Heart rate variability helps classify phenotype in systemic sclerosis.

We aimed to develop a systemic sclerosis (SSc) subtypes classifier tool to be used at the patient's bedside. We compared the heart rate variability (HRV) at rest (5-min) and in response to orthostatism (5-min) of patients (n = 58) having diffuse (n = 16, dcSSc) and limited (n = 38, lcSSc) cutaneous forms. The HRV was evaluated from the beat-to-beat RR intervals in time-, frequency-, and nonlinear-domains. The dcSSc group differed from the lcSSc group mainly by a higher heart rate (HR) and a lower HRV, in decubitus and orthostatism conditions. Stand-up maneuver lowered HR standard deviation (sd_HR), the major axis length of the fitted ellipse of Poincaré plot of RR intervals (SD2), and the correlation dimension (CorDim) in the dcSSc group while increased these HRV indexes in the lcSSc group (p = 0.004, p = 0.002, and p = 0.004, respectively). We identified the 5 most informative and discriminant HRV variables. We then compared 341 classifying models (1 to 5 variables combinations × 11 classifier algorithms) according to mean squared error, logloss, sensitivity, specificity, precision, accuracy, area under curve of the ROC-curves and F1-score. F1-score ranged from 0.823 for the best 1-variable model to a maximum of 0.947 for the 4-variables best model. Most specific and precise models included sd_HR, SD2, and CorDim. In conclusion, we provided high performance classifying models able to distinguish diffuse from limited cutaneous SSc subtypes easy to perform at the bedside from ECG recording. Models were based on 1 to 5 HRV indexes used as nonlinear markers of autonomic integrated influences on cardiac activity.

Quality of sleep in individuals with systemic sclerosis and its correlation with functional disability and quality of life: a cross-sectional study.

OBJECTIVE: This study aimed to evaluate the quality of sleep in individuals with systemic sclerosis and its correlation with the quality of life and disability. METHODS: This is a cross-sectional study, carried out in a tertiary service of a university hospital. Inclusion criteria were diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology/European League Against Rheumatism 2013 or the preliminary criteria of the American College of Rheumatology 1980, age ≥ 18 years; regularly monitored at the outpatient clinic of rheumatology. Clinical and demographic data of the patients were obtained through a structured interview and evaluation of the medical records. Sleep quality was assessed using the Pittsburgh Sleep Quality Index questionnaire, daytime sleepiness using the Epworth Sleepiness Scale, quality of life using 12-item short-form health survey, and disability using the scleroderma health assessment questionnaire. RESULTS: A total of 50 patients with systemic sclerosis were included, with 92% female, mean age 48.9 years, mean disease duration 8.9 years, and 60% limited cutaneous form. Most systemic sclerosis patients (84%) have poor sleep quality and 20% have excessive daytime sleepiness. There was a significant negative correlation between Pittsburgh Sleep Quality Index and the physical and mental components of the 12-item short-form health survey (r=-0.42, p=0.003 and r=-0.43, p=0.002, respectively) and a positive correlation with the scleroderma health assessment questionnaire (r=0.52, p=<0.001). CONCLUSION: This study showed that poor sleep quality is a very common finding among systemic sclerosis patients, and it negatively affects both the quality of life and the degree of disability. Sleep quality is an unmet need in patients with systemic sclerosis Poor sleep quality is very common in patients with systemic sclerosis Poor sleep quality correlated with worse quality of life and greater disability.

Severity and impact of digestive impairment perceived by patients with systemic sclerosis: a cross-sectional study.

OBJECTIVES: To describe the severity and impact of gastrointestinal involvement in patients with systemic sclerosis (SSc) and identify associated factors. PATIENTS AND METHODS: Non-controlled cross-sectional study of patients with SSc (2013 American College of Rheumatology/European League Against Rheumatism criteria). The main variables were severity of gastrointestinal involvement according to the University of California, Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 instrument (UCLA SCTC GIT 2.0) and dysphagia according to the Eating Assessment Tool-10 (EAT-10). We evaluated reflux, distension, diarrhoea, faecal soilage, constipation, emotional well-being and social functioning, as well as dysphagia. Clinical and epidemiological data were collected using the Mini Nutritional Assessment Short Form (MNA-SF) and the EuroQol-5D-3L. The degree of skin fibrosis was assessed using the modified Rodnan skin score (mRSS). Multivariate models were constructed to analyse factors associated with gastrointestinal involvement and dysphagia. RESULTS: Of the 75 patients with SSc included, 58.7% had moderate, severe or very severe reflux, 57.4% had constipation according to UCLA SCTC GIT 2.0 and 49.7% had abdominal distension. Gastrointestinal symptoms interfered significantly with social functioning (42.7%) and emotional well-being (40.0%). Dysphagia (EAT-10≥3) was recorded in 52% of patients, and according to MNA-SF poor nutrition in 30.7%, and clear malnutrition requiring a nutritional intervention in 5.3%. Multivariate adjustment revealed an association between severity of gastrointestinal symptoms according to the mRSS (ß=0.249; p=0.002) and Visual Analogue Scale 3-Level EuroQol-5D (VAS-EQ-5D-3L) (ß=-0.302; p=0.001), whereas presence of dysphagia was associated with the mRSS (OR=2.794; p=0.015), VAS-EQ-5D-3L (OR=0.950; p=0.005) and malnutrition (MNA-SF≤7; OR=3.920; p=0.041). CONCLUSIONS: Patients with SSc frequently present severe gastrointestinal symptoms. These are associated with poor quality of life, more severe skin involvement and malnutrition.

Prognostic and functional importance of both overt and subclinical left ventricular systolic dysfunction in systemic sclerosis.

OBJECTIVES: To quantify the frequency and clinical implications of systemic sclerosis (SSc)-associated left ventricular function (LV) impairment. METHODS: Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc with ≥1 echocardiographic LVEF measurement were included. Overt LV dysfunction was indicated by reduced LV ejection fraction (LVEF) and subclinical LV dysfunction was measured using impaired LV global longitudinal strain (LV-GLS>-16 %). Those with secondary causes of LV dysfunction (myocardial ischaemia, valvulopathy and pulmonary arterial hypertension) were excluded. Chi-squared tests, two-sample t-tests or Wilcoxon rank-sum tests were used for between-group comparison as appropriate. Generalised estimating equations(GEE) were used to model longitudinal data. Kaplan-Meier and Cox proportional hazard models were used for survival analyses. RESULTS: Of 1141 participants with no co-morbid cardiac disease, 2.4 % ever recorded a LVEF<50 %, while only 0.6 % ever recorded a LVEF≤40 %. LV-GLS data were available for 90 % of participants at one centre (n = 218). Impaired LV-GLS was detected in 21 % despite LVEF≥50 %. Those with a LVEF<50 % were more frequently male (p = 0.01) with dcSSc (p < 0.01), higher inflammatory markers (p < 0.02) and skeletal muscle disease (p < 0.05). In multivariable analyses, recording a LVEF<50 % was associated with increased mortality (HR2.3, 95 %CI1.0-4.8, p = 0.04). Impaired LV-GLS was also associated with poorer survival in univariable analyses (HR3.4, 95 %CI1.0-11.8, p = 0.05). Those with a LVEF<50 % more frequently recorded WHO Class III/IV dyspnoea (OR3.5, 95 %CI1.6-7.7, p < 0.01), with shorter six-minute walk distance (p = 0.01), higher Health Assessment Questionnaire-Disability Index scores (p < 0.01) and lower Short Form-36 Physical Component Summary scores (p = 0.02). Increased dyspnoea (WHO Class III/IV dyspnoea; OR3.6, 95 %CI1.4-9.2, p < 0.01) was also seen in those with impaired LV-GLS. CONCLUSIONS: Both overt and subclinical SSc-associated LV dysfunction are associated with worse survival and impaired physical function. The frequency of abnormal LV-GLS in those with consistently normal LVEF suggests an under-appreciated burden of subtle LV systolic dysfunction in SSc that has a significant impact on patient symptomatology.

What have we learned on pre, very early, and early systemic sclerosis microcirculatory pathophysiology? A scoping review.

OBJECTIVE: Microvascular dysfunction is an early event in the pathogenesis of systemic sclerosis (SSc). The objective of this scoping review is to update the current information and the level of knowledge about the mechanisms of microvascular dysfunction in pre-SSc, very early diagnosis of SSc (VEDOSS) and early SSc. METHODS: A PubMed® database search allowed us to include original data from full-length articles in English in which the main topic was microvascular dysfunction in pre-SSC, VEDOSS or early SSc. Data was extracted using a customized form. RESULTS: In the present review 437 articles were identified, and 42 studies included, reporting data from a total of 1069 patients with pre-SSc, VEDOSS or early-SSc. Distinct mechanisms of microvascular injury were identified comprising, angiogenesis and vasculogenesis, cell surface proteins and adhesion, molecules expression, cytokines profile, inflammatory and oxidation pathways, and skin perfusion determinants. Most of the studies were conducted in early SSc, with a reduced number in pre-disease stages, in which the prompt recognition of specific mechanisms and biomarkers may allow targeted treatment to prevent disease progression. CONCLUSIONS: Although different molecular expression patterns and signaling pathways related to microvascular dysfunction in pre-SSc, VEDOSS, and early SSc were identified, additional prospective longitudinal studies and combined work with functional evaluation of peripheral skin perfusion are needed.

Impact of foot functionality in patients with systemic sclerosis: Cross-sectional study.

BACKGROUND: Progressive systemic sclerosis or systemic scleroderma (SS) is a chronic and rare autoimmune disease that mainly affects the skin and various internal organs. Raynaud's phenomenon and digital ulcers are some of the symptoms that affect the foot, causing a decrease in the quality of life of patients. The objective of this study is to determine the functionality of the feet in patients with SS and determine the impact on their daily lives. METHODS: A sample of 165 patients (154 women, 11 men) diagnosed with SS with a mean age of 46.29 ± 11.36 years and a mean body mass index (BMI) of 24.90 ± 5.77 was recruited. Each participant completed the Foot Function Index (FFI) questionnaire and the Systemic Sclerosis Questionnaire (SySQ). A multivariate analysis was performed to determine which factors were related to a higher score in both questionnaires. RESULTS: 32.1% of the participants (n = 53) had claw toe deformities, 79.4% (n = 131) Raynaud's disease and 20% (n = 33) a history of foot ulcers. 51.5% of the participants (n = 85) presented symptoms in their nails, the most frequent sign being thickening, hardening and yellow coloration. The final score of the FFI questionnaire was 3.51 ± 2.41 (0-9.9), the pain subscale being the highest, with a score of 5.06 ± 2.75, followed by foot disability (3.26 ± 2.91) and difficulty performing activities (1.55 ± 2.22). The final score of the SySQ questionnaire was 0.95 ± 0.45 (0.18-2.45), and the subscales with the highest score were symptom frequency (1.30 ± 0.47), symptom intensity (1.11 ± 0.55), and general skill limitation (0.47 ± 0.51). A high correlation was observed between the final FFI score and the final SySQ score (r = 0.712; p=<0.001). Also, between foot activity limitation and general skill limitation (r = 0.658; p=<0.001). A moderate correlation was observed between foot pain score and overall symptom intensity (r = 0.482; p=<0.001). Also, between foot disability and overall symptom frequency (r = 0.556; p=<0.001). The multivariate analysis (R2 0.51) showed that the final FFI score had a significant relationship with the final SySQ score (p < 0.001). No significant correlation was found between age (p = 0.15), gender (p = 0.49), BMI (p = 0.74) or time of diagnosis (p = 0.57) and FFI. CONCLUSION: SS is a disease that affects foot functionality in patients, with a greater impact on the pain scale. There is a correlation between the final FFI score and the final SySQ score, so improving foot functionality could help to improve the overall functionality of the patient with sclerosis.

Saliva Production and Esophageal Motility Influence Esophageal Acid Clearance Related to Post-reflux Swallow-Induced Peristaltic Wave.

