Targeting inflammatory pathways in axial spondyloarthritis.

The triggers and pathogenesis of axial spondyloarthritis (axSpA) are not yet completely understood. However, therapeutic agents targeting tumor necrosis factor-α and interleukin-17 inflammatory pathways have proven successful in suppressing many of the clinical symptoms and signs of axSpA, giving us an indication of which pathways are responsible for initiating and maintaining the inflammation. The mechanisms that eventuate in syndesmophytes and ankyloses are less clear. This review addresses these two critical pathways of inflammation, discussing their nature and these factors that may activate or enhance the pathways in patients with axSpA. In addition, genetic and other markers important to the inflammatory pathways implicated in axSpA are explored, and prognostic biomarkers are discussed. Treatment options available for the management of axSpA and their associated targets are highlighted

Trial design: how must we move ahead?

Scleroderma is clinically heterogeneous and a variety of plausible mechanisms of disease have been hypothesized. Recent years have witnessed a significant improvement in overall survival although all of the gains in management have been therapies for specific organ involvement, e.g. renal crisis and pulmonary arterial hypertension. Future studies will rely on improved clinical science, which involves structured validation of proposed measures of outcome; development of a combined response index; and further refinement of specific subsets of disease expression. Immunoablation with stem cell reconstitution is an example of aggressive therapy chosen as appropriate for a particularly severe disease subset and in whom the pilot data are encouraging. Good science and clinical ethics force continued consideration of equipoise between risk and benefi

Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis

OBJECTIVES: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA.METHODS: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).RESULTS: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates.CONCLUSION: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. OBJECTIVES: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA.METHODS: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).RESULTS: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates.CONCLUSION: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs.SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014014842

G328.4+0.2 : A large and luminous Crab-like supernova remnant

We report on radio continuum and HI observations of the radio source G328.4+0.2 using the Australia Telescope Compact Array. Our results confirm G328.4+0.2 to be a filled-center nebula with no surrounding shell, showing significant linear polarization and an almost flat spectral index. These results lead us to conclude that G328.4+0.2 is a Crab-like, or ``plerionic'', supernova remnant (SNR), presumably powered by an unseen central pulsar. HI absorption towards G328.4+0.2 puts a lower limit on its distance of 17.4 +/- 0.9 kpc, making it the largest (D=25 pc) and most luminous (L_R = 3e35 erg/s) Crab-like SNR in the Galaxy. We infer G328.4+0.2 to be significantly older than the Crab Nebula, but powered by a pulsar which is fast spinning (P<20 ms) and which has a comparatively low magnetic field (B<1e12 G). We propose G328.4+0.2, G74.9+1.2 and N157B as a distinct group of large-diameter, high-luminosity Crab-like SNRs, all powered by fast-spinning low-field pulsars.Comment: 7 pages, 3 embedded EPS figures, uses emulateapj.sty. Accepted to ApJ. Abstract corrected so that distance is now in kpc, not pc

On the Enhanced Interstellar Scattering Toward B1849+005

(Abridged) This paper reports new Very Large Array (VLA) and Very Long Baseline Array (VLBA) observations of the extragalactic source B1849+005 at frequencies between 0.33 and 15 GHz and the re-analysis of archival VLA observations at 0.33, 1.5, and 4.9 GHz. The structure of this source is complex but interstellar scattering dominates the structure of the central component at least to 15 GHz. An analysis of the phase structure functions of the interferometric visibilities shows the density fluctuations along this line of sight to be anisotropic (axial ratio = 1.3) with a frequency-independent position angle, and having an inner scale of roughly a few hundred kilometers. The anisotropies occur on length scales of order 10^{15} cm (D/5 kpc), which within the context of certain magnetohydrodynamic turbulence theories indicates the length scale on which the kinetic and magnetic energy densities are comparable. A conservative upper limit on the velocity of the scattering material is 1800 km/s. In the 0.33 GHz field of view, there are a number of other sources that might also be heavily scattered. Both B1849+005 and PSR B1849+00 are highly scattered, and they are separated by only 13'. If the lines of sight are affected by the same ``clump'' of scattering material, it must be at least 2.3 kpc distant. However, a detailed attempt to account for the scattering observables toward these sources does not produce a self-consistent set of parameters for such a clump. A clump of H\alpha emission, possibly associated with the H II region G33.418-0.004, lies between these two lines of sight, but it seems unable to account for all of the required excess scattering.Comment: 23 pages, LaTeX2e AASTeX, 13 figures in 14 PostScript files, accepted for publication in Ap

Infrared Excess and Molecular Gas in the Galactic Worm GW46.4+5.5

We have carried out high-resolution (~3') HI and CO line observations along one-dimensional cuts through the Galactic worm GW46.4+5.5. By comparing the HI data with IRAS data, we have derived the distributions of I_100 excess and tau_100 excess, which are respectively the 100 mum intensity and 100 mum optical depth in excess of what would be expected from HI emission. In two observed regions, we were able to make a detailed comparison of the infrared excess and the CO emission. We have found that tau_100 excess has a very good correlation with the integrated intensity of CO emission, W_CO, but I_100 excess does not. There are two reasons for the poor correlation between I_100 excess and W_CO: firstly, there are regions with enhanced infrared emissivity without CO, and secondly, dust grains associated with molecular gas have a low infrared emissivity. In one region, these two factors completely hide the presence of molecular gas in the infrared. In the second region, we could identify the area with molecular gas, but I_100 excess significantly underestimates the column density of molecular hydrogen because of the second factor mentioned above. We therefore conclude that tau_100 excess, rather than I_100 excess, is an accurate indicator of molecular content along the line of sight. We derive tau_100/N(H)=(1.00+-0.02)*10^-5~(10^20 cm^-2)^-1, and X=N(H_2)/W_CO=~0.7*10^20 cm^-2 (K km s^-1)^-1. Our results suggest that I_100 excess could still be used to estimate the molecular content if the result is multiplied by a correction factor xi_c=_HI/_H_2 (~2 in the second region), which accounts for the different infrared emissivities of atomic and molecular gas. We also discuss some limitations of this work.Comment: 10 pages, 9 postscript figures, uses aas2pp4.sty to be published in Astrophyslcal Journa

Production of a high-density state-selected metastable neon beam

We have developed a high-density source of metastable neon and have selectively quenched both metastable species using a standing-wave dye laser. The source is compact, stable, and produces an average intensity of 3.6 x 1014 sr -1 s -1 and a density on target of 7.7 x 106 cm-3