The Efficacy of Sequential Biologic Agents in Refractory Rheumatoid Arthritis After Failure of Initial DMARD and Anti-Tumor Necrosis Factor Therapy

Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease

Emerging Evidence and Treatment Perspectives from Randomized Clinical Trials in Systemic Sclerosis: Focus on Interstitial Lung Disease

Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD

The COVID-19 Assessment for Survival at Admission (CASA) Index: A 12 Months Observational Study

Objective: Coronavirus disease 2019 (COVID-19) is a disease with a high rate of progression to critical illness. However, the stratification of patients at risk of mortality is not well defined. In this study, we aimed to define a mortality risk index to allocate patients to the appropriate intensity of care. Methods: This is a 12 months observational longitudinal study designed to develop and validate a pragmatic mortality risk score to stratify COVID-19 patients aged ≥18 years and admitted to hospital between March 2020 and March 2021. Main outcome was in-hospital mortality. Results: 244 patients were included in the study (mortality rate 29.9%). The Covid-19 Assessment for Survival at Admission (CASA) index included seven variables readily available at admission: respiratory rate, troponin, albumin, CKD-EPI, white blood cell count, D-dimer, Pa02/Fi02. The CASA index showed high discrimination for mortality with an AUC of 0.91 (sensitivity 98.6%; specificity 69%) and a better performance compared to SOFA (AUC = 0.76), age (AUC = 0.76) and 4C mortality (AUC = 0.82). The cut-off identified (11.994) for CASA index showed a negative predictive value of 99.16% and a positive predictive value of 57.58%. Conclusions: A quick and readily available index has been identified to help clinicians stratify COVID-19 patients according to the appropriate intensity of care and minimize hospital admission to patients at high risk of mortality

Design and implementation of a seismic Newtonian-noise cancellation system for the Virgo gravitational-wave detector

Terrestrial gravity perturbations caused by seismic fields produce the so-called Newtonian noise in gravitational-wave detectors, which is predicted to limit their sensitivity in the upcoming observing runs. In the past, this noise was seen as an infrastructural limitation, i.e., something that cannot be overcome without major investments to improve a detector's infrastructure. However, it is possible to have at least an indirect estimate of this noise by using the data from a large number of seismometers deployed around a detector's suspended test masses. The noise estimate can be subtracted from the gravitational-wave data; a process called Newtonian-noise cancellation (NNC). In this article, we present the design and implementation of the first NNC system at the Virgo detector as part of its AdV+ upgrade. It uses data from 110 vertical geophones deployed inside the Virgo buildings in optimized array configurations. We use a separate tiltmeter channel to test the pipeline in a proof-of-principle. The system has been running with good performance over months

Analysis methods for gravitational wave from binary neutron star coalescences: investigation on the post-merger phase

The coalescence of binary neutron stars (BNS) is amongst the most promising sources for advanced gravitational wave (GW) detectors. The forthcoming addition of the advanced Virgo interferometer to the LIGO detector network will greatly improve the estimation of GW characteristics and therefore the capabilities to test features in the GW signal emitted by the coalescence of a NS binary. Such an observation can constrain the equation of state of these stars in at least two ways: by investigating smaller effects on top of the signal from the inspiral phase due to the tidal deformability of the components and by characterizing the emission from the possible highly excited NS remnant after the merger. Both methods promise to probe matter up to yet unknown and unexplored supranuclear densities, provided that the signal-to-noise ratio (SNR) at which the single GW is detected is sufficiently high or that the results from more detections can be combined together. Depending on mass and Equation of State (EoS) of the NS progenitors, the final fate of the merger can produce either a prompt collapse to black hole (BH) or a massive NS remnant. In the latter case, the merger remnant could be a short-lived, hypermassive NS (HMNS) collapsing to a BH within a few tens of ms after merger, or a long-lived NS, which in turn can be either supramassive (SMNS), i.e. collapsing to a BH on much longer timescales of order of seconds, or even a stable NS. These remnants will be highly excited, showing transient nonaxisymmetric deformations and quadrupolar oscillations, which are expected to emit GWs peaked in the frequency range around 2-3 kHz. The observation of these Post Merger (PM) fingerprints, would allow to constrain the EoS and at the same time to estimate combinations of stellar parameters, such as mass and radius of the two objects. With these motivations, my PhD thesis addressed the development of a new data analysis tool in order to investigate the GW signal emitted during the PM phase following a NS coalescence. The analysis procedure is developed inside the framework of the Coherent Wave Burst (cWB) pipeline which is employed by LIGO and Virgo collaboration to search for burst signals, i.e. it makes minimal assumption on the GW morphology and provides a robust coverage of generic GW transients

The Efficacy of Sequential Biologic Agents in Refractory Rheumatoid Arthritis after Failure of Initial DMARD and anti-Tumor Necrosis Factor Therapy

Introduction/Objective: The efficacy of biologic therapy in the treatment of rheumatoid arthritis (RA) has been well-established but, in practice, a quarter of patients will either not respond to the first biologic agent or will suffer an adverse event requiring a switch to a different drug. While clinical guidelines exist to help guide therapy and previous studies have examined sequential use of anti-TNF agents, there is little data to inform a multiple switch strategy. Our aim was to measure the efficacy of multiple switches of biologic in severe refractory RA. Methods: We enrolled 111 patients whose therapy with one anti-TNF agent had failed in this open-label observational study. These patients were all treated with a second biologic agent and 27 ultimately required treatment with a third. The response to the therapy and disease activity were assessed at 6 and 12 months after each switch. Results: The remission rates at 6 months were lower than previously reported and the initiation of a second biologic agent resulted in significant improvement at 12 months, including DAS remission in 36% of patients. The response in those receiving a third biologic was less pronounced, as might be expected in this relatively treatment-refractory population. In this group, only patients treated with tocilizumab had maintained remission at one year. Conclusion: Patients who do not respond to an anti-TNF agent often benefit from being switched to a second, or even third, biologic. Importantly, it may take longer than expected to fully assess the effectiveness of a second or third agent in patients with refractory disease

Study of the cosmic muon rate nearby the Advanced Virgo detector at the end of the O3 run

International audienceCosmic-ray particles have long been studied as a potential source of noise for interferometric gravitational-wave detectors. These particles, mostly muons at sea level, can interact with the detector mirrors inducing thermal effects, which, at the detector output, could be observed as transient excesses of noise, namely glitches. For the Advanced Virgo detector, the rate of these particles is monitored by a muon telescope located in the vicinity of the detector central building. We present here the correlation study of the rate of muons with the rate of glitches during a couple of weeks at the end of the third joint LIGO-Virgo observing, O3. We also present the correlation of the previous quantities with other environmental effects, showing how the latter dominate the glitch rate and can explain a significant part of its variations

Adaptive algorithms for low-latency cancellation of seismic Newtonian-noise at the Virgo gravitational-wave detector

International audienceA system was recently implemented in the Virgo detector to cancel noise in its data produced by seismic waves directly coupling with the suspended test masses through gravitational interaction. The data from seismometers are being filtered to produce a coherent estimate of the associated gravitational noise also known as Newtonian noise. The first implementation of the system uses a time-invariant (static) Wiener filter, which is the optimal filter for Newtonian-noise cancellation assuming that the noise is stationary. However, time variations in the form of transients and slow changes in correlations between sensors are possible and while time-variant filters are expected to cope with these variations better than a static Wiener filter, the question is what the limitations are of time-variant noise cancellation. In this study, we present a framework to study the performance limitations of time-variant noise cancellation filters and carry out a proof-of-concept with adaptive filters on seismic data at the Virgo site. We demonstrate that the adaptive filters, at least those with superior architecture, indeed significantly outperform the static Wiener filter with the residual noise remaining above the statistical error bound

Design and implementation of a seismic Newtonian-noise cancellation system for the Virgo gravitational-wave detector

International audienceTerrestrial gravity perturbations caused by seismic fields produce the so-called Newtonian noise in gravitational-wave detectors, which is predicted to limit their sensitivity in the upcoming observing runs. In the past, this noise was seen as an infrastructural limitation, i.e., something that cannot be overcome without major investments to improve a detector's infrastructure. However, it is possible to have at least an indirect estimate of this noise by using the data from a large number of seismometers deployed around a detector's suspended test masses. The noise estimate can be subtracted from the gravitational-wave data; a process called Newtonian-noise cancellation (NNC). In this article, we present the design and implementation of the first NNC system at the Virgo detector as part of its AdV+ upgrade. It uses data from 110 vertical geophones deployed inside the Virgo buildings in optimized array configurations. We use a separate tiltmeter channel to test the pipeline in a proof-of-principle. The system has been running with good performance over months