The first composite score predicting Digital Ulcers in systemic sclerosis patients using Clinical data, Imaging and Patient history-CIP-DUS

Background: Digital ulcers (DU) present a challenging complication in systemic sclerosis (SSc). The aim of this study was to combine clinical characteristics and imaging methods to a composite score for the prediction of DU in SSc patients. Methods: Seventy-nine SSc patients received clinical examination, their patient history was taken and nailfold capillaroscopy (NC), colour Doppler ultrasonography (CDUS) and fluorescence optical imaging (FOI) of the hands were performed at baseline. Newly developed DU over a period of approximately 12 months were registered. We used criteria with area under the curve (AUC) of at least 0.6 in regard to the development of these new DU to create the score (CIP-DUS, clinical features, imaging, patient history-digital ulcer score). Results: Twenty-nine percent of all SSc patients developed new DU during follow-up (48.1% diffuse, 18.4% limited SSc). Based on the cross-validated (cv) AUC, a weight (cvAUC > 0.6 and ≤ 0.65: 1; cvAUC > 0.65 and ≤ 0.7: 2; cvAUC > 0.7: 3) was assigned to each selected parameter. The performance of the final CIP-DUS was assessed with and without the CDUS/FOI component. For the scleroderma patterns in NC, three points were appointed to late, two to active and one point to early capillaroscopy pattern according to Cutolo et al. The CIP-DUS including the CDUS and FOI parameters resulted in a good diagnostic performance (AUC after cross-validation: 0.83, 95%CI 0.74 to 0.92) and was well calibrated (chi-square = 12.3, p = 0.58). The cut-off associated with the maximum of sensitivity and specificity was estimated at ≥ 10 points resulting in a sensitivity of 100% and specificity of 74% for new DU during follow-up. Excluding CDUS and FOI parameters leads to a non-statistically significant lower performance (AUC after cross-validation: 0.81, 95%CI 0.72 to 0.91). However, including CDUS and FOI resulted in a better classification of patients in respect to the outcome new DU in follow-up due to significantly better reclassification performance (NRI = 62.1, p = 0.001) and discrimination improvement (IDI = 9.7, p = 0.01). Conclusion: A new score was introduced with the aim to predict digital ulcers. If applied correctly and with the new imaging techniques proposed, all patients at risk of digital ulcers throughout 12 months could be identified

Monitoring of patients with rheumatoid arthritis by indocyanine green (ICG)-enhanced fluorescence optical imaging treated with anti-TNFα therapy

Background: Fluorescence optical imaging (FOI) enables visualisation of inflammation in both hands in rheumatoid arthritis (RA). Objective: To investigate the usefulness of FOI in treatment monitoring under anti-TNF alpha therapy with certolizumab pegol (CZP) in patients with RA in comparison to clinical and laboratory outcome parameters. Methods: CZP-naive patients with RA were eligible for this open-label study with an observational period of 52 weeks. Disease activity was monitored by the clinical score DAS28, tender/swollen joint count (TJC-28/SJC-28) and laboratory outcomes for systemic inflammation (CRP and ESR). FOI results were analysed in three different phases (P1-3) and PrimaVistaMode (PVM) by the FOI activity score (FOIAS). Results: Twenty-eight RA patients (median age 52.5 years, 26 females, thirteen with a history of other biologic therapy) were included. DAS28 (CRP) decreased from moderate disease activity at baseline (median 4.6, IQR 1.8) to low disease activity at week (w)52 (median 2.7, IQR 2.1; p < 0.001). Statistically significant decreases could also be demonstrated for SJC-28 and TJC-28. CRP/ESR were reduced numerically from baseline to w52. FOIAS in P1 (early phase) showed a continuous decrease of enhancement during the course of treatment period: from baseline (median 1.5, IQR 9.3) over w6 (median 1.0, IQR 3.0; p= 0.069), w12 (median 0.5, IQR 3.0; p = 0.171), w24 (n = 27 , median 0.0, IQR 3.0; p = 0.004), until w52 (n= 18, median 0.0, IQR 2.8; p = 0.091), which could not be presented for FOIAS in P2, P3 and PVM. Conclusion: FOI in P1 appears to be a valuable tool for fast and easy monitoring of treatment response to certolizumab in a clinical setting

Oral anticoagulants (NOAC and VKA) in chronic thromboembolic pulmonary hypertension

EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH

Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients

Objective: Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. Design: Prospective cohort study with a 4.5-year follow-up period. Methods: From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. Results: At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m2. No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2–Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2–Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33–0.74; adjusted HR 0.62, 95% CI 0.42–0.939; CV events: Q2–Q5 versus Q1: crude HR 0.54, 95% CI 0.38–0.77; adjusted HR 0.68, 95% CI 0.48–0.97). Kaplan–Meier curves revealed similar data. Conclusions: Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population

GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

A survey of national and multi-national registries and cohort studies in juvenile idiopathic arthritis: Challenges and opportunities

Background: To characterize the existing national and multi-national registries and cohort studies in juvenile idiopathic arthritis (JIA) and identify differences as well as areas of potential future collaboration. Methods: We surveyed investigators from North America, Europe, and Australia about existing JIA cohort studies and registries. We excluded cross-sectional studies. We captured information about study design, duration, location, inclusion criteria, data elements and collection methods. Results: We received survey results from 18 studies, including 11 national and 7 multi-national studies representing 37 countries in total. Study designs included inception cohorts, prevalent disease cohorts, and new treatment cohorts (several of which contribute to pharmacosurveillance activities). Despite numerous differences, the data elements collected across the studies was quite similar, with most studies collecting at least 5 of the 6 American College of Rheumatology core set variables and the data needed to calculate the 3-variable clinical juvenile disease activity score. Most studies were collecting medication initiation and discontinuation dates and were attempting to capture serious adverse events. Conclusion: There is a wide-range of large, ongoing JIA registries and cohort studies around the world. Our survey results indicate significant potential for future collaborative work using data from different studies and both combined and comparative analyses

Differences sustained between diffuse and limited forms of juvenile systemic sclerosis in expanded international cohort. www.juvenile-scleroderma.com

OBJECTIVES: To evaluate the baseline clinical characteristics of juvenile systemic sclerosis (jSSc) patients in the international Juvenile SSc Inception Cohort (jSScC), compare these characteristics between the classically defined diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes, and among those with overlap features. METHODS: A cross-sectional study was performed using baseline visit data. Demographic, organ system evaluation, treatment, and patient and physician reported outcomes were extracted and summary statistics applied. Comparisons between dcjSSc and lcSSc subtypes and patients with and without overlap features were performed using Chi-square and Mann Whitney U-tests. RESULTS: At data extraction 150 jSSc patients were enrolled across 42 centers, 83% were Caucasian, 80% female, dcjSSc predominated (72%), and 17% of the cohort had overlap features. Significant differences were found between dcjSSc and lcjSSc regarding the modified Rodnan Skin Score, presence of Gottron's papules, digital tip ulceration, 6 Minute walk test, composite pulmonary and cardiac involvement. All more frequent in dcSSc except for cardiac involvement. DcjSSc patients had significantly worse scores for physician rated disease activity and damage. A significantly higher occurrence of Gottron's papules, musculoskeletal involvement and composite pulmonary involvement, and significantly lower frequency of Raynaud's phenomenon, were seen in those with overlap features. CONCLUSION: Results from a large international jSSc cohort demonstrate significant differences between dcjSSc and lcjSSc patients including more globally severe disease and increased frequency of ILD in dcjSSc patients, while those with lcSSc have more frequent cardiac involvement. Those with overlap features had an unexpected higher frequency of interstitial lung disease

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified