of vaccine in a cohort of SSc patients and healthy controls (HC). Differences were made with Student's or Mann-Whitney's t-test and with the chi-square or Fisher exact test. Logistic regression model including immunosuppressive treatments (corticosteroids, CCS; mycophenolate mofetil, MMF; methotrexate, MTX; rituximab, RTX) was built to assess the predictivity for seropositivity., Results: The seropositivity rate was similar in 78 SSc patients compared to 35 HC at t1 but lower at t3. SSc patients had lower serum IgG levels than HC at t1 but not at t3. SSc patients treated with immunosuppressive therapy showed both a lower seropositive rate (t1, 90.3% vs 100%; t3, 87.1% vs 97.9%; p < 0.05) and serum IgG levels than untreated patients both at t1 [851 BAU/ml (IQR 294-1950) vs 1930 BAU/ml (IQR 1420-3020); p < 0.001] and t3 [266 BAU/ml (IQR 91.7-597) vs 706 BAU/ml (IQR 455-1330); p < 0.001]. In logistic regression analysis, only MTX was significant [OR 39.912 (95% CI 1.772-898.728); p < 0.05]., Conclusions: SSc patients treated with MTX had a lower serological response to mRNA vaccine, and even low doses of CCS can adversely affect antibody titer and vaccination response. Key Points • SSc patients are able to produce vaccine-induced antibodies after mRNA vaccination. • In SSc patients, clinical characteristics of disease did not influence seropositivity rate. • In SSc patients, even low doses of CCS can adversely affect antibody titer and vaccination response. • In SSc patients, MTX treatment is mainly associated with reduced seropositivity and lower serum IgG levels., (© 2022. The Author(s).)

Systemic sclerosis (SSc) is autoimmune disease characterized by endothelial dysfunction and microvascular damage. Resistin has been implied in microvascular dysfunction. Objective of this study is to evaluate the association between baseline resistin and development of new digital ulcers (DUs) in SSc patients. At baseline, serum resistin has been assessed in 70 female SSc patients and 26 healthy controls (HC). In SSc patients, clinical assessment was performed at baseline and after a 52-weeks follow-up. Serum resistin level was increased in SSc patients compared to HC [5.89 ng/ml (2.5 ng/ml-8.1 ng/ml) vs 2.3 ng/ml (0.4 ng/ml-2.4 ng/ml), p = 0.0004)]. Resistin was lower (p = 0.005) in SSc patients with early capillaroscopic pattern than patients with active or late capillaroscopic pattern [2.49 ng/ml (0.89 ng/ml-5.81 ng/ml) vs 7.11 ng/ml (3.48 ng/ml-11.35 ng/ml) and 6.49 ng/ml (3.35 ng/ml-8.87 ng/ml), respectively]. After a 52-weeks follow-up, 34 (48.6%) patients developed new DUs. Median serum resistin was significantly higher in patients with new DUs than in patients without new DUs [6.54 ng/ml (3.35 ng/ml-11.02 ng/ml) vs 4.78 ng/ml (1.06 ng/ml-7.6 ng/ml), p = 0.019]. Kaplan-Meier curves show a significantly reduced free survival from DUs in patients with increased resistin (p = 0.002). In multivariate analysis, resistin is associated with the development of new DUs. Increased serum resistin level is a predictive marker of new DUs in SSc., (© 2021. The Author(s).)

