OBJECTIVES:To describe the prevalence of gastrointestinal (GI) symptoms in SSc and Very Early Diagnosis of SSc (VEDOSS), identify clinical and serological features associated with GI involvement and explore a cranio-caudal pattern of symptom distribution, using data from the Italian SPRING-SIR registry. METHODS:This cross-sectional analysis included patients fulfilling 2013 ACR/EULAR SSc or VEDOSS criteria. GI involvement was defined as symptoms in at least one GI tract segment and categorized as upper and lower. Associations between GI involvement and clinical variables were assessed using logistic and ordinal regression models, adjusting for demographics, disease characteristics and autoantibodies. RESULTS:Among 1917 SSc patients, 56% had GI symptoms, associated with longer disease duration, dcSSc, interstitial lung disease (ILD), digital ulcers (DU), telangiectasias and tobacco exposure. Extensive GI involvement correlated with more severe disease. Ordinal regression identified female sex, dcSSc, ILD, DU, telangiectasias, tobacco exposure and anti-centromere antibodies as variables significantly associated with more extensive GI involvement. Disease duration did not show a significant association with GI symptom extent. Among 211 VEDOSS patients, 41.2% reported GI symptoms (mostly oesophageal), significantly associated with puffy fingers and dyspnoea. Among VEDOSS, puffy fingers and anti-centromere antibodies were independent predictors of presence of oesophageal symptoms. CONCLUSION:GI involvement in SSc is linked to more severe disease and longer disease duration. Disease duration resulted linked to the presence of GI symptoms rather than extent of GI involvement. Puffy fingers and anti-centromere antibodies may associate with presence of early oesophageal symptoms in VEDOSS.

OBJECTIVES:To assess the relationship between disease duration and the prevalence/distribution of nailfold videocapillaroscopy (NVC) patterns, named according to the current classification as 'early', 'active' and 'late', in a large cohort of systemic sclerosis (SSc) patients. METHODS:A cross-sectional analysis was conducted on 1689 patients undergoing standardized NVC. Clinical-serological data and treatments were collected. Statistical comparisons and multivariable logistic regression models were applied, including analyses based on disease duration. RESULTS:The prevalence of NVC patterns was as follows: 'early' 21.6%, 'active' 47.4%, 'late' 25.7% and normal/non-specific 5.3%. The distribution by disease duration showed that the three main patterns were always present. While the 'early' and 'active' progressively decreased (from 30.3% and 51.9% in patients with ≤5 yrs, to 14.6% and 43.5% in those >10 yrs, P < 0.01), the 'late' pattern increased from 13.2% (≤5 yrs) to 36.0% (>10 yrs) (P < 0.001) and was associated with internal organ involvement, anti-topoisomerase antibodies and more therapies (P < 0.01). Conversely, the 'early' and 'active' patterns were associated with the limited-cutaneous subset (P < 0.01) and anti-centromere antibodies (P < 0.001). Multivariable analysis confirmed a strong association between the 'late' pattern and skin/peripheral vascular involvement. Notably, the presence of the 'late' pattern in patients with ≤2 yrs (10.9%) was significantly associated with scleroderma renal crisis (P = 0.012). CONCLUSION:SSc-NVC patterns are not strictly time-dependent and can be observed at any stage of the disease, suggesting that microvascular damage progression is heterogeneous across different disease periods. Therefore, a revised classification of NVC changes considering both disease duration and NVC severity could improve its prognostic accuracy.

