Advances in Identification and Management of Systemic Sclerosis

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t₀) and after 12 (±4) (t₁) and 24 (±4) (t₂) months. Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t₂. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t₂ (p = 0.0031). Neither the mean t₀ to t₁ change (Δ) of DLCO nor the mean t₀ to t₁ FVCΔ predicted the appearance of ILD at t₂. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t₀ DLCO < 80%, stronger than that of FVC < 80%. Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc. Full article

Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune collagen diseases. Specific autoantibodies are known to be involved in their pathogeneses, each presenting with a different clinical manifestation. Although immunoprecipitation is the gold standard method for detecting autoantibodies, it is difficult to perform in all cases owing to the use of radioisotopes. In this study, we developed a new detection method for SSc and DM autoantibodies (A-cube) using cell-free protein synthesis and examined its validity. Proteins were synthesized using wheat germ cell-free protein synthesis. A total of 100 cases of SSc, 50 cases of DM, and 82 healthy controls were examined. The validity of the method was examined by a comparison with existing test results. Anti-centromere antibody, anti-topoisomerase I antibody, anti-RNA polymerase III antibody, anti-U1RNP anti-body, anti-Jo-1 antibody, anti-TIF1γ antibody, anti-Mi-2 antibody, and anti-ARS antibody were tested for. The results suggested that A-cube is comparable with existing testing methods or has a high sensitivity or specificity. In addition, there was a case in which the diagnosis was reconsidered using the A-cube. The quality of the A-cube was ensured, and its usefulness for a comprehensive analysis was demonstrated. The A-cube can therefore contribute to the clinical assessment and treatment of SSc and DM. Full article

Background: Juvenile systemic sclerosis (jSSc) is a systemic inflammatory and fibrotic autoimmune disease. Adult guidelines recommend obtaining a screening high-resolution computed tomography scan (CT) at diagnosis. As these recommendations are adopted as standard of care for jSSc, increased screening with CT may lead to increased detection of nodules. The implications of nodules identified in jSSc are unclear and unreported. Methods: A retrospective chart review was performed on the prospectively enrolled National Registry for Childhood-Onset Scleroderma (NRCOS) cohort over an enrollment period of 20 years. Clinical associations with presence of nodules and nodule characteristics were investigated. Results: In this jSSc cohort, the prevalence of pulmonary nodules was 31% (n = 17 of 54). Nodule characteristics were heterogeneous, and most displayed stability over time. More participants with nodules had structural esophageal abnormalities, restriction, and reduced diffusing capacity on lung function tests, and follow-up imaging. Most participants had multiple nodules, and although most nodules were <5 mm, most participants had at least one nodule >5 mm. Conclusions: Pulmonary nodules are seen in children with jSSc and may be related to more severe disease and/or esophageal dysfunction. More work is needed to provide guidance on radiologic follow-up and clinical management of pulmonary nodules in jSSc. Full article

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

Objectives: The aim of this work was to determine hand joint inflammation in systemic sclerosis (SSc); patients with rheumatoid arthritis (RA) with hand joint involvement were used as controls. Our investigation also aimed at examining the relationship between these subclinical inflammatory changes in the hands, verified by low-frequency MRI, and clinical (especially cardiopulmonary) manifestations, disease activity, and functional capacity in patients with diffuse cutaneous (dcSSc) and limited cutaneous SSc (lcSSc). Methods: Out of 250 SSc patients, the selection included 82 patients with signs and symptoms of joint involvement, and 35 consecutive RA patients. These patients underwent clinical and laboratory investigations, and hand X-ray and MRI of the dominant hand. Synovitis/tenosynovitis, bone edema, and erosions were investigated, and the bone changes were quantified and scored using the RAMRIS method. HAQ index, modified Rodnan skin score, examination of internal organ involvement, and serological markers for SSc, as well as rheumatoid factor (RF) and cyclic citrullinated peptides antibodies (ACPA), were performed on all experimental group subjects. Results: MRI of the dominant hand showed a significantly higher number of cases with synovitis (78%) than the number of patients with clinically swollen joints (17.1%; p < 0.001); bone edema was found in 62 (75.6%) SSc patients. MRI also showed a higher number of erosions (52; 63.4%) compared to those (22; 27.5%) detected with X-ray (p < 0.001). The average values of the total MRI score of synovitis/edema and erosions in the wrist (p < 0.001) and MCP joints (p < 0.001) were statistically higher in RA than in SSc patients (p < 0.001). The probability of the MRI-detected inflammatory changes was considerably higher in SSc patients who had vascular complications (digital ulceration, OR = 4.68; 95% IP: 1.002–22.25; p < 0.05), in patients with more severe functional impairment (OR = 8.22; 95% IP: 1.74–38.89; p < 0.01), and in patients with active disease (OR = 3.132; 95% IP: 1.027–9.551; p < 0.05). In our investigation, patients with a limited form of the disease and with inflammatory changes on MR more often had higher functional impairment compared to the other group without MRI inflammation. Conclusions: Our data show that in SSc MRI can detect a significant subclinical joint inflammation. RAMRIS confirmed the high degree of joint inflammation in RA, but also revealed a great deal of joint inflammation in SSc. That inflammation is associated with systemic inflammation (disease activity), vascular complications, and more severe forms of the disease, as synovitis cannot be precisely diagnosed by the clinical examination of joints. These results suggest that a careful joint investigation is necessary in SSc, and that in symptomatic patients, MRI may identify joint inflammation. In clinical practice, this evidence might drive to an early targeted therapy, thus preventing joint erosions. Full article