BACKGROUND: The post-reflux swallow-induced peristaltic wave (PSPW) brings salivary bicarbonate to neutralize residual distal esophageal mucosal acidification. AIMS: To determine if reduced saliva production and esophageal body hypomotility would compromise PSPW-induced pH recovery in the distal esophagus. METHODS: In this multicenter retrospective cross-sectional study, patients with confirmed Sjogren's syndrome and scleroderma/mixed connective tissue disease (MCTD) who underwent high resolution manometry (HRM) and ambulatory pH-impedance monitoring off antisecretory therapy were retrospectively identified. Patients without these disorders undergoing HRM and pH-impedance monitoring for GERD symptoms were identified from the same time-period. Acid exposure time, numbers of reflux episodes and PSPW, pH recovery with PSPW, and HRM metrics were extracted. Univariate comparisons and multivariable analysis were performed to determine predictors of pH recovery with PSPW. RESULTS: Among Sjogren's syndrome (n = 34), scleroderma/MCTD (n = 14), and comparison patients with reflux symptoms (n = 96), the scleroderma/MCTD group had significantly higher AET, higher prevalence of hypomotility, lower detected reflux episodes, and very low numbers of PSPW (p ≤ 0.004 compared to other groups). There was no difference in pH-impedance metrics between Sjogren's syndrome, and comparison patients (p ≥ 0.481). Proportions with complete pH recovery with PSPW was lower in Sjogren's patients compared to comparison reflux patients (p = 0.009), predominantly in subsets with hypomotility (p < 0.001). On multivariable analysis, diagnosis of Sjogren's syndrome, scleroderma/MCTD or neither (p = 0.014) and esophageal hypomotility (p = 0.024) independently predicted lack of complete pH recovery with PSPW, while higher total reflux episodes trended (p = 0.051). CONCLUSIONS: Saliva production and motor function are both important in PSPW related pH recovery.

Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis-Associated Interstitial Lung Disease.

OBJECTIVE: To explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD. METHODS: There were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling. RESULTS: LVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P = 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P = 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P = 0.08). Older age (95% CI 1.0-6.4; P = 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P < 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P < 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P < 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P = 0.04). CONCLUSION: LVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

AIMS: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). METHODS AND RESULTS: Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). CONCLUSION: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Anti-Gephyrin Antibodies: A Novel Specificity in Patients With Systemic Sclerosis and Lower Bowel Dysfunction.

OBJECTIVE: Autoantibodies are clinically useful in phenotyping patients with systemic sclerosis (SSc). Gastrointestinal (GI) function is regulated by the enteric nervous system (ENS) and commonly impaired in SSc, suggesting that the SSc autoimmune response may target ENS antigens. We sought to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction. METHODS: Serum from a patient with SSc with GI dysfunction but without defined SSc-associated autoantibodies was used for autoantibody discovery. Immunoprecipitations performed with murine myenteric plexus lysates were on-bead digested, and autoantigens were identified by mass spectrometry. Prevalence was determined, and clinical features associated with novel autoantibodies were evaluated in a SSc cohort using regression analyses. The expression of gephyrin in human GI tract tissue was examined by immunohistochemistry. RESULTS: We identified gephyrin as a novel SSc autoantigen. Anti-gephyrin antibodies were present in 9% of patients with SSc (16/188) and absent in healthy controls (0/46). Anti-gephyrin antibody-positive patients had higher constipation scores (1.00 vs 0.50, P = 0.02) and were more likely to have severe constipation and severe distention/bloating (46% vs 15%, P = 0.005; 54% vs 25%, P = 0.023, respectively). Anti-gephyrin antibody levels were significantly higher among patients with severe constipation (0.04 vs 0.00; P = 0.001) and severe distention and bloating (0.03 vs 0.004; P = 0.010). Severe constipation was associated with anti-gephyrin antibodies even in the adjusted model. Importantly, gephyrin was expressed in the ENS, which regulates gut motility. CONCLUSION: Gephyrin is a novel ENS autoantigen that is expressed in human myenteric ganglia. Anti-gephyrin autoantibodies are associated with the presence and severity of constipation in patients with SSc.

Performance of DETECT Pulmonary Arterial Hypertension Algorithm According to the Hemodynamic Definition of Pulmonary Arterial Hypertension in the 2022 European Society of Cardiology and the European Respiratory Society Guidelines.

OBJECTIVE: The evidence-based DETECT pulmonary arterial hypertension (PAH) algorithm is frequently used in patients with systemic sclerosis (SSc) to help clinicians screen for PAH by using noninvasive data to recommend patient referral to echocardiography and, if applicable, for a diagnostic right-sided heart catheterization. However, the hemodynamic definition of PAH was recently updated in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines. The performance of DETECT PAH in identifying patients with a high risk of PAH according to this new definition was assessed. METHODS: In this post hoc analysis of DETECT, which comprised 466 patients with SSc, the performance of the DETECT PAH algorithm in identifying patients with a high risk of PAH as defined in the 2022 ESC/ERS guidelines (mean pulmonary arterial pressure [mPAP] >20 mm Hg, pulmonary capillary wedge pressure [PCWP] ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units) was assessed using summary statistics and was descriptively compared to the known performance of DETECT PAH as defined in 2014, when it was developed (mPAP ≥25 mm Hg and PCWP ≤15 mm Hg). RESULTS: The sensitivity of DETECT PAH in identifying patients with a high risk of PAH according to the 2022 ESC/ERS definition was lower (88.2%) compared to the 2014 definition (95.8%). Specificity improved from 47.8% to 50.8%. CONCLUSION: The performance of the DETECT algorithm to screen for PAH in patients with SSc is maintained when PAH is defined according to the 2022 ESC/ERS hemodynamic definition, indicating that DETECT remains applicable to screen for PAH in patients with SSc.