Objective: Early detection of pulmonary arterial hypertension (PAH) is crucial for improving patient outcomes. The aim of this study was to compare the positive predictive value (PPV) of the echocardiography-derived tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio with that of the DETECT algorithm for PAH screening in a cohort of SSc patients., Methods: Fifty-one SSc patients were screened for PAH using the DETECT algorithm and echocardiography., Results: Echocardiography was recommended by the DETECT algorithm step 1 in 34 patients (66.7%). Right heart catheterization (RHC) was recommended by the DETECT algorithm step 2 in 16 patients (31.4%). PAH was confirmed by RHC in 5 patients. The DETECT algorithm PPV was 31.3%. The TAPSE/sPAP ratio was higher in SSc patients not referred for RHC than in SSc patients referred for RHC according to the DETECT algorithm step 2 [0.83 (0.35-1.40) mm/mmHg vs 0.74 (0.12-1.09)  mm/mmHg, P < 0.05]. Using a cut-off of 0.60 mm/mmHg, 8 (15.7%) SSc patients had a TAPSE/sPAP ratio of ≤0.60 mm/mmHg. PAH was confirmed by RHC in 5 patients. The PPV of TAPSE/sPAP was 62.5%. In multiple regression analysis, TAPSE/sPAP was associated with age [β coefficient = -0.348 (95% CI: -0.011, -0.003); P < 0.01], DETECT algorithm step 1 [β coefficient = 1.023 (95% CI: 0.006, 0.024); P < 0.01] and DETECT algorithm step 2 (β coefficient = -1.758 [95% CI: -0.059, -0.021]; P < 0.0001)., Conclusion: In SSc patients with a DETECT algorithm step 2 total score of >35, the TAPSE/sPAP ratio can be used to further select patients requiring RHC to confirm PAH diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The study aim was to evaluate the estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with respect to mortality in SSc patients from the European Scleroderma Trials and Research Group (EUSTAR) database., Methods: SSc patients from the EUSTAR database who had items required for the calculation of eGFR at a baseline visit and a second follow-up visit available were included. A cut-off eGFR value of 60 ml/min was chosen for all SSc patients, and 30 ml/min for those with scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the use of eGFR as a predictive factor of mortality., Results: A total of 3650 SSc patients were included in this study. The median serum level of creatinine and the mean of eGFR were 0.8 mg/dl (interquartile range = 0.6-0.9) and 86.6 ± 23.7 ml/min, respectively. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR < 60 ml/min compared with patients with eGFR ≥ 60 ml/min [OS at 5 years 0.763 (95% CI: 0.700, 0.814) vs 0.903 (95% CI: 0.883, 0.919; P < 0.001)]. In multivariable analysis, OS was associated with male gender (P < 0.01), systolic pulmonary arterial pressure (sPAP) (P < 0.001) and eGFR (P < 0.001). The cumulative incidence of deaths due to SSc was associated with increased sPAP (P < 0.001) and reduced eGFR (P < 0.05). The OS at 5 years of 53 SRC patients was not significantly different between SSc patients with eGFR > 30 ml/min and those with eGFR <30 ml/min., Conclusion: eGFR represents a predictive risk factor for overall survival in SSc. The eGFR, however, does not represent a risk factor for death in SRC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The aim of this study was to evaluate the role of Color Doppler Ultrasonography (CDUS) of proper palmar digital arteries (PPDA) as predictive marker of new digital ulcers (DUs) in systemic sclerosis (SSc) patients during 5 years follow-up., Methods: 36 SSc patients were examined using nailfold videocapillaroscopy (NVC) and CDUS of PPDA., Results: Fourteen (38.9%) patients had chronic or acute occlusions (C and D pattern) on CDUS evaluation. Using a cut-off of 0.70, 21 (58.3%) patients had a Resistive Index (RI) ≥0.70. Nineteen (52.8%) patients developed new DUs during the follow-up. The median value of RI was higher in SSc patients with DUs than in SSc patients without DUs [0.73 (IQR 0.70-0.81) vs 0.67 (IQR 0.57-0.70), p < 0.0001]. The Kaplan-Meier analysis showed a free survival from new DUs higher (p < 0.01) in SSc patients with Pattern A and B than SSc patients with Pattern C and D. The Kaplan-Meier curves showed that free survival from new DUs is lower (p < 0.001) in SSc patients with increased RI (≥0.70) than in SSc patients with normal RI. In multivariate analysis with two co-variates, RI ≥ 0.70 [HR 5.197 (1.471-18.359), p < 0.01] and NVC late scleroderma pattern [HR 7.087 (1.989-25.246), p < 0.01] were predictive markers of new DUs., Conclusions: RI of PPDA in association with NVC could be used to evaluate SSc patients with increased risk of new DUs development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the predictive role of CD21 low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12-month follow-up. After a 12-month follow-up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21 low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3-13.6) versus 4.8 (3.5-7.4); p < 0.01]. The 10% cut-off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587-0.878; P = 0.01]. Kaplan-Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21 low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21 low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21 low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients., (© 2021 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)

Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients., (© 2021 British Society for Immunology.)