Objective: to describe the prevalences, characteristics, and survivals of patients with anti-topoisomerase 1 antibodies (ATA) and limited cutaneous systemic sclerosis (lSSc) and anti-centromere antibodies (ACA) and diffuse cutaneous systemic sclerosis (dSSc). Methods: patients with ATA lSSc or with ACA dSSc were included in a case-control retrospective study. Results: In our cohort of scleroderma, the prevalence of ACA dSSc and ATA lSSc was 1.1% (12/1040) and 8.9% (93/1040), respectively. ACA dSSc patients had less interstitial lung disease (ILD) (5 (41.7) vs. 74 (79.6); p < 0.01), more cardiac involvement, and more muscle involvement (3 (25) vs. 4 (4.3); p = 0.03 and 4 (33.3) vs. 4 (7.5); p = 0.02,) than ATA dSSc patients. ATA lSSc patients had a higher modified Rodnan skin score than ACA lSSc patients (4 [2–7.5] vs. 2 [0–5]; p < 0.01) and less cardiac or muscle involvement than ATA dSSc patients (6 (6.5) vs. 19 (20.4%); p < 0.01 and 15 (16.1) vs. 54 (58.1); p < 0.0001, respectively). The cumulative 5-year survival rate was 71% in ACA dSSc patients, 95% in ATA lSSc patients, 84% in ACA lSSc patients, and 66% in ATA dSSc patients (p < 0.0001). Conclusion: ATA lSSc and ACA dSSc have specific characteristics when compared to ATA dSSc or ACA lSSc. ATA lSSc patients have more ILD than ACA lSSc patients, and ATA dSSc patients have the worst prognosis. Overall, inverted phenotypes show the value of a patient assessment combining antibody and skin subset and should be considered as a separate group. Full article

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. Full article

The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) varies among individuals. Red blood cell distribution width (RDW) has been reported to be a predictor of idiopathic pulmonary fibrosis. However, there are no studies on the relationship between RDW and SSc-ILD. We conducted a retrospective study of 28 patients who were diagnosed with SSc-ILD on their first visit to our hospital and were followed-up for 5 years. The correlation between the changes in RDW, KL-6, and SP-D (ΔRDW, ΔKL-6, ΔSP-D) and the changes in percent-predicted forced lung volume and % carbon monoxide diffusion (Δ%FVC, Δ%DLco) was investigated. ΔRDW at 1 year after diagnosis was significantly inversely correlated with Δ%FVC at 5 years after diagnosis (r = −0.51, p < 0.001) and Δ%DLco at 5 years after diagnosis (r = −0.47, p < 0.001), whereas ΔKL-6 and ΔSP-D at 1 year were not correlated with Δ%FVC or Δ%DLco at 5 years. In the group of SSc-ILD patients with RDW increase in the first year after diagnosis, %FVC and %DLco were significantly lower than baseline at 3-, 4-, and 5-year assessments. In the group of patients without RDW increase in the first year, %FVC and %DLco did not decrease during the follow-up period. In conclusion, the changes in RDW in the first year after diagnosis may be useful surrogate markers to predict the long-term course of SSc-ILD. Full article

Background: Heart involvement (HInv) in systemic sclerosis (SSc) may relate to myocarditis and is associated with poor prognosis. Serum anti-heart (AHA) and anti-intercalated disk autoantibodies (AIDA) are organ and disease-specific markers of isolated autoimmune myocarditis. We assessed frequencies, clinical correlates, and prognostic impacts of AHA and AIDA in SSc. Methods: The study included consecutive SSc patients (n = 116, aged 53 ± 13 years, 83.6% females, median disease duration 7 years) with clinically suspected heart involvement (symptoms, abnormal ECG, abnormal troponin I or natriuretic peptides, and abnormal echocardiography). All SSc patients underwent CMR. Serum AHA and AIDA were measured by indirect immunofluorescence in SSc and in control groups of non-inflammatory cardiac disease (NICD) (n = 160), ischemic heart failure (IHF) (n = 141), and normal blood donors (NBD) (n = 270). AHA and AIDA status in SSc was correlated with baseline clinical, diagnostic features, and outcome. Results: The frequency of AHA was higher in SSc (57/116, 49%, p < 0.00001) than in NICD (2/160, 1%), IHF (2/141, 1%), or NBD (7/270, 2.5%). The frequency of AIDA was higher (65/116, 56%, p < 0.00001) in SSc than in NICD (6/160, 3.75%), IHF (3/141, 2%), or NBD (1/270, 0.37%). AHAs were associated with interstitial lung disease (p = 0.04), history of chest pain (p = 0.026), abnormal troponin (p = 0.006), AIDA (p = 0.000), and current immunosuppression (p = 0.01). AHAs were associated with death (p = 0.02) and overall cardiac events during follow-up (p = 0.017). Conclusions: The high frequencies of AHA and AIDA suggest a high burden of underdiagnosed autoimmune HInv in SSc. In keeping with the negative prognostic impact of HInv in SSc, AHAs were associated with dismal prognosis. Full article

Systemic sclerosis (SSc) patients exhibit a plethora of risk factors for nutritional decline, including the presence of chronic inflammation and the progressive nature of disease-related multisystem involvement. The prevalence and consequences of nutritional decline in scleroderma are frequently underestimated, its management currently remaining a subject of debate. The main objective of the present study was to perform a detailed assessment of scleroderma patients’ diet as well as their eating habits and to describe the relationships with weight loss and malnutrition risk in the absence of professional nutritional counseling. Methods: We used a translated and validated version of the EPIC-Norfolk FFQ (European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire) to evaluate the patients’ diet and MUST (Malnutrition Universal Screening Tool) to investigate the risk of malnutrition. Disease activity was estimated using the EUSTAR-AI (European Scleroderma Trials and Research group Activity Index). Results: We included 69 patients with SSc, of which 42 underwent a detailed dietary assessment. Dietary factors were connected to body composition and digestive symptoms. We found high sodium intake and frequent suboptimal energy consumption in our study group, including patients with cardiopulmonary involvement. Liver transaminases were inversely correlated with the consumption of nuts and seeds. Malnutrition and weight loss were significantly associated with pulmonary hypertension, heart failure, albumin levels, and the extent of skin fibrosis, but not advanced age. Although the patients with EUSTAR-AI ≥ 2.5 were more frequently included in the moderate and high malnutrition risk categories, these results did not reach statistical significance. Conclusions: Currently, there is an unmet need for longitudinal and interventional research focusing on the long-term significance, ramifications, and management of nutritional impairment in SSc patients with various clinical manifestations. Our results indicate that scleroderma patients could benefit from personalized nutritional counseling in an interdisciplinary setting. Full article

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc. Full article

Krebs von den Lungen-6 (KL-6) levels measured at baseline have been reported as a circulating biomarker useful for the detection, evaluation of severity and assessment of risk of the progression of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). In this retrospective study, longitudinal changes in serum KL-6 levels over 2 years were examined in 110 patients with SSc using prospectively collected cohort data. Serum KL-6 levels fluctuated in a significant proportion of the patients but remained stable in the remaining patients. A wide range of variability of longitudinal KL-6 levels was associated with the presence of ILD, diffuse cutaneous SSc, positive anti-topoisomerase I antibodies, negative anticentromere antibodies, increased ILD extent on high-resolution computed tomography, extensive disease, low pulmonary function parameters, high KL-6 levels at baseline and immunomodulatory treatment. Extensive disease was consistently identified as an independent factor associated with variability in KL-6 levels in different models of multiple regression analysis. We failed to demonstrate correlations between trends for KL-6 level changes during the 6 months after SSc diagnosis and ILD progression over 2 years in patients with SSc-ILD. Serum KL-6 levels fluctuate in SSc patients with ILD, especially in those with extensive disease, but the clinical utility of a serial KL-6 level measurement remains uncertain. Full article

Introduction: Systemic sclerosis (SSc) is a systemic immune-mediated disease, featuring fibrosis of the skin and organs, and has the greatest mortality among rheumatic diseases. The nervous system involvement has recently been demonstrated, although actual lung involvement is considered the leading cause of death in SSc and, therefore, should be diagnosed early. Pulmonary function tests are not sensitive enough to be used for screening purposes, thus they should be flanked by other clinical examinations; however, this would lead to a risk of overtesting, with considerable costs for the health system and an unnecessary burden for the patients. To this extent, Machine Learning (ML) algorithms could represent a useful add-on to the current clinical practice for diagnostic purposes and could help retrieve the most useful exams to be carried out for diagnostic purposes. Method: Here, we retrospectively collected high resolution computed tomography, pulmonary function tests, esophageal pH impedance tests, esophageal manometry and reflux disease questionnaires of 38 patients with SSc, applying, with R, different supervised ML algorithms, including lasso, ridge, elastic net, classification and regression trees (CART) and random forest to estimate the most important predictors for pulmonary involvement from such data. Results: In terms of performance, the random forest algorithm outperformed the other classifiers, with an estimated root-mean-square error (RMSE) of 0.810. However, this algorithm was seen to be computationally intensive, leaving room for the usefulness of other classifiers when a shorter response time is needed. Conclusions: Despite the notably small sample size, that could have prevented obtaining fully reliable data, the powerful tools available for ML can be useful for predicting early lung involvement in SSc patients. The use of predictors coming from spirometry and pH impedentiometry together might perform optimally for predicting early lung involvement in SSc. Full article

Background: to compare three existing screening algorithms of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) with the results of a multidisciplinary team (MDT) meeting from a tertiary center. Methods: we conducted a monocentric longitudinal study from 2015 to 2018. All patients with SSc according to LeRoy’s classification were eligible. Patients were excluded in the case of missing data required by any of the three screening algorithms. The algorithms were applied for each patient at inclusion. Right heart catheterization (RHC) was performed based on the MDT decision. MDT members were all blinded from the results of the three algorithms regarding RHC recommendations. The RHC recommendations of each algorithm were compared with the MDT decision, and the impact on diagnosis and management was evaluated. Results: 117 SSc patients were consecutively included in the study, and 99 had follow-up data over the three-year duration of the study (10 deaths). Among the 117 patients, the MDT suggested RHC for 16 patients (14%), DETECT algorithm for 28 (24%), ASIG for 48 (41%) and ESC/ERS 2015 for 20 (17%). Among the 16 patients who had RHC, SSc-PAH was diagnosed in seven. Among patients with an initial recommendation of RHC based on at least one algorithm but not according to the MDT meeting, no SSc-PAH was diagnosed during the three-year follow-up. Results were unchanged when the new 2018 definition of PAH was applied instead of the previous definition. Conclusion: a MDT approach appears interesting for the screening of SSc-PAH, with a significant reduction of RHC performed in comparison with dedicated algorithms. The specific relevance of a MDT for the management and follow-up of patients with RHC recommended by existing algorithms but with no PAH warrants further studies. Full article

Introduction: Nailfold video capillaroscopy (NVC) is a useful tool for measuring capillary density (CD) and capillary morphology parameters and is mainly used in systemic sclerosis (SSc). Objective: We aimed to assess the prevalence of an SSc pattern and CD in different connective tissue diseases (CTDs). Methods: NVC was performed on 268 patients with CTDs. Control groups consisted of 104 healthy volunteers (HVs) and 36 primary Raynaud’s patients (PRPs). Results: Decreased CD was more prevalent in SSc, systemic lupus erythematosus (SLE), inflammatory myopathies (IIM), and overlap CTD patients compared with both controls. Average CD, the prevalence of decreased CD, and the prevalence of an SSc pattern did not differ significantly between SSc patients with (n = 39) and without (n = 50) overlap syndrome. An SSc pattern was significantly more prevalent in SLE (23%), SSc (82%), IIM (35%), and rheumatoid arthritis (17%) compared with both control groups. The prevalence of an elevated microangiopathy evaluation score (MES) was significantly higher in SLE, SSc, and IIM than in the HVs. Conclusion: The presence of another CTD in SSc did not influence CD or morphology. An SSc pattern may also be present in CTDs other than SSc. The MES is a useful instrument to distinguish between patients with CTDs and controls. Full article