Pathophysiology of systemic sclerosis (scleroderma).

Systemic sclerosis (scleroderma) is an autoimmune-triggered chronic fibrosing disease that affects the skin and many other organs. Its pathophysiology is complex and involves an early endothelial damage, an inflammatory infiltrate and a resulting fibrotic reaction. Based on a predisposing genetic background, an altered balance of the acquired and the innate immune system leads to the release of many cytokines and chemokines as well as autoantibodies, which induce the activation of fibroblasts with the formation of myofibroblasts and the deposition of a stiff and rigid connective tissue. A curative treatment is still not available but remarkable progress has been made in the management of organ complications. In addition, several breakthroughs in the pathophysiology have led to new therapeutic concepts. Based on these, many new compounds have been developed during the last years, which target these different pathways and offer specific therapeutic approaches.

Integrative analysis of lung molecular signatures reveals key drivers of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease is a significant comorbidity and the leading cause of mortality in patients with systemic sclerosis. Transcriptomic data of systemic sclerosis-associated interstitial lung disease (SSc-ILD) were analysed to evaluate the salient molecular and cellular signatures in comparison with those in related pulmonary diseases and to identify the key driver genes and target molecules in the disease module. METHODS: A transcriptomic dataset of lung tissues from patients with SSc-ILD (n=52), idiopathic pulmonary fibrosis (IPF) (n=549), non-specific interstitial pneumonia (n=49) and pulmonary arterial hypertension (n=81) and from normal healthy controls (n=331) was subjected to filtration of differentially expressed genes, functional enrichment analysis, network-based key driver analysis and kernel-based diffusion scoring. The association of enriched pathways with clinical parameters was evaluated in patients with SSc-ILD. RESULTS: SSc-ILD shared key pathogenic pathways with other fibrosing pulmonary diseases but was distinguishable in some pathological processes. SSc-ILD showed general similarity with IPF in molecular and cellular signatures but stronger signals for myofibroblasts, which in SSc-ILD were in a senescent and apoptosis-resistant state. The p53 signalling pathway was the most enriched signature in lung tissues and lung fibroblasts of SSc-ILD, and was significantly correlated with carbon monoxide diffusing capacity of lung, cellular senescence and apoptosis. EEF2, EFF2K, PHKG2, VCAM1, PRKACB, ITGA4, CDK1, CDK2, FN1 and HDAC1 were key regulators with high diffusion scores in the disease module. CONCLUSIONS: Integrative transcriptomic analysis of lung tissues revealed key signatures of fibrosis in SSc-ILD. A network-based Bayesian approach provides deep insights into key regulatory genes and molecular targets applicable to treating SSc-ILD.

Cardiopulmonary exercise testing and prognosis in patients with systemic sclerosis without baseline pulmonary hypertension: a prospective cohort study.

