Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: An individual meta-analysis of 5792 patients

Objectives: To determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA). Methods: Meta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0-10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire-Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared. Results: Individual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%). Conclusion: 4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets

The impact of patient global assessment in the definition of remission as a predictor of long-term radiographic damage in patients with rheumatoid arthritis: protocol for an individual patient data meta-analysis

BACKGROUND: Remission is the target for management of rheumatoid arthritis (RA) and intensification of immunosuppressive therapy is recommended for those that do not achieve this status. Patient global assessment (PGA) is the single patient reported outcome considered in the American College of Rheumatology/European League Against Rheumatism remission criteria, but its use as target has been questioned. The primary aim of this study is to assess whether excluding PGA from the definition of disease remission changes the association of disease remission with long-term radiographic damage and physical function in patients with RA. METHODS: Individual Patient Data Meta-analysis using data from randomized controlled trials of biological and targeted synthetic agents, identified through ClinicalTrials.gov and PubMed. Different remission states will be defined: (i) 4v-remission [tender (TJC28) and swollen 28-joint counts (SJC28) both≤1, C-reactive protein (CRP)≤1 (mg/dl), and PGA≤1 (0-10 scale)], (ii) 4v-near-remission (TJC28≤1, SJC28≤1, CRP≤1, and PGA>1), (iii) non-remission (TJC28>1 or SJC28>1 or CRP>1), all mutually exclusive, and (iv) 3v-remission (TJC28≤1, SJC28≤1, CRP≤1). Likelihood ratios will be used to descriptively compare whether meeting the 3v and 4v-remission criteria in a single visit (at 6 or 12 months) predicts good outcome in the second year (1-2y). Differences in the predictive value of PGA in the definition of remission will be assessed by comparing the three mutually exclusive disease states using logistic regression analysis. Good outcome is defined primarily by radiographic damage (no deterioration in radiographic scores, whatever the instrument used in each trial), and secondarily by functional disability (Health Assessment Questionnaire consistently ≤0.5 and no deterioration), and their combination ("overall good outcome"). Additional analyses will consider longer periods over which to (concurrently) define remission status and outcome (between 1-5y and 1-10y), different cut-offs to define good radiographic outcome (change ≤0.5, ≤3 and ≤5 in radiographic score), sustained remission and the influence of treatment and other clinical factors. DISCUSSION: If 4v-remission and 4v-near-remission are associated with a similar probability of good outcomes, particularly regarding structural damage, the 3v-remission (excluding PGA) could be adopted as the target for immunosuppressive therapy. Patients' perspectives would remain essential, but assessed separately from disease activity, using instruments adequate to guide adjunctive therapies. Systematic review registration: PROSPERO, CRD42017057099

Correspondence on “Re‐examining remission definitions in rheumatoid arthritis: considering the 28‐Joint Disease Activity Score, C‐reactive protein level and patient global assessment” by Felson et al

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Observations of the unidentified gamma-ray source TeV J2032+4130 by VERITAS

TeV J2032+4130 was the first unidentified source discovered at very high energies (VHE; E $>$ 100 GeV), with no obvious counterpart in any other wavelength. It is also the first extended source to be observed in VHE gamma rays. Following its discovery, intensive observational campaigns have been carried out in all wavelengths in order to understand the nature of the object, which have met with limited success. We report here on a deep observation of TeV J2032+4130, based on 48.2 hours of data taken from 2009 to 2012 by the VERITAS (Very Energetic Radiation Imaging Telescope Array System) experiment. The source is detected at 8.7 standard deviations ($\sigma$) and is found to be extended and asymmetric with a width of 9.5$^{\prime}$$\pm$1.2$^{\prime}$ along the major axis and 4.0$^{\prime}$$\pm$0.5$^{\prime}$ along the minor axis. The spectrum is well described by a differential power law with an index of 2.10 $\pm$ 0.14$_{stat}$ $\pm$ 0.21$_{sys}$ and a normalization of (9.5 $\pm$ 1.6$_{stat}$ $\pm$ 2.2$_{sys}$) $\times$ 10$^{-13}$TeV$^{-1}$ cm$^{-2}$ s$^{-1}$ at 1 TeV. We interpret these results in the context of multiwavelength scenarios which particularly favor the pulsar wind nebula (PWN) interpretation

Deep Broadband Observations of the Distant Gamma-ray Blazar PKS 1424+240

We present deep VERITAS observations of the blazar PKS 1424+240, along with contemporaneous Fermi Large Area Telescope, Swift X-ray Telescope and Swift UV Optical Telescope data between 2009 February 19 and 2013 June 8. This blazar resides at a redshift of $z\ge0.6035$, displaying a significantly attenuated gamma-ray flux above 100 GeV due to photon absorption via pair-production with the extragalactic background light. We present more than 100 hours of VERITAS observations from three years, a multiwavelength light curve and the contemporaneous spectral energy distributions. The source shows a higher flux of (2.1$\pm0.3$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV in 2009 and 2011 as compared to the flux measured in 2013, corresponding to (1.02$\pm0.08$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV. The measured differential very high energy (VHE; $E\ge100$ GeV) spectral indices are $\Gamma=$3.8$\pm$0.3, 4.3$\pm$0.6 and 4.5$\pm$0.2 in 2009, 2011 and 2013, respectively. No significant spectral change across the observation epochs is detected. We find no evidence for variability at gamma-ray opacities of greater than $\tau=2$, where it is postulated that any variability would be small and occur on longer than year timescales if hadronic cosmic-ray interactions with extragalactic photon fields provide a secondary VHE photon flux. The data cannot rule out such variability due to low statistics.Comment: ApJL accepted March 17, 201

The 2009 multiwavelength campaign on Mrk 421: Variability and correlation studies

We performed a 4.5-month multi-instrument campaign (from radio to VHE gamma rays) on Mrk421 between January 2009 and June 2009, which included VLBA, F-GAMMA, GASP-WEBT, Swift, RXTE, Fermi-LAT, MAGIC, and Whipple, among other instruments and collaborations. Mrk421 was found in its typical (non-flaring) activity state, with a VHE flux of about half that of the Crab Nebula, yet the light curves show significant variability at all wavelengths, the highest variability being in the X-rays. We determined the power spectral densities (PSD) at most wavelengths and found that all PSDs can be described by power-laws without a break, and with indices consistent with pink/red-noise behavior. We observed a harder-when-brighter behavior in the X-ray spectra and measured a positive correlation between VHE and X-ray fluxes with zero time lag. Such characteristics have been reported many times during flaring activity, but here they are reported for the first time in the non-flaring state. We also observed an overall anti-correlation between optical/UV and X-rays extending over the duration of the campaign. The harder-when-brighter behavior in the X-ray spectra and the measured positive X-ray/VHE correlation during the 2009 multi-wavelength campaign suggests that the physical processes dominating the emission during non-flaring states have similarities with those occurring during flaring activity. In particular, this observation supports leptonic scenarios as being responsible for the emission of Mrk421 during non-flaring activity. Such a temporally extended X-ray/VHE correlation is not driven by any single flaring event, and hence is difficult to explain within the standard hadronic scenarios. The highest variability is observed in the X-ray band, which, within the one-zone synchrotron self-Compton scenario, indicates that the electron energy distribution is most variable at the highest energies.Comment: Accepted for publication in A&A, 18 pages, 14 figures (v2 has a small modification in the acknowledgments, and also corrects a typo in the field "author" in the metadata

Calibration of FRAX ® 3.1 to the Dutch population with data on the epidemiology of hip fractures

SummaryThe FRAX tool has been calibrated to the entire Dutch population, using nationwide (hip) fracture incidence rates and mortality statistics from the Netherlands. Data used for the Dutch model are described in this paper.IntroductionRisk communication and decision making about whether or not to treat with anti-osteoporotic drugs with the use of T-scores are often unclear for patients. The recently developed FRAX models use easily obtainable clinical risk factors to estimate an individual's 10-year probability of a major osteoporotic fracture and hip fracture that is useful for risk communication and subsequent decision making in clinical practice. As of July 1, 2010, the tool has been calibrated to the total Dutch population. This paper describes the data used to develop the current Dutch FRAX model and illustrates its features compared to other countries.MethodsAge- and sex-stratified hip fracture incidence rates (LMR database) and mortality rates (Dutch national mortality statistics) for 2004 and 2005 were extracted from Dutch nationwide databases (patients aged 50+ years). For other major fractures, Dutch incidence rates were imputed, using Swedish ratios for hip to osteoporotic fracture (upper arm, wrist, hip, and clinically symptomatic vertebral) probabilities (age- and gender-stratified). The FRAX tool takes into account age, sex, body mass index (BMI), presence of clinical risk factors, and bone mineral density (BMD).ResultsFracture incidence rates increased with increasing age: for hip fracture, incidence rates were lowest among Dutch patients aged 50–54 years (per 10,000 inhabitants: 2.3 for men, 2.1 for women) and highest among the oldest subjects (95–99 years; 169 of 10,000 for men, 267 of 10,000 for women). Ten-year probability of hip or major osteoporotic fracture was increased in patients with a clinical risk factor, lower BMI, female gender, a higher age, and a decreased BMD T-score. Parental hip fracture accounted for the greatest increase in 10-year fracture probability.ConclusionThe Dutch FRAX tool is the first fracture prediction model that has been calibrated to the total Dutch population, using nationwide incidence rates for hip fracture and mortality rates. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Dutch FRAX tool a good candidate for implementation into clinical practice