Objective: Subclinical nephropathy is underestimated in systemic sclerosis (SSc). Study aim is to evaluate the role of renal resistance indices (RRI) and estimated glomerular filtration rate (eGFR) assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as predictive markers of mortality during 10 years of follow-up in SSc patients., Methods: 181 SSc patients (60 years, 152 females) were enrolled. At baseline, the GFR was estimated in 181 SSc patients and RRI was measured in 122 SSc patients. During a follow-up of 10 years we recorded the main complications of disease, date and causes of death., Results: eGFR shows a linear negative correlation with RRI. RRI showed a correlation with systolic pulmonary artery pressure (sPAP). Overall survival is lower in SSc patients with eGFR<60 ml/min and RRI ≥0.70 than in SSc patients with eGFR≥60 ml/min (p<0.0001) and with RRI<0.70 (p<0.01) both for mortality due to SSc and all causes. In multivariate analysis, eGFR<60 ml/min [HR 6.429, 95%CI (1.006-41.08), p<0.05] and forced vital capacity (FVC) [HR 0.954, 95%CI (0.911-1), p<0.05] are predictive markers of mortality due to SSc, while eGFR [HR 3.617, 95%CI (1.370-9.554), p<0.01], RRI [HR 0.210, 95% CI (0.068-0.649), p<0.01], age [HR 1.062, 95%CI (1.023-1.103), p<0.01], FVC [HR 0.967, 95%CI (0.946-0.989), p<0.01] and disease activity index (DAI) [HR 1.663, 95%CI (1.262-2.191), p<0.0001] are predictive markers of mortality due to all causes., Conclusion: We demonstrate that eGFR is a predictive marker of mortality due to SSc and to all causes, conversely RRI is predictive marker of mortality due to all causes., (Copyright © 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: Major vascular complication, such as digital ulcers (DUs), pulmonary arterial hypertension (PAH) and scleroderma renal crisis (SRC) are hallmarks of systemic sclerosis (SSc). Interstitial lung disease (ILD) is the major cause of mortality in SSc. The aim of study is to identify cardiopulmonary exercise testing (CPET) variables that predict MVC and mortality for ILD in SSc patients., Methods: In this cohort study, 45 SSc patients underwent clinical evaluation, echocardiography, pulmonary function tests (PFTs), high resolution computerised tomography (HRCT) and CPET. PFTs and echocardiography were performed annually for a 5-year follow-up., Results: 16 (35.6%) SSc patients had MVC: 14 new DUs (31.1%), 1 PAH (2.2%) and 1 SRC (2.2%). At univariate regression analysis, mRss [HR 1.099 (1.008-1.199), p<0.05], NVC patterns (active and late) [HR 0.032 (0.004-0.250), p<0.001], V'E/V'CO2 slope [HR 1.123 (1.052-1.198), p<0.001] were predictive of new onset of MVC. In multivariate analysis, NVC patterns (active and late) (HR 0.044 (0.004-0.486), p<0.05), V'E/V'CO2 (HR 1.094 (1.020-1.198), p<0.05) were predictive of new onset of MVC. The 5-year mortality for ILD is 8.9%. In univariate analysis, DLco [(HR 0.927(CI 0.874- 0.983), p<0.05], V'E/V'CO2 slope and lung parenchymal with radiological patterns of ILD [(1.2.02 (CI 1.018-1.419), p<0.05], represent risk factors for 5-year mortality for ILD [HR 1.142 (1.030-1.267), p<0.05]. In multivariate analysis, only V'E/V'CO2 slope [1.268 (CI 1.003-1.602), p<0.05] represents a risk factor for 5-year mortality for ILD., Conclusions: V' E/V' CO2 slope is a prognostic marker of MVC and five-year mortality for ILD.

Objectives: To evaluate expansion of CD21 low B cells and their role in B cell homeostasis, apoptosis, clinical manifestations and serum vascular endothelial growth factor (VEGF) in systemic sclerosis (SSc)., Materials and Methods: B-cells subpopulations and apoptosis have been assessed in 74 SSc patients and 20 healthy donors. Renal Doppler ultrasound, echocardiography, pulmonary function test and VEGF were performed., Results: SSc patients with expanded CD21 low B cells (SSc-CD21 low ) show a distinct B cell profile with increased memory B cells compared to patients without CD21 low B cells (SSc-CD21 + ). Renal resistive index, systolic pulmonary arterial pressure and FVC/DLCO ratio were significantly higher in SSc-CD21 low group than SSc-CD21 + , DLCO was lower in SSc-CD21 low group than SSc-CD21 + . We found a positive linear correlation between CD21 low and sPAP, RI and FVC/DLCO ratio whereas a negative correlation was observed between CD21 low and DLCO and VEGF levels., Conclusions: CD21 low B cells are increased in SSc patients with visceral vascular manifestations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)