Cardiopulmonary Exercise Testing (CPET) is a standardized, non-invasive procedure assessing pulmonary, cardiovascular, hematopoietic, and skeletal muscle functions during a symptom-limited test. Few studies have examined whether CPET is of prognostic value in Systemic Sclerosis (SSc), a disease characterized by highly increased cardiorespiratory morbidity and mortality. To examine the prognostic value of CPET in SSc patients without baseline pulmonary hypertension (PH). Sixty-two consecutive SSc patients underwent CPET, Pulmonary Function Tests (PFTs) and echocardiography at baseline. Four patients with Right Ventricular Systolic Pressure ≥ 40 mmHg, were excluded. Participants repeated PFTs approximately every 3 years. At the end of the follow-up period [median (IQR): 9.79 (2.78) years] patient vital status was recorded. Cox Regression analysis was used to identify predictors of deterioration of PFTs and 10-year survival. Median (IQR) age of 58 patients (90% women) at baseline was 54.0 (15.0) years, whereas 10-year survival was 88%. Baseline respiratory Oxygen uptake (VO2max) predicted PFT deterioration, defined either as a decline in FVC ≥ 10% or a combined decline in FVC 5%-9% plus DLCO ≥ 15%, during follow-up, after correction for age, gender and smoking status (HR: 0.874, 95%CI: 0.779-0.979, p = 0.021). In addition, lower baseline VO2max (HR = 0.861, 95%CI:0.739-1.003, p = 0.054) and DLCO (HR = 0.957, 95%CI: 0.910-1.006 p = 0.088), as well as male gender (HR = 5.68, 95%CI: 1.090-29.610 p = 0.039) and older age (HR = 1.069, 95%CI: 0.990-1.154, p = 0.086) were associated, after adjustment, with an increased risk for death. In the absence of baseline PH, CPET indices may predict pulmonary function deterioration and death in SSc patients during a nearly 10-year follow-up period.

Baseline characteristics of systemic sclerosis patients with restrictive lung disease in a multi-center US-based longitudinal registry.

AIM: Interstitial lung disease (ILD) is the leading cause of disease-related death in systemic sclerosis (SSc). Here, we assess baseline characteristics of SSc subjects with and without restrictive lung disease (RLD) in a multi-center, US-based registry. METHODS: SSc patients within 5 years of disease onset were enrolled in the Collaborative National Quality and Efficacy Registry (CONQUER), a multi-center US-based registry of SSc study participants (age ≥ 18 years) enrolled at 13 expert centers. All subjects met 2013 American College of Rheumatology / European League Against Rheumatism criteria. Subjects with a pulmonary function test (PFT) at baseline before April 1, 2020 were included. High-resolution computed tomography scan of the chest was not available to characterize ILD for all subjects. RLD was defined as forced vital capacity (FVC) <80% or total lung capacity (TLC) <80% predicted. RESULTS: There were 160 (45%) SSc subjects characterized as having RLD. There was no significant difference in age, gender or disease duration. RLD subjects had a mean disease duration from date of first non-Raynaud's symptom of 2.6 years and a mean FVC% predicted of 67% at baseline. In multivariable analysis, non-White race, higher physician global health assessment and modified Medical Research Council (mMRC) dyspnea scores, were independently associated with RLD. In the subgroup of RLD subjects with ILD, ILD had a negative correlation with RNA polymerase III antibody. CONCLUSION: CONQUER is the largest, multi-center, prospective cohort of early SSc patients in the US. Non-White race was independently associated with RLD. In addition, 45% of CONQUER subjects already had RLD, highlighting the importance of screening for SSc-ILD at initial diagnosis.

Definition and application of proximal-distal gradient finger perfusion in systemic sclerosis by laser speckle contrast analysis.

OBJECTIVE: In patients with systemic sclerosis (SSc) the perfusion of the fingers shows an alteration of the physiological proximal-distal gradient (PDG). The aim of this study is to provide a generalizable definition of PDG, applying it in a cohort of SSc patients and healthy controls (HC) using laser speckle contrast analysis (LASCA). METHODS: Adult consecutive SSc patients and HC were enrolled. Peripheral blood perfusion of the hands was evaluated by LASCA, subsequently obtaining 3 different regions of interest: from the distal interphalangeal joint to the fingertip (DIST), from the metacarpophalangeal joint to the distal interphalangeal joint (PROX), and of the whole finger (TOT). A PDG formula independent of both intra- and inter-personal factors was then built. The PDG formula so obtained was: [(DIST × 2.63) - PROX]/TOT. RESULTS: Ninety-four SSc patients (79.8% female, mean age 58.7 years) were enrolled. Applying the PDG formula, SSc patients revealed mean PDG values significantly lower than HC (1.82 ± 0.44 PU vs 2.70 ± 0.38 PU; p < 0.0001). Patients with a previous history of digital ulcers presented significant lower PDG values (p = 0.002). The ROC curve analysis identified in 2.28 PU the best PDG cut-off value between SSc and HC, with 86% sensibility and 90% specificity. CONCLUSION: This study provided a PDG formula generalizable to all kind of subjects, applying it in SSc with great sensibility and specificity using LASCA, the best non-invasive imaging technique for the dynamical evaluation of peripheral perfusion. LASCA-PDG appears also as a tool able to identify a subclinical microangiopathic impairment.