The most powerful flaring activity from the NLSy1 PMN J0948+0022

We report on multifrequency observations performed during 2012 December-2013 August of the first narrow-line Seyfert 1 galaxy detected in gamma rays, PMN J0948+0022 ($z$ = 0.5846). A gamma-ray flare was observed by the Large Area Telescope on board Fermi during 2012 December-2013 January, reaching a daily peak flux in the 0.1-100 GeV energy range of (155 $\pm$ 31) $\times$10$^{-8}$ ph cm$^{-2}$ s$^{-1}$ on 2013 January 1, corresponding to an apparent isotropic luminosity of about 1.5$\times$10$^{48}$ erg s$^{-1}$. The gamma-ray flaring period triggered Swift and VERITAS observations in addition to radio and optical monitoring by OVRO, MOJAVE, and CRTS. A strong flare was observed in optical, UV, and X-rays on 2012 December 30, quasi-simultaneously to the gamma-ray flare, reaching a record flux for this source from optical to gamma rays. VERITAS observations at very high energy (E > 100 GeV) during 2013 January 6-17 resulted in an upper limit of F (> 0.2 TeV) < 4.0$\times$10$^{-12}$ ph cm$^{-2}$ s$^{-1}$. We compared the spectral energy distribution (SED) of the flaring state in 2013 January with that of an intermediate state observed in 2011. The two SEDs, modelled as synchrotron emission and an external Compton scattering of seed photons from a dust torus, can be modelled by changing both the electron distribution parameters and the magnetic field.Comment: 13 pages, 5 Figures, 5 Tables. Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Unprecedented study of the broadband emission of Mrk 421 during flaring activity in March 2010

A flare from the TeV blazar Mrk 421, occurring in March 2010, was observed for 13 consecutive days from radio to very high energy (VHE, E > 100 GeV) gamma-rays with MAGIC, VERITAS, Whipple, FermiLAT, MAXI, RXTE, Swift, GASP-WEBT, and several optical and radio telescopes. We model the day-scale SEDs with one-zone and two-zone synchrotron self-Compton (SSC) models, investigate the physical parameters, and evaluate whether the observed broadband SED variability can be associated to variations in the relativistic particle population. Flux variability was remarkable in the X-ray and VHE bands while it was minor or not significant in the other bands. The one-zone SSC model can describe reasonably well the SED of each day for the 13 consecutive days. This flaring activity is also very well described by a two-zone SSC model, where one zone is responsible for the quiescent emission while the other smaller zone, which is spatially separated from the first one, contributes to the daily-variable emission occurring in X-rays and VHE gamma-rays. Both the one-zone SSC and the two-zone SSC models can describe the daily SEDs via the variation of only four or five model parameters, under the hypothesis that the variability is associated mostly to the underlying particle population. This shows that the particle acceleration and cooling mechanism producing the radiating particles could be the main one responsible for the broadband SED variations during the flaring episodes in blazars. The two-zone SSC model provides a better agreement to the observed SED at the narrow peaks of the low- and high-energy bumps during the highest activity, although the reported one-zone SSC model could be further improved by the variation of the parameters related to the emitting region itself ($\delta$, $B$ and $R$), in addition to the parameters related to the particle population.Comment: Published in A&A, 30 pages, 15 figures, 6 tables. Online-data: multi-wavelength light curves (data in Fig. 1) and broadband spectral energy distributions (the data in Figs. 6, and B1-B4) are available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/578/A22. Corresponding authors: David Paneque ([email protected]), Shangyu Sun ([email protected]), Hajime Takami ([email protected]

Design concepts for the Cherenkov Telescope Array CTA: an advanced facility for ground-based high-energy gamma-ray astronomy

Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA