Analysis of nailfold capillaroscopy images with artificial intelligence: Data from literature and performance of machine learning and deep learning from images acquired in the SCLEROCAP study.

OBJECTIVE: To evaluate the performance of machine learning and then deep learning to detect a systemic scleroderma (SSc) landscape from the same set of nailfold capillaroscopy (NC) images from the French prospective multicenter observational study SCLEROCAP. METHODS: NC images from the first 100 SCLEROCAP patients were analyzed to assess the performance of machine learning and then deep learning in identifying the SSc landscape, the NC images having previously been independently and consensually labeled by expert clinicians. Images were divided into a training set (70 %) and a validation set (30 %). After features extraction from the NC images, we tested six classifiers (random forests (RF), support vector machine (SVM), logistic regression (LR), light gradient boosting (LGB), extreme gradient boosting (XGB), K-nearest neighbors (KNN)) on the training set with five different combinations of the images. The performance of each classifier was evaluated by the F1 score. In the deep learning section, we tested three pre-trained models from the TIMM library (ResNet-18, DenseNet-121 and VGG-16) on raw NC images after applying image augmentation methods. RESULTS: With machine learning, performance ranged from 0.60 to 0.73 for each variable, with Hu and Haralick moments being the most discriminating. Performance was highest with the RF, LGB and XGB models (F1 scores: 0.75-0.79). The highest score was obtained by combining all variables and using the LGB model (F1 score: 0.79 ± 0.05, p < 0.01). With deep learning, performance reached a minimum accuracy of 0.87. The best results were obtained with the DenseNet-121 model (accuracy 0.94 ± 0.02, F1 score 0.94 ± 0.02, AUC 0.95 ± 0.03) as compared to ResNet-18 (accuracy 0.87 ± 0.04, F1 score 0.85 ± 0.03, AUC 0.87 ± 0.04) and VGG-16 (accuracy 0.90 ± 0.03, F1 score 0.91 ± 0.02, AUC 0.91 ± 0.04). CONCLUSION: By using machine learning and then deep learning on the same set of labeled NC images from the SCLEROCAP study, the highest performances to detect SSc landscape were obtained with deep learning and in particular DenseNet-121. This pre-trained model could therefore be used to automatically interpret NC images in case of suspected SSc. This result nevertheless needs to be confirmed on a larger number of NC images.

Comorbidity burden on mortality in patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a serious life-threatening tissue disease. A significant aspect of its mortality arises from comorbid conditions. Our study aimed at mapping out the prevalence of these comorbidities and their relation to mortality, thus creating a 'comorbidome'. METHODS: In our retrospective, single-centre observational study, we recorded each patient's data, including demographic informations, vital stats and SSc-related organ involvement, along with the presence or absence of 14 predefined comorbidities. We also documented the dates of their initial and most recent visits. To construct survival curves, we used the Kaplan-Meier method, followed by a Cox regression model for multivariate analysis. RESULTS: Our study involved 400 participants, 74 of whom unfortunately passed away. It is important to note that three specific comorbidities showed significant correlation to mortality: neoplasia, cardiovascular diseases and polypharmacy, as well as two SSc-specific organ involvements (lung and cardiac). CONCLUSION: Our research led to the successful creation of the SSc comorbidome. Comorbidities are a major concern for patients suffering from SSc, particularly cardiovascular diseases and neoplasms. Our study highlights the effects of polypharmacy. The resultant comorbidome offers a comprehensive and analytical perspective on this complex issue and underscores the inter-relatedness of the data. Our study, however, was limited by a small sample size. Therefore, to confirm our findings, validation on a larger scale is necessary. This could potentially contribute to the creation of a future mortality scoring tool.

Digital ulcers in systemic sclerosis are strongly associated with digital arterial disease: a finger-by-finger analysis of Finger Brachial Pressure Index Measurements.