OBJECTIVE:Mycophenolate mofetil (MMF) use in limited cutaneous systemic sclerosis (lcSSc) is relatively uncommon because of the lower fibrotic burden and the predominance of vascular complications. In vitro observations and clinical data from transplanted patients suggest a protective effect of MMF on endothelial function. Our aim was to evaluate the reasons for prescribing MMF treatment in patients with lcSSc and its impact on the need for escalation of vascular complication-related treatments during follow-up. METHODS:Patients with lcSSc enrolled in the Italian Systemic Sclerosis Progression Investigation registry were retrospectively evaluated. All patients treated with MMF were matched to patients not treated with MMF, which was based on a roll-entry time-dependent propensity score built on demographics, clinical features, and baseline treatment. The escalation of vasoactive or vasodilator treatment up to 60 months was defined as the introduction of iloprost, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors on top of the ongoing treatment, because of uncontrolled or newly diagnosed vascular complications. A hazards Cox model was also adopted to quantify the association of MMF treatment with treatment escalation. RESULTS:A total of 1,435 patients with lcSSc were evaluated, of whom 152 were prescribed MMF (17.1% male; mean age at lcSSc onset 48.7 ± 13.9 years, 54.6% anti-Scl70 positive). The prescription of MMF was more common in men and in anti-Scl70 positive, anticentromere negative patients with interstitial lung disease, myositis, and without a history of digital ulcers. After matching 107 patients with MMF-untreated controls, the overall incidence of vasoactive/vasodilator treatment escalation events related to digital ulcers over a median follow-up of 40.5 months (interquartile range 23.3-60.0) was 0.3 per 100 patient-years in the MMF-treated group and 5.4 per 100 patient-years in the matched control group, with a significant difference in treatment escalation-free survival between the two groups (hazard ratio 0.05, 95% confidence interval 0.01-0.38; P value = 0.004). CONCLUSION:In patients with lcSSc, the introduction of MMF has reduced the need for escalation of vasoactive or vasodilator treatment, suggesting that it may also help to prevent vascular complications, which frequently affect patients with lcSSc.

OBJECTIVES:Systemic sclerosis is a rare autoimmune disorder marked by vasculopathy, immune dysregulation, and progressive fibrosis. Digital ulcers (DUs) reflect severe microvascular dysfunction. This pilot, single-centre, observational study investigated whether circulating miR-29b is associated with DU occurrence, recurrence, and microvascular impairment. METHODS:Twenty-nine patients with systemic sclerosis and 17 healthy controls (HC) were evaluated. Clinical data, including DU history and recurrence, were collected. Cutaneous blood perfusion was assessed by laser speckle contrast analysis (LASCA), and proximal-distal gradient was calculated as perfusion difference between distal and proximal finger regions. Nailfold videocapillaroscopy classified microangiopathy as early, active, or late, while renal resistive index (RRI) served as an additional systemic vascular marker. Circulating miR-29b was quantified by RT-qPCR. RESULTS:Different modulation of miR-29b were observed between SSc and C (p<0.001). Patients with previous or recurrent DUs (p=0.024) and those with proximal-distal gradient <30 perfusion units showed significantly reduced miR-29b levels (p=0.028). Lower expression also characterised patients with RRI > 0.70 (p=0.03) and a late pattern (p<0.01). MiR-29b inversely correlated with disease activity (r=-0.472, p<0.01), fibrosis extent (r=-0.471, p<0.01), Cochin hand function score (r=-0.454, p<0.01), and RRI (r=-0.506, p<0.01), while showing a positive correlation with disease duration (r=0.333, p<0.05). In exploratory multivariable Cox regression analysis, lower miR-29b remained an independently associated with DU recurrence (p<0.05). CONCLUSIONS:Overall, reduced circulating miR-29b was associated with advanced digital vasculopathy. Combined evaluation with LASCA-derived proximal-distal gradient and NVC pattern could may provide exploratory information for microvascular dysfunction and stratify patients at high risk of vascular complications.