Background: Antinuclear antibody pattern recognition is vital for autoimmune disease diagnosis but labor-intensive for manual interpretation. To develop an automated pattern recognition system, we established machine learning models based on the International Consensus on Antinuclear Antibody Patterns (ICAP) at a competent level, mixed patterns recognition, and evaluated their consistency with human reading. Methods: 51,694 human epithelial cells (HEp-2) cell images with patterns assigned by experienced medical technologists collected in a medical center were used to train six machine learning algorithms and were compared by their performance. Next, we choose the best performing model to test the consistency with five experienced readers and two beginners. Results: The mean F1 score in each classification of the best performing model was 0.86 evaluated by Testing Data 1. For the inter-observer agreement test on Testing Data 2, the average agreement was 0.849 (κ) among five experienced readers, 0.844 between the best performing model and experienced readers, 0.528 between experienced readers and beginners. The results indicate that the proposed model outperformed beginners and achieved an excellent agreement with experienced readers. Conclusions: This study demonstrated that the developed model could reach an excellent agreement with experienced human readers using machine learning methods. Full article

In systemic sclerosis (SSc) mortality is mainly linked to lung involvement which is characterized by interstitial lung disease (ILD) and pulmonary hypertension (PH). In SSc, PH may be due to different etiologies, including ILD, chronic thromboembolic disease, pulmonary veno-occlusive disease, and pulmonary arterial hypertension (PAH). The main tool to screen PAH is transthoracic echocardiography (TTE), which has a sensitivity of 90%, even if definitive diagnosis should be confirmed by right heart catheterization (RHC). The radiological evaluation (i.e., HRTC) plays an important role in defining the possible causes and in monitoring the evolution of lung damage. For PAH, identifying individuals who have borderline elevation of pulmonary arterial pressure needs to be appropriately managed and followed. In the past few years, the strategy for the management of PAH has significantly evolved and new trials are underway to test other therapies. This review provides an overview of the tools to evaluate PAH in SSc patients and on treatment options for these patients. Full article

Imaging plays a pivotal role in systemic sclerosis for both diagnosis management of pulmonary complications, and high-resolution computed tomography (HRCT) is the most sensitive technique for the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Indeed, several studies have demonstrated that HRCT helps radiologists and clinicians to make a correct diagnosis on the basis of recognised typical patterns for SSc-ILD. Most SSc patients affected by ILD have a non-specific interstitial pneumonia pattern (NISP) on HRCT scan, whilst a minority of cases fulfil the criteria for usual interstitial pneumonia (UIP). Moreover, several recent studies have demonstrated that lung ultrasound (LUS) is an emergent tool in SSc diagnosis and follow-up, although its role is still to be confirmed. Therefore, this article aims at evaluating the role of LUS in SSc screening, aimed at limiting the use of CT to selected cases. Full article

The diagnosis and classification of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is essential to improve the prognosis of systemic sclerosis (SSc) patients. The risk-stratification of disease severity and follow-up requires a multidisciplinary approach, integrating high-resolution computed tomography (HRTC) of the lung, pulmonary function tests (PFT), along with clinical and symptomatic evaluations. The use of HRCT in detecting SSc-ILD is not so much based on a definitive validation, but rather reflects the widespread clinician recognition of dissatisfaction with other modalities. However, due to the heterogeneity of SSc-ILD and the potential absence of symptoms in early or mild disease, it is prudent to consider as many parameters as possible in the assessment and monitoring of newly diagnosed patients. An early diagnosis meets the primary goal, i.e., the prevention of disease progression. The current first line treatment regimens are mainly centered on immunosuppressive therapy. This review assesses the role HRCT plays in optimizing care and improving clinical outcomes in SSc-ILD patients. Full article

Cardiac disease is a leading cause of death in systemic sclerosis (SSc) and sudden cardiac death (SCD) is thought to occur more commonly in SSc than in the general population. Diffuse myocardial fibrosis, myocarditis and ischaemic heart disease are all prevalent in SSc and can be reasonably hypothesised to contribute to an increased risk of SCD. Despite this, SCD remains a relatively understudied area of SSc with little understood about SSc-specific risk factors and opportunities for primary prevention. In this review, we present an overview of the possible mechanisms of SCD in SSc and our current understanding of how each of these mechanisms may contribute to cardiac death. This review highlights the need for a future research agenda that addresses the underlying epidemiology of SCD in SSc and identifies opportunities for intervention to modify the disease course of heart disease in SSc. Full article

Objective: To investigate in an unselected, systemic sclerosis (SSc) cohort if baseline laser speckle contrast analysis (LASCA) peripheral blood perfusion (PBP) measurements differ between ‘early’ SSc (without skin involvement, or ‘limited’ SSc—LSSc) and ‘clinically overt’ SSc (with skin involvement, limited cutaneous SSc—LcSSc and diffuse cutaneous SSc—DcSSc) in routine setting. Methods: A group of twenty consecutive ‘early’ SSc patients and forty consecutive ‘clinically overt’ SSc patients (twenty LcSSc and twenty DcSSc) underwent clinical and LASCA examinations (to assess the peripheral blood perfusion [PBP] of both hands volar). Results: No statistically significant difference in adjusted PBP was found in the ‘early’ versus the ‘clinically overt’ group (p = 0.77) when adjusted for possible confounding factors (e.g., vasoactive medication, active smoking, history of DTL and disease duration). A wide variability was noted when observing the individual datapoints of each subset. Conclusion: This study with an unselected SSc population in daily routine, non-research setting, showed there was no difference in adjusted PBP at baseline between ‘early’ SSc and ‘clinically overt’ SSc when corrected for possible confounding factors. Interestingly a wide variation of individual datapoints were observed in each subset, which emphasizes the heterogeneity of SSc. Full article

Background: Chest computed tomography (CT) is the gold standard for the evaluation of systemic sclerosis-related interstitial lung disease (SSc-ILD). Lung ultrasound (LUS) is a radiation-free tool that identifies the B-lines as a main feature of ILD. We aimed to investigate the role of LUS in the evaluation of the extent of SSc-ILD. Methods: Adult SSc patients underwent pulmonary function tests (PFTs), LUS and CT. The CT images were qualitatively, semi-quantitatively (the Wells score on five levels and the categorical Goh et al. staging) and quantitatively (histogram-based densitometry) analysed for ILD. LUS quantified B-lines in 21 intercostal spaces on both the anterior and posterior chest wall. Results: Out of the 77 SSc patients eligible for the study, 35 presented with ILD on CT (21 limited, 14 extensive). Total B-lines significantly differentiated ILD vs. no ILD (median 24 vs. 8, p < 0.001). Posterior and total B-lines significantly differentiated limited from absent ILD, while anterior B-lines distinguished extensive from limited ILD. Total B-lines correlated with the Wells score (r = 0.446, p < 0.001) and MLA (r = −0.571, p < 0.001); similar results were confirmed when anterior and posterior B-lines were analysed separately. Conclusions: LUS is a useful tool to identify SSc-ILD and to correlate with different evaluations of ILD extent and severity. Full article

In recent years, a novel Doppler ultrasonography (US) modality—superb microvascular imaging (SMI)—has been presented as a reliable method to evaluate small vessel blood flow with minimised motion artefacts. In this review, we present the challenges of incorporating SMI in daily practice with detailed and comparable US images of a fingertip. The main focus of this paper is the discussion of all tested US techniques, artefacts, and practical challenges for evaluating Raynaud’s syndrome in systemic sclerosis. Despite a few reports on SMI use in assessing nailfold capillaries, there is still a need for more evidence of its value and possibilities for its standardisation. Full article

Background: The detection of additional autoantibodies is of great concern in systemic sclerosis (SSc) when those included in the ACR/EULAR classification are negative. In this context, the interest of antifibrillarin (anti-U3RNP) autoantibodies (AFAs) in the routine evaluation of SSc remains unclear. We aimed to assess the relevance of AFAs and their clinical association in SSc patients. Methods: In a multicenter observational retrospective study, we collected immunological and clinical data associated with AFA positivity in SSc (n = 42) and non-SSc patients (n = 13). Patients with SSc negative for AFAs (n = 83) were considered as a control group. AFAs were detected by indirect immunofluorescence (IIF) using HEp-2 cells, EliA or immunoblot techniques. Results: We confirmed a typical nuclear IIF pattern and showed that AFAs are mostly exclusive towards SSc conventional autoantibodies. Although also observed in non-SSc patients, high levels of AFAs with the ELiA technique allowed the diagnosis of SSc. Compared to AFA-negative SSc patients, AFA-positive SSc patients more frequently exhibited visceral involvements. They more frequently suffered from the diffuse cutaneous form and had a higher global severity of the disease. Conclusions: We demonstrate the usefulness of quantifying AFAs in the immunological exploration of SSc, especially when patients are seronegative for SSc conventional autoantibodies and display a typical IIF pattern. AFAs might constitute an interesting marker of SSc severity. Full article