OBJECTIVES: The digital ulcers of systemic sclerosis are disabling and frequent· Their pathogenesis involves a capillary microangiopathy and a digital arterial disease that few studies were able to quantify up to now. A multicentre observational study about the predictive value of capillaroscopy in systemic sclerosis offered us the opportunity to evaluate further the complementary information provided by both capillary and arterial evaluations. METHODS: During the SCLEROCAP study, five out of the nine centers performed a systematic evaluation of the finger brachial pressure index (FBPI) in the last four fingers of both hands at baseline, using the same laser-doppler device. In the present work, FBPI measurements were compared between fingers with vs without digital ulcers or scars, before and after adjusting for the capillaroscopic pattern and systemic factors. RESULTS: FBPI measurements were performed in 2537 fingers from 326 patients. Active ulcers or scars were found in 10·8% of those fingers, more often on the right hand, and in the second and third fingers. FBPI was lower than 0·70 in 26% of all fingers and in 57·5% of those with ulcers. A strong association was found between a low FBPI and the presence of digital ulcers, even after adjusting for capillaroscopic pattern, ulcer location and the patient himself. CONCLUSION: These results confirm the importance of digital arterial disease in the pathogenesis of digital ulcers of systemic sclerosis, which is independent from the microangiopathy. FBPI measurements complement the information provided by capillaroscopy and might have an important predictive value for subsequent digital ulcers.

Influenza vaccination coverage and determinants of vaccination in peripheral arterial disease patients.

Background: In the latest American Heart Association guidelines, influenza vaccination is recommended for patients with peripheral arterial disease (PAD). The vaccination coverage in this specific population is currently unknown. This study aims to determine the adherence to influenza vaccination in a PAD population and identify associated determinants. Patients and methods. Hospitalized patients and outpatients with PAD from two university departments of vascular medicine were prospectively included. A questionnaire was administered to collect sociodemographic data, cardiovascular risk factors, influenza vaccination status, history of cardiovascular disease, and perception and knowledge about vaccination. Logistic regression was conducted to assess vaccination determinants. Results: Over a six-month period, 494 patients were included (median age 69.5, IQR [63-77], 78% male). Overall, 60.1% were either vaccinated or intended to be (Group 1). Vaccination was associated with age (odds-ratio [OR]=1.055, 95% confidence intervals [95%CI]: 1.035-1.075, p<0.0001), abdominal aorta aneurysm (OR=0.390, 95%CI: 0.229-0.664, p=0.001), chronic obstructive pulmonary disease (OR=0.545, 95%CI: 0.367-0.810, p=0.003), chronic renal disease (OR=0.630, 95%CI: 0.400-0.993, p=0.046), and valvulopathy (OR=2.444, 95%CI: 1.122-5.326, p=0.025). Only 25.3% received vaccination information mainly from their general practitioners. Among patients against vaccination, 59.9% considered themselves not concerned about potential influenza consequences on their PAD, and 37.6% did not intend to change their decision. Conclusions: This study highlights the low adherence to influenza vaccination in the PAD population of 2 university hospital centers. Vaccination is often related to age, and there is a need for adapted information regarding influenza consequences on cardiovascular disease overall, particularly on PAD. Addressing common information and advice about vaccination will be a challenge.

Update About the Management of Low-Density Lipoprotein Cholesterol and Hypertriglyceridemia in Lower Extremity Peripheral Artery Disease Patients: Consensus of the French Society of Vascular Medicine and the French Society for Vascular and Endovascular Surgery.

BACKGROUND: A French intersociety consensus on behalf the Société Française de Médecine Vasculaire and the Société de Chirurgie Vasculaire et Endovasculaire was proposed in 2021 for the management of patients with lower extremity peripheral artery disease (LEAD). Recent studies have been published and an update of this consensus about the management of low-density lipoprotein cholesterol (LDLc) and hypertriglyceridemia was required. METHODS: A steering committee of 12 vascular physicians and surgeons defined questions of interest about LDLc and hypertriglyceridemia management. A French expert panel voted the proposals. Consensus was considered to have been achieved if more than 80% of the responses corresponded to either "Agreement" or "Disagreement". RESULTS: Among the 56 experts who were asked to participate, 46 (82%) accepted. After the first round of the Delphi procedure, the 4 proposals reached consensus. The following suggestions and recommendations were approved: 1. For LEAD patients treated by the highest tolerated statin dose ± ezetimibe and who have an LDLc ≥0.70 g/L, we recommend adding a proprotein convertase subtilisin/kexin type 9 inhibitor. 2. For LEAD patients treated by statin and who have elevated triglyceride level between ≥150 mg/dL and ≤500 mg/dL, we suggest adding Icosapent Ethyl. 3. Before adding Icosapent Ethyl in LEAD patients treated with statin, we suggest looking for symptoms that may suggest atrial fibrillation. 4. For LEAD patients treated by Icosapent Ethyl and who have symptoms that suggest atrial fibrillation, we recommend performing an electrocardiogram. CONCLUSIONS: This update will help clinicians to improve LEAD patient management.