Screening rates and prevalence of osteoporosis in a real-world, Australian systemic sclerosis cohort.

AIM: Despite reports of decreased bone mineral density in patients with systemic sclerosis (SSc) in international cohorts, the prevalence of osteoporosis in Australian SSc patients remains unknown. We report rates of dual-energy X-ray absorptiometry (DXA) scanning in an SSc cohort at a tertiary hospital specialized outpatient clinic and the prevalence and associations of osteoporosis in screened patients. METHOD: We performed retrospective chart review to determine if patients underwent DXA scanning between 2007 and 2018 and extracted lumbar spine and femoral neck T-scores, fracture history, and osteoporosis therapy. RESULTS: Of 244 patients, 104 (42.6%) underwent DXA scanning and among patients in whom T-scores were available (n = 91), 30 (33.0%) had osteoporosis and 48 (52.7%) had osteopenia. Screened patients were more likely to have longer disease duration (19.9 vs 15.2 years, P = 0.002), calcinosis (50.5% vs 36.4%, P = 0.028), myositis (12.6% vs 0.7%, P < 0.001), synovitis (42.7% vs 28.6%, P = 0.022), ever used prednisolone (76.7% vs 47.1%, P < 0.001) or fractures (23.0% vs 0.0%, P < 0.001). Patients with osteoporosis more commonly had a history of nasogastric feeding, percutaneous endoscopic gastrostomy feeding or intravenous total parenteral nutrition (6.9% vs 0.0%, P = 0.038) and, unexpectedly, less commonly ever used prednisolone (58.6% vs 85.2%, P = 0.005) compared with patients with osteopenia or normal bone density. CONCLUSION: We identified high rates of osteoporosis among screened Australian SSc patients. Further assessment in larger, prospective studies is needed to establish guidelines for formal osteoporosis screening in SSc patients.

Autonomic Nervous System Indices in Patients with Systemic Sclerosis without Overt Cardiac Disease.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease. OBJECTIVES: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged. METHODS: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls. RESULTS: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups. CONCLUSIONS: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies.

Determinants of left ventricular structure, filling and long axis function in systemic sclerosis.

BACKGROUND: Abnormalities of left ventricular (LV) structure, filling and long-axis function have all been reported in subjects with systemic sclerosis (SSc) and a normal LV ejection fraction (EF), but previous study findings have not been consistent. The aim of this study was to identify factors which could have confounded the analyses in previous studies of SSc, and in particular to consider the variables of body surface area (BSA), sex, age, heart rate, blood pressure (BP), disease duration (DD), disease type (limited versus diffuse) and interstitial lung disease (ILD). METHODS: Echocardiography was performed on 100 subjects with SSc (79 women; age 56±15 years) with a LVEF ≥50% and free of pulmonary arterial hypertension, coronary artery disease, more than mild valvular heart disease and atrial fibrillation. Measurements were performed of the LV end-diastolic dimension (LVEDD) and septal wall thickness (SWT), the transmitral Doppler E, A and deceleration time (DT), and the peak systolic (s') and early diastolic (e') LV long-axis velocities. Multivariate analyses were performed to investigate correlations of the above LV variables with BSA, sex, age, heart rate, BP, DD, disease type, and the presence of ILD. RESULTS: DD varied between 0.1 and 41.2 years, 25% had diffuse and 75% had limited disease, and 37% had ILD. SWT and LVEDD were positively correlated with BSA, SWT was also positively correlated with age and larger in males, and LVEDD was larger in diffuse disease. Age was positively correlated with A and DT, and inversely correlated with E and E/A, and heart rate was inversely correlated with E and E/A. None of E, A, E/A, or DT were independently associated with DD or disease type. Septal and lateral LV wall s' and e' were all inversely correlated with age, and there was a small independent contribution to the prediction of lateral s' from DD, but no association of either s' or e' with disease type. The presence of ILD was not a predictor of any of the LV variables. CONCLUSION: In SSc there are associations of sex, body size, age and disease type with LV structural variables, of age and heart rate with E/A, and of age with both systolic and early diastolic LV long-axis velocities. Appropriate adjustment for these variables could help to resolve current uncertainties regarding SSc effects on the left ventricle.