BACKGROUND:As precision medicine is needed in systemic sclerosis (SSc) and SSc-associated interstitial lung disease (ILD), SSc non-specific antibodies might improve the risk stratification in this population. RESEARCH QUESTION:To evaluate the prevalence and characterize the disease phenotype of SSc patients positive for anti-Ro/SSA alone or in combination with RF antibodies in the largest cohort of SSc patients, focusing on lung involvement. METHODS:Patients from the EUSTAR database with available data on anti-Ro/SSA and RF antibodies were included. Clinical characteristics of patients with or without anti-Ro/SSA and RF antibodies were compared at baseline. Multivariable logistic regression models were built to identify factors associated with ILD. In patients with ILD at baseline, multivariable mixed-effects models for longitudinal FVC and DLCO were built to assess the impact of anti-Ro/SSA and RF. Prognostic factors for the ILD progression and death during follow-up were tested by multivariable Cox proportional hazards regression. RESULTS:Among the 4,221 patients fulfilling the inclusion criteria, 641 (15.2%) had anti-Ro/SSA antibodies. These patients exhibited a higher prevalence of muscular involvement (p < 0.01), pulmonary hypertension (p = 0.06), and ILD (p < 0.01) at baseline. Over 14,066 follow-up visits, anti-Ro/SSA independently predicted the presence of ILD (OR 1.24 [1.07-1.43], p < 0.01). Among anti-Ro/SSA+/RF+ patients, who represented 4.1% of the cohort, ILD was more prevalent as compared to single positive or negative anti-Ro/SSA and RF patients. Anti-Ro/SSA+/RF+ double-positive patients had a more severe ILD, with lower FVC% (R -4.12 [-7.85;-0.40]; p = 0.03) and lower DLCO% (R -5.4[-9.05;-1.74]; p < 0.01). INTERPRETATION:In the large EUSTAR cohort, anti-Ro/SSA antibodies are detected in 15% of SSc patients and represent an independent risk factor for the presence and severity of ILD, particularly for cases with anti-Ro/SSA+/RF+ double positivity. These data support the inclusion of anti-Ro/SSA and RF antibodies in routine clinical practice to improve the risk stratification of SSc patients.

Background:The sequence and temporal relationship between Raynaud's phenomenon (RP) and the first non-Raynaud's sign/symptom (NRP) in systemic sclerosis (SSc) have been partially investigated. Objectives:To evaluate whether the mode and ages of clinical onset are associated with disease endotype and survival in SSc. Design:We included SSc patients from the Systemic sclerosis Progression INvestiGation registry of the Italian Society of Rheumatology (SPRING-SIR) registry in a cohort study, with post hoc cross-sectional and longitudinal analysis. Methods:Patients were grouped based on age-RP and age-NRP quartiles. Additionally, categories were defined based on mode of onset: RP group-RP onset at least 1 year before NRP; Simultaneous group-RP onset within the same year of NRP; NRP group-RP onset after at least 1 year after NRP. Comparisons were made using Chi-square and ANOVA tests. Logistic, linear, and multinomial regression models were applied to assess associations, while Kaplan-Meier curves and Cox regression were used to assess mortality. Results:A total of 1748 patients were eligible: 682 (39.0%) in the RP group, 1026 (58.8%) in the simultaneous group, and 39 (2.2%) in the NRP group. A higher prevalence of anti-centromere antibodies was found In the RP group, while the simultaneous group had more diffuse cutaneous SSc (dcSSc), anti-topoisomerase-I antibodies, and higher Rodnan's skin score (mRSS). The NRP group presented higher prevalence of pulmonary arterial hypertension. On logistic regression, the simultaneous group was associated with a higher prevalence of dcSSc compared to the RP group (odds ratio, 1.491, 95% confidence interval (CI): 1.032-2.154). Younger age at RP onset was associated with lower systolic pulmonary artery pressure and mRSS. In 943 patients with available follow-up (median 24 months), the simultaneous group had higher mortality compared to the RP group (hazard ratio, 1.975, 95% CI: 1.002-3.893). Conclusion:The timing of RP and NRP onset may help define SSc endotype and survival. Patients with simultaneous RP-NRP onset have more severe disease features and higher mortality risk, emphasizing the relevance of onset timing in disease stratification.

Background:Microvascular alterations can be detected with nailfold videocapillaroscopy, useful for systemic sclerosis (SSc) diagnosis upon identification of the "scleroderma pattern" (NVC-SP). However, this pattern is missing in a subset of SSc patients. Methods:This retrospective analysis on the multicenter Italian SPRING cohort of SSc patients assessed the prevalence and characteristics of patients without NVC-SP. Associations with demographic and clinical features were evaluated using logistic regression (cross-sectional) and mixed-effects models (longitudinal). Results:Out of 1689 SSc patients with available NVC information, 90 (5.3%) did not have the NVC-SP. These patients were older at SSc onset (53 vs. 49 years) and more frequently sine scleroderma (31% vs 12%, p < 0.001). The overall burden of vascular complications was milder in this subset, with a lower prevalence of pitting scars (33% vs 48%), telangiectasias (52% vs 74%), and calcinosis (3.4% vs 12%). During the follow-up, mRSS remained lower (60-month mean 4 vs 7, p = 0.002), as well as the estimated probability of vascular complications. Moreover, despite comparable values at baseline, DLCO remained significantly higher in patients without NVC-SP at the following time points (12, 24, and 60 months, p < 0.05). The presence of "late" NVC-SP was independently associated with ILD (OR 1.83, 95% CI 1.05-3.18). Conclusions:The absence of NVC-SP in 5.3% of SPRING SSc patients may identify a subset characterized by milder disease, with a lower burden of vascular and organ complications. Conversely, lung involvement was more frequently observed in patients with more severe NVC microangiopathy.

Background Antitopoisomerase I (ATA), anticentromere (ACA) and anti-RNA polymerase III (RNAP3) antibodies are included in the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for systemic sclerosis (SSc). A subset of patients with SSc satisfy criteria but may lack these specific autoantibodies, being classified as ‘triple-negative’.Methods We conducted a retrospective evaluation of triple-negative patients with SSc prevalence and clinical features among the multicentric Systemic sclerosis Progression INvestiGation registry.Results Out of 1480 patients with SSc, 295 (19.9%) were triple-negative, while 1185 (81.1%) had SSc-specific antibodies: ACA (54.3%), ATA (43.6%) and RNAP3 (2.1%). The triple-negative group showed a higher prevalence of myopathy (16.7% vs 10.1%, p=0.003), suggested by higher creatine phosphokinase (CPK) levels (126.2 vs 92.5 U/mL, p=0.002), more frequent CPK increase over 2–3 times (2.4% vs 0.2%, p=0.028). Triple-negative patients also exhibited fewer vascular complications, including digital ulcers (17.3% vs 22.8%, p=0.04) and calcinosis (8.2% vs 12.8%, p=0.027), and a higher prevalence of interstitial lung disease (p<0.001). Consistently, lower diffusing capacity for carbon monoxide (66.4% vs 70.98%, p=0.004) and forced vital capacity (97.01% vs 102.92%, p<0.001) were found in the triple-negative group. Triple-negative patients more frequently received corticosteroids (79.3% vs 67.9%, p=0.003), cyclophosphamide (43.4% vs 26%, p<0.001) and azathioprine (38.5% vs 22.3%, p=0.002), while less frequently received prostanoids (71.6% vs 85.9%, p<0.001), calcium channel blockers (80.1% vs 87.7%, p=0.005) and phosphodiesterase-5 inhibitors (4% vs 20%, p<0.001).Conclusions A higher prevalence of myopathy and interstitial lung disease and a reduced vascular burden were found in the triple-negative patients, suggesting that the non-specific and non-routinely tested autoantibodies may identify an SSc endotype resembling sclero-myositis.

Background/Objectives: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by endothelial dysfunction, immune system dysregulation, and fibrosis of the skin and internal organs. Gastrointestinal involvement occurs in over 90% of patients and contributes to metabolic alterations and changes in body composition. Given the lack of specific markers of organ damage, zonulin has been investigated as a potential indicator of intestinal permeability. This study aims to evaluate the relationship between intestinal permeability, assessed by zonulin levels, and changes in body composition in SSc patients. Methods: Forty patients meeting EULAR criteria were included. Clinical evaluation, biochemical assessment including zonulin, and body composition analysis using bioelectrical impedance analysis (BIA) were performed. The BIA assessed the following parameters: fat-free mass index (FFMI; kg/m2); body cellular mass index (BCMI); fat mass index (FMI; kg/m2) and visceral fat area (VFA; cm2). Results: 32 of 40 patients enrolled were female (80%) with a median age of 55 years (IQR 49-62.5). Median zonulin level was 0.92 pg/mL (IQR 0.86-1.05). Reduced FFMI was present in 35% of patients and was associated with higher zonulin levels [1.16 pg/mL (IQR 0.91-1.34) vs. 0.92 pg/mL (IQR 0.83-0.96), p < 0.01]. Zonulin correlated negatively with BCMI (r = -0.332, p < 0.05), FFM (r = -0.302, p < 0.05) and muscle mass (r = -0.276, p < 0.05). Conclusions: Elevated serum zonulin levels, reflecting increased intestinal permeability, are associated with adverse body composition changes in SSc, suggesting gut barrier dysfunction as a potential mechanism of muscle loss and a therapeutic target in SSc.

Pulmonary arterial hypertension (PAH) is a severe disease characterised by a progressive thickening and obliteration of pulmonary vessels, resulting in increased vascular resistance, elevated pulmonary artery pressures, and right heart failure. Among the various conditions associated with PAH, systemic sclerosis (SSc) is the most common in Western countries. Compared to other forms of PAH, SSc-PAH presents with a more aggressive clinical course, poorer response to conventional therapies and a worse prognosis. However, despite these differences, the overall management of SSc-PAH remains close to idiopathic PAH; and therefore, there is a crucial need for treatment strategies dedicated to this disease. To help fill this gap, we assessed the level of evidence currently available on SSc-PAH management in a systematic literature review that compiled data regarding conventional therapies, immunosuppressants, nonconventional drugs and surgical/interventional procedures. For each study, we highlighted the results specific to the connective tissue disease or SSc subgroups, the haemodynamic characteristics of the patients, and their comorbidities. By doing so, we identified critical gaps in the field, consisting mostly of the lack of studies focusing on SSc-PAH, a substantial heterogeneity in haemodynamic severity (with notable scarcity of data for mild PAH) and the systematic exclusion of relevant comorbidities (such as interstitial lung disease). Building on these data and our cumulative experience, we provide pragmatic, experience-based suggestions tailored to the management of SSc-PAH, that tries to capture the full scope of clinical situations encountered in these patients and help clinicians manage difficult cases where robust data are lacking.

Systemic sclerosis (SSc) is an autoimmune disease associated with a high burden of morbidity and mortality due to organ complications. Pulmonary arterial hypertension (PAH) and cardiac involvement, characterized by chronic right ventricular (RV) pressure overload with consequent RV dysfunction and ultimately right heart failure (HF), are among these. A common comorbidity in SSc is chronic kidney disease (CKD). CKD is often present at the time of PAH diagnosis or a decline in renal function may occur during the course of the disease. CKD is strongly and independently associated with mortality in patients with PAH and HF. The cardiovascular and renal systems are closely interconnected, and disruption of this balance may result in cardiorenal syndrome (CRS). Type 2 CRS refers to CKD as a consequence of chronic HF. In clinical practice, non-specific markers such as troponin, B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and serum creatinine aid in CRS diagnosis. More specific biomarkers, including cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), galectin-3, and soluble urokinase plasminogen activator receptor (suPAR), have shown value for diagnosis and prognosis in CRS. This study aimed to evaluate comprehensively heart/kidney damage markers related to CRS in SSc patients compared with healthy controls (HC) and to examine their association with renal and cardiac ultrasound parameters. SSc patients showed significantly higher CRS markers than HC (p < 0.001). SSc patients with clinically diagnosed CRS had significantly elevated galectin-3, suPAR, sNGAL, and uNGAL levels (p < 0.05) than SSc patients without CRS. Positive correlations were found between renal resistive index (RRI) and NT-proBNP (r = 0.335, p < 0.05), and between RRI and suPAR (r = 0.331, p < 0.05). NT-proBNP, suPAR, galectin-3, sNGAL, and uNGAL emerge as promising biomarkers for the early detection of cardiac and renal involvement in SSc patients.

Serum uric acid (SUA), the final product of purine metabolism, is an independent risk factor for cardiovascular (CV) disease. Since SUA levels depend on renal function, SUA to serum creatinine ratio (SUA/sCr) is emerging as a more specific biomarker of CV risk. To evaluate in hospitalized patients with cardiorenal multimorbidity (CRM) if the SUA/sCr ≥ 5.35 is associated with clinical outcomes. The primary outcome was in-hospital mortality. The secondary outcome was the composite of all-cause of mortality and adverse clinical events. We conducted a retrospective review of medical records from consecutive CRM inpatients admitted to the medical ward. The composite endpoint was calculated as all-cause mortality and adverse clinical events such as acute coronary syndrome, stroke, infections, and renal replacement therapy. In our cohort, 141 patients (mean age of 75.6 ± 10.2 years) were identified with CRM. In-hospital mortality occurred in 17 patients (16

INTRODUCTION:Primary heart involvement (pHI) is an overlooked and poorly characterised complication of systemic sclerosis (SSc), associated with the risk of heart failure, arrhythmia and death. Despite consensus definition by the World Scleroderma Foundation/Heart Failure Association (WSF/HFA), diagnostic criteria and risk factors remain poorly elucidated. METHODS:Out of 1922 patients in the Italian national SPRING registry, we excluded those with potentially confounding conditions according to WSF/HFA, and those with incomplete ECG or echocardiographic assessment, resulting in 600 subjects with clearly defined parameters to intercept SSc-pHI. Cross-sectional and longitudinal analyses were performed to identify factors associated with pHI. RESULTS:ECG and/or echocardiographic signs of SSc-pHI were identified in 25% of patients at enrollment and were associated with older age (OR 1.04; 95% CI 1.02-1.06), diffuse cutaneous SSc (OR 1.85; 95% CI 1.05-3.26) and intestinal symptoms (OR 1.79; 95% CI 1.03-3.08). Diastolic dysfunction (62%) and conduction disturbances (34%) were the most frequent phenotypes, while diffuse hypokinesia with reduced ejection fraction was the least common (3%). During follow-up, new-onset signs of pHI were observed in an additional 25% of patients, particularly in those with skeletal muscle involvement (HR 2.83; 95% CI 1.01-7.73). CONCLUSIONS:pHI is a severe complication potentially affecting one-quarter of patients with SSc. Early detection is crucial, particularly in those with diffuse skin fibrosis, muscular involvement and intestinal manifestations.

ObjectiveBosentan (BOS) is approved for treating pulmonary arterial hypertension (PAH) and preventing digital ulcers (DU) in systemic sclerosis (SSc). Our study aimed to evaluate whether BOS prescribed for DU could reduce the incidence of PAH in a large SSc cohort from the Systemic Sclerosis Progression Investigation (SPRING) registry.MethodsPatients with SSc from the SPRING registry, meeting 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria with data on PAH onset, DU status, BOS exposure, and at least 1 year of follow-up between 2015 and 2020, and having no known PAH at baseline, were included. PAH was diagnosed with right heart catheterization during the follow-up, and its incidence rate (IR) was calculated. Kaplan-Meier curves were determined, and multivariate regression identified PAH risk factors.ResultsAmong 727 eligible patients with SSc, followed for a median of 2.0 years, 54 (7.4%) developed PAH (IR 3.71 per 100 patient-years [PYs]). Patients with DU who were never exposed to BOS had a higher incidence of PAH (IR 4.90 per 100 PYs) compared to those exposed to BOS, whose rates matched those without DU and who were never exposed to BOS. Risk factors independently associated with PAH development included DU (hazard ratio [HR] 1.86), age (HR 1.05), modified Rodnan skin score > 4 (HR 2.07), interstitial lung disease (HR 2.29), and acetylsalicylic acid treatment (HR 1.78).ConclusionIn our cohort, the presence of DU was confirmed as a leading risk factor for PAH development, and BOS use for DU prevention may reduce this risk. Only patients with DU who were not using BOS had an increased PAH incidence.

Digital ulcers (DU) are one of the most frequent manifestations in systemic sclerosis (SSc). The presence of DU seems to be a sentinel sign of internal organ involvement and is related to a poor prognosis of the disease. The aim of this study was to evaluate the prevalence and the relationship of DU with clinical manifestations/variants in a large SSc cohort from the SPRING registry. SSc patients fulfilling the ACR/EULAR 2013 classification criteria without missing data on digital ulcers were enrolled in a cross-sectional study. Logistic regression models were built to test the association between the presence of DU and SSc-related features. Among 1873 eligible SSc patients, the presence of DU was significantly associated with gastrointestinal involvement (OR 1.88, 2.04 and 1.74; p < 0.001) and serum ATA positivity (OR 2.15; p < 0.001), as well as with telangiectasias, sclerodactyly, digital pitting scar, and calcinosis (OR 1.40, p = 0.005; OR 3.43, p < 0.001, OR 9.12, p < 0.001 and OR 2.77, p < 0.001; respectively). In the multivariable regression models, even after adjustment for covariates, ATA positivity (OR 1.76, p = 0.039), puffy fingers (OR 2.82, p < 0.001), and a higher revEUSTAR-AI (OR 6.63, p < 0.001) emerged as risk factors for the presence of DU. Moreover, a low presence of DU was recorded in SSc patients with a history of previous immunosuppressive treatments (OR 0.53, p = 0.032). In our Italian SSc cohort, DUs were significantly associated with the presence of puffy fingers, high revEUSTR-AI, and ATA seropositivity. Noteworthy, immunosuppressive treatments were associated with a low rate of DU, suggesting that they might contribute to the prevention of these harmful manifestations. Key Points • Digital ulcers were significantly associated with the presence of puffy fingers, high disease activity, and anti-Scl70 seropositivity. • Immunosuppressive treatments were associated with a low rate of digital ulcers, suggesting that they might contribute to the prevention of these harmful manifestations.

A monocentric cross-sectional study was performed to investigate the role of serum calprotectin as a biomarker for disease severity and activity in systemic sclerosis (SSc). Serum calprotectin was measured in 74 consecutive SSc patients admitted to a tertiary hospital in Rome, and in 50 healthy controls (HCs) who were healthcare workers, using Aptiva's particle-based multianalyte technology. In SSc patients, a statistically significant correlation was found between calprotectin and the modified Rodnan skin score (mRSS) (r = 0.402, p < 0.001), disease activity index (DAI) (r = 0.420, p < 0.001), disease severity scale (DSS) (r = 0.365, p < 0.01), forced vital capacity (FVC) (r = -0.459, p < 0.001), and diffusion lung capacity for carbon monoxide (DLco) (r = -0.445, p < 0.001). Calprotectin was higher in SSc patients with digital ulcers (DUs) than in SSc patients without DUs [2.98 mcg/mL (IQR 2.07;4.29) vs. 2.08 mcg/mL (IQR 1.71;2.45), p < 0.01] and in SSc patients with interstitial lung disease (ILD) compared to SSc patients without ILD [2.56 mcg/mL (IQR 1.94;3.03) vs. 1.96 mcg/mL (IQR 1.7;2.35), p < 0.01]. The multivariable stepwise logistic regression analysis showed calprotectin to be independently associated with DUs [OR 2.531 (CI 95%: 1.074;5.961), p < 0.05] and ILD [OR 3.687 (CI 95%: 1.336;10.170), p < 0.05] in SSc patients. Serum calprotectin is associated with DUs and ILD in SSc patients.

OBJECTIVES:Systemic sclerosis (SSc) is an autoimmune disease, characterised by microvascular alterations, dysregulation of immune system and fibrosis. The most important complication is interstitial lung disease (ILD). The aim of this study was to evaluate serum levels of thymic stromal lymphopoietin (TSLP) in SSc patients and healthy controls (HC). The secondary aim was to correlate TSLP with skin fibrosis and extension of ILD. METHODS:75 SSc patients and 20 HC were enrolled and serum TSLP levels were measured in both cohorts. Pulmonary function tests (PFTs), high-resolution computed tomography (HRCT) and exhaled fraction of nitric oxide (FeNO) were assessed in SSc patients. A visual semi-quantitative staging system, tomographic fibrosis score (TFS), was used to assess SSc-ILD. RESULTS:Serum levels of TSLP were higher in SSc patients than HC. A positive correlation between TSLP and mRSS was observed (r=0.409, p<0.001) and a negative correlation was found between TSLP and FVC (r=-0.356, p<0.01). Serum TSLP was significantly higher in SSc patients with Type 2 inflammation than patients without Type 2 inflammation [172 pg/ml (IQR 154.67;224.67) vs. 150 pg/ml (IQR 110;210.33), p<0.05]. The median value of serum TSLP was significantly higher in SSc patients with TFS ≥ 5% than SSc patients with TFS <5% [216.67 pg/ml (IQR 172;298.67) vs 140.67 pg/ml (IQR 122;166.67), p<0.001). CONCLUSIONS:In conclusion, TSLP might have a key role in ILD and skin fibrosis.