Venous dysfunction in obstructive hypertrophic cardiomyopathies: Results from the "HCM-Vein" pilot study.

Background: Hypertrophic cardiomyopathies (HCM) can be complicated by left ventricular outflow-tract obstruction (LVOTO) responsible for disabling exercise symptoms, a phenomenon influenced by hemodynamic factors including venous return. Methods: We aimed to evaluate venous dysfunction in obstructive HCM patients compared to healthy controls, and to investigate the relationship between venous dysfunction parameters and LVOTO in HCM. This is a clinical, monocentric, prospective, pilot study, in a tertiary care center. We investigated venous function using venous air plethysmography, and endothelial function. Results: Among the 30 symptomatic obstructive HCM patients, 30% (n = 9) presented abnormal venous residual volume fraction (RVFv) which translates in elevated ambulatory venous pressure vs. 0% in the 10 healthy controls (p < 0.05). Comparing obstructive HCM patients with abnormal RVFv (n = 9) to other obstructive HCM patients with normal RVFv (n = 21), there were no significant differences in terms of age, sex (67% male), and classical echocardiographic parameters both at rest and during exercise, except for left ventricular end-diastolic volume index which was significantly lower in the group with abnormal RVFv compared to the other HCM patients (40.1 ± 9.0 ml/m2 vs. 50.2 ± 10.6 ml/m2, p = 0.01). Fifty six percent of obstructive HCM patients with abnormal RVFv had an absolute increase in Willebrand factor (vs. 26% of other obstructive HCM patients, p < 0.05). Conclusions: In this pilot monocentric study, venous insufficiency was observed in about 30% of symptomatic obstructive HCM patients. Patients with venous insufficiency had more frequently a smaller LV cavity volume. Due to the small sample size, this study is only hypothesis-generating, and further investigations are needed.

Clinical and immunological features of patients with cancer-associated systemic sclerosis: An observational study.

INTRODUCTION: Clinical and immunological features of patients with cancer-associated systemic sclerosis: an observational study. OBJECTIVE: Several studies have reported an increased incidence of cancer in patients with systemic sclerosis (SSc). The presence of RNA polymerase III antibodies (anti-RNA Pol 3) associates with an increased risk of cancer, but other risk factors need yet to be identified. We aimed to assess clinical and immunological predictive factors of cancer-associated SSc to guide clinicians when setting up selective cancer screening. METHODS: We conducted a monocentric, retrospective, observational study of SSc patients with and without associated malignancy. Clinical, laboratory and imaging data were collected, as well as SSc treatment. Subgroup analyses were performed according to the type of cancer and the time of diagnosis. RESULTS: Of 464 SSc patients, 74 (16%) had cancer, with breast (n=26) and lung cancer (n=13) being the most frequent. Diagnosis of cancer was made less than 3 years before or after SSc diagnosis for 23 patients (31%). In a multivariate analysis, anti-RNA Pol 3 and anti-SSA antibodies were significantly associated with an increased overall risk of cancer with an odds ratio (OR) of 4.12 (95% CI [1.6-10.7]; P<0.01) and 2.43 (95% CI [1.1-5.4]; P<0.05), respectively. Age at diagnosis of SSc and delay from the SSc diagnosis were also independent risk factors of cancer. Interstitial lung disease and anti-topoisomerase antibodies were associated with an increased risk of lung cancer and cancer occuring more than three years after SSc diagnosis. CONCLUSION: In addition to anti-RNA Pol 3 antibodies, anti-SSA antibodies associated with an increased risk of cancer in SSc patients. Interstitial lung disease was a risk factor specifically for lung cancer and cancers diagnosed more than 3 years after SSc diagnosis. For these patients, a systematic and regular cancer screening should be considered.

Quality of life in SSc-ILD patients: Understanding the impact of the ILD and the needs of the SSc-ILD patients and their need for caregivers in France.

Objectives: The objectives of this study were to describe the impact of systemic sclerosis associated interstitial lung disease, on quality of life, to estimate the correlation between quality of life and severity of lung disease and to assess the impact of interstitial lung disease on caregivers. Methods: Seven investigators included systemic sclerosis associated interstitial lung disease patients from December 2019 to April 2020. Sociodemographics and clinical data were collected. Patients reported outcomes and questionnaires were used with 1 generic patients reported outcome (EQ-5D-5L), 1 specific PRO (Brief Interstitial Lung Disease) and 2 self-reported questionnaires on impact of SSc complications and impact on caregivers. The correlation between forced vital capacity and EQ-5D-5L score was estimated with a multivariate linear regression model adjusted on several covariates. Results: In all, 89 patients were included. 26.4% were males, mean age was 58.2 ± 14.5 years. Mean EQ-5D-5L score = 0.79 ± 0.22 (median = 0.85). Mean EQ-5D-5L visual analog scale score = 60.8 ± 20.4 (median = 61.5). Mean King's Brief Interstitial Lung Disease score = 58.4 ± 12.7 (median = 58.0). After adjustment on covariates, a significant correlation between forced vital capacity and EQ-5D-5L score was found with an increase of 0.003 of the EQ-5D-5L score for a 1% increase of FVC (p = 0.0096). No significant correlation between forced vital capacity and the EQ-VAS and King's Brief Interstitial Lung Disease score were found. The impact of SSc on other organs was significantly correlated with EQ- 5D-5L score, respectively, for the impact scores on the lung system (p = 0.0003), heart system (p = 0.0182), Raynaud's syndrome (p = 0.0015), digestive system (p = 0.0032), joints/muscles (p = 0.0003), skin (p < 0.0001), kidney (p = 0.0052) and gastro-oesophageal reflux (p = 0.0063). Significant correlations between King's Brief Interstitial Lung Disease score and lung system (p < 0.0001), heart system (p < 0.0001), digital ulcers (p = 0.058), digestive system (p < 0.0001), kidney (p = 0.0004), skin (p = 0.0499) and gastro-oesophageal reflux (p = 0.0033) scores were found 68.5% of patients reported their need for a caregiver to help them in their daily life activities. Conclusion: Our study highlighted the strong burden of systemic sclerosis associated interstitial lung disease` for patients, especially with an impact on quality of life, on other organs manifestations and need for caregivers in their daily life.

Correlation of nailfold capillaroscopy findings with history of digital ulcer on same finger: Results of SCLEROCAP study.

Systemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger. METHOD: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed. RESULTS: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85]. CONCLUSION: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.

Mortality, Cardiovascular and Limb Events in Patients With Symptomatic Lower Extremity Artery Disease and Diabetes.

The aim of this study was to compare the prognosis of patients according to diabetes status, during a 1-year follow-up after hospital admission for lower extremity artery disease, in the prospective COPART (COhorte de Patients ARTériopathes) registry. Inclusion criteria were intermittent claudication, ischemic rest pain, tissue loss, or acute limb ischemia, with radiological and hemodynamic confirmation. Among 2494 patients, 1235 (49.5%) had diabetes. Incidence rates for major adverse cardiovascular events (MACE) were 18.0/100 person-years (95% confidence interval [CI], 15.4-21.0) for the diabetes group and 11.1/100 person-years (95% CI, 9.2-13.4) for the non-diabetes group. Incidence rates of all-cause mortality were 29.8/100 person-years (95% CI, 26.5-33.4) for the diabetes group and 19.7/100 person-years (95% CI, 17.2-22.7) for the non-diabetes group. Incidence rates of major limb amputation were 24.2/100 person-years (95% CI, 21.1-27.8) for the diabetes group and 11.6/100 person-years (95% CI, 9.6-14.0) for the non-diabetes group. Diabetes was associated with MACE, adjusted hazard ratio 1.60 (95% CI, 1.16-2.22), and all-cause mortality, unadjusted HR 1.49 (95% CI, 1.24-1.78). In the multivariate analysis, diabetes was no longer associated with major amputation, adjusted HR 1.15 (95% CI, .87-1.51). Patients hospitalized for LEAD with diabetes had a higher risk of MACE than those without diabetes.

Toe Pressure Measurements in Patients Suspected of Critical Limb Ischemia.

An objective hemodynamic assessment is mandatory to confirm Critical Limb Ischemia (CLI). Toe pressure measurement is recommended. We compared toe measurements obtained using the Laser Doppler method (LD) (PERIMED PeriFlux, Sweden) considered as the reference test, with those obtained with a portable device using photoplethysmography (PPG) (Sys Toe Atys Medical, France). A total of 93 (123 legs) patients from 3 French hospitals with a clinical suspicion of CLI were included and had measurements with each device carried out by skilled operators. PPG was unable to provide a measurement in 10 patients. Lin's Coefficient correlation concordance (CCC) and Bland and Altman's scatter plot were analyzed for the 83 remaining patients, CCC was .84 95%CI (.77-.89). For detection of CLI, Cohen's kappa was .67 95%CI (.53-.81). The PPG device is fairly reliable for toe pressure measurement in patients suspected of CLI and could be useful when LD is not available. However, it fails to deliver a measurement in approximately 10% of cases. No conclusion should be made about CLI for these patients when no measurement is obtainable and other methods should be used (LD, transcutaneous oxygen pressure) to assess perfusion of the limbs.

Interleukin-1ß-Activated Microvascular Endothelial Cells Promote DC-SIGN-Positive Alternatively Activated Macrophages as a Mechanism of Skin Fibrosis in Systemic Sclerosis.

OBJECTIVE: To characterize the role of interleukin-1ß (IL-1ß) and microvascular endothelial cells (MVECs) in the generation of alternatively activated macrophages in the skin, and to explore their role in the development of skin fibrosis in patients with systemic sclerosis (SSc; scleroderma). METHODS: Conditioned medium prepared with MVECs purified from the skin of healthy donors and the skin of SSc patients was used to generate monocyte-derived macrophages. Flow cytometry, multiplex protein assessment, real-time quantitative polymerase chain reaction, and tissue immunofluorescence were used to characterize MVEC-induced polarization of alternatively activated macrophages. Coculture experiments were conducted to assess the role of MVEC-induced alternatively activated macrophages in fibroblast activation. Alternatively activated macrophages were characterized in the skin of healthy donors and SSc patients using multiparametric immunofluorescence and multiplex immunostaining for gene expression. Based on our in vitro data, we defined a supervised macrophage gene signature score to assess correlation between the macrophage score and clinical features in patients with SSc, using the Spearman's test. RESULTS: IL-1ß-activated MVECs from SSc patients induced monocytes to differentiate into DC-SIGN+ alternatively activated macrophages producing high levels of CCL18, CCL2, and CXCL8 but low levels of IL-10. DC-SIGN+ alternatively activated macrophages showed significant enhancing effects in promoting the production of proinflammatory fibroblasts and were found to be enriched in perivascular regions of the skin of SSc patients who had a high fibrosis severity score. A novel skin transcriptomic macrophage signature, defined from our in vitro findings, correlated with the extent of skin fibrosis (Spearman's r = 0.6, P = 0.0018) and was associated with early disease manifestations and lung involvement in patients with SSc. CONCLUSION: Our findings shed new light on the vicious circle implicating unabated IL-1ß secretion, MVEC activation, and the generation of DC-SIGN+ alternatively activated macrophages in the development of skin fibrosis in patients with SSc.

Rivaroxaban vs Dalteparin in Cancer-Associated Thromboembolism: A Randomized Trial.

BACKGROUND: Direct oral anticoagulants (DOACs) are an alternative to low-molecular-weight heparin for treating cancer-associated VTE. RESEARCH QUESTION: Is rivaroxaban as efficient and safe as dalteparin to treat patients with cancer-associated VTE? STUDY DESIGN AND METHODS: In a randomized open-label noninferiority trial, patients with active cancer who had proximal DVT, pulmonary embolism (PE), or both were assigned randomly to therapeutic doses of rivaroxaban or dalteparin for 3 months. The primary outcome was the cumulative incidence of recurrent VTE, a composite of symptomatic or incidental DVT or PE, and worsening of pulmonary vascular or venous obstruction at 3 months. RESULTS: Of 158 randomized patients, 74 and 84 patients were assigned to receive rivaroxaban and dalteparin, respectively. Mean age was 69.4 years, and 115 patients (76.2%) had metastatic disease. The primary outcome occurred in 4 and 6 patients in the rivaroxaban and dalteparin groups, respectively (both the intention-to-treat and per-protocol populations: cumulative incidence, 6.4% vs 10.1%; subdistribution hazard ratio [SHR], 0.75; 95% CI, 0.21-2.66). Major bleeding occurred in 1 and 3 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 1.4% vs 3.7%; SHR, 0.36; 95% CI, 0.04-3.43). Major or clinically relevant nonmajor bleeding occurred in 9 and 8 patients in the rivaroxaban and dalteparin groups, respectively (cumulative incidence, 12.2% vs 9.8%; SHR, 1.27; 95% CI, 0.49-3.26). Overall, 19 patients (25.7%) and 20 patients (23.8%) died in the rivaroxaban and dalteparin groups, respectively (hazard ratio, 1.05; 95% CI, 0.56-1.97). INTERPRETATION: In this trial comparing rivaroxaban and dalteparin in the treatment of cancer-associated VTE, the number of patients was insufficient to reach the predefined criteria for noninferiority, but efficacy and safety results were consistent with those previously reported with DOACs. An updated meta-analysis of randomized trials comparing DOACs with low-molecular-weight heparin in patients with cancer-associated VTE is provided. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02746185; URL: www. CLINICALTRIALS: gov.

Finger Systolic Blood Pressure Index Measurement: A Useful Tool for the Evaluation of Arterial Disease in Patients With Systemic Sclerosis.

OBJECTIVE: To evaluate the prevalence and clinical correlates of peripheral arterial disease of the upper limbs in patients with systemic sclerosis (SSc), as detected with finger brachial pressure index (FBPI) measurements. METHODS: This work is based on the baseline data of the SCLEROCAP multicenter cohort of SSc patients. Finger systolic blood pressure was measured with laser Doppler flowmetry, and the FBPI was obtained as its ratio over the ipsilateral brachial systolic blood pressure. An FBPI of <0.70 was used as the diagnostic criterion for occlusive arterial disease of the upper limbs. Thus, the prevalence of defined arterial disease as well as its clinical, biologic, and capillaroscopic correlates were evaluated. RESULTS: Among 326 enrolled patients, 177 (54.3%) met the criterion for arterial disease (FBPI <0.70). No association was found with the type of SSc nor with the type of associated antinuclear antibodies, but a significant association was found with the duration of the disease (P < 0.001), the capillaroscopic pattern (P < 0.001), and most strikingly with the presence of digital ulcers (42.9% versus 13.4%; P < 0.001). A quantitative relationship was found between the FBPI and the prevalence of digital ulcers and was shown to be independent from the capillaroscopic pattern. CONCLUSION: This cross-sectional study shows a high prevalence of arterial disease of the upper limbs in patients with SSc. FBPI appears to be a strong and independent predictor of digital ulcers. This study suggests that both macro- and microangiopathy are contributing to the ischemic damage of the fingertips.

The prognostic value of respiratory symptoms and performance status in ambulatory cancer patients and unsuspected pulmonary embolism; analysis of an international, prospective, observational cohort study.

BACKGROUND: Optimal risk stratification of unsuspected pulmonary embolism (UPE) in ambulatory cancer patients (ACPs) remains unclear. Existing clinical predictive rules (CPRs) are derived from retrospective databases and have limitations. The UPE registry is a prospective international registry with pre-specified characteristics of ACPs with a recent UPE. The aim of this study was to assess the utility of risk factors captured in the UPE registry in predicting proximate (30-, 90- and 180-day) mortality and how they performed when applied to an existing CPR. OBJECTIVES: To evaluate risk factors for proximate mortality, overall survival, recurrent venous thromboembolism and major bleeding, in the patients enrolled in the UPE registry cohort. METHODS: Data from the 695 ACPs in this registry were subjected to multivariate logistic regression analyses to identify predictors independently associated with proximate mortality and overall survival. The most consistent predictors were applied to the Hull CPR, an existing 5-point prediction rule. RESULTS: The most consistent predictors of mortality were patient-reported respiratory symptoms within 14 days before, and ECOG performance status at the time of UPE. These predictors applied to the Hull-CPR produced a consistent correlation with proximate mortality and overall survival (area under the curve [AUC] = 0.70 [95% CI 0.63, 077], AUC = 0.65 [95% CI 0.60, 070], AUC = 0.64 [95% CI 0.59, 068], and AUC = 0.61, 95% CI 0.57, 0.65, respectively). CONCLUSION: In ACPs with UPE, ECOG performance status logged contemporaneously to the UPE diagnosis and respiratory symptoms prior to UPE diagnosis can stratify mortality risk. When applied to the HULL-CPR these risk predictors confirmed the risk stratification clusters of low-intermediate and high-risk for proximate mortality as seen in the original derivation cohort.

French recommendations for the management of systemic sclerosis.

Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis.

Editor's Choice - External Applicability of the COMPASS and VOYAGER-PAD Trials on Patients with Symptomatic Lower Extremity Artery Disease in France: The COPART Registry.

OBJECTIVE: The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world. METHODS: This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models. RESULTS: Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 - 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 - 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 - 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 - 6.9) in the VOYAGER-PAD control arm for major adverse limb events. CONCLUSION: Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials.

TGFß promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis.

OBJECTIVE: Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc). METHODS: Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc. RESULTS: We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1- ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-ß (TGFß), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFß-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis. CONCLUSION: Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFß and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc.