Prediction of disease flare by biomarkers after discontinuing biologics in patients with rheumatoid arthritis achieving stringent remission

To elucidate the disease-flare process in rheumatoid arthritis (RA) after discontinuing biological disease-modifying antirheumatic drugs (bDMARDs), we first focused on RA-flare prediction after achieving stringent remission criteria. Patients with RA who maintained a simplified disease activity index ≤ 3.3 for ≥ 3 months during November 2014–January 2018 in our medical centre in Tokyo, Japan, were eligible. The primary endpoint was flare (disease activity score 28—erythrocyte sedimentation rate ≥ 3.2 with increase from baseline > 0.6) within 2 years after bDMARD discontinuation. Comprehensive clinical assessments, ultrasonographic evaluation of 40 joints, and blood sampling for 12 biomarkers were performed every 2–3 months for 2 years unless patients experienced flare. Flare-positive and flare-negative patients were compared using univariate and Kaplan–Meier analyses. Thirty-six patients (80.6% female, median disease duration, 5.2 years; median treatment period with discontinued bDMARD, 2 years; median remission duration, 18 months) were enrolled. Twenty patients (55.6%) experienced RA flare 43–651 (median, 115) days after the first skipped date of bDMARDs. Two patients who withdrew without disease flare were excluded from the comparison. Clinical and ultrasonographic evaluations did not show significant between-group differences; Kaplan–Meier analysis showed that higher baseline soluble tumour necrosis factor receptor 1 (sTNFR1) concentration impacted subsequent disease flare (p = 0.0041); higher baseline interleukin (IL)-2 concentration was exclusively beneficial to patients with lower sTNFR1 (p = 0.0058), resulting in remission maintenance in 83.3% of patients with lower sTNFR1 and higher IL-2. We demonstrated the usefulness of combined biomarker evaluation for predicting sustained remission after bDMARD discontinuation in RA.

Generation of Low-Frequency Kinetic Waves at the Footpoints of Pre-Flare Coronal Loops

In this study we discuss the excitation of low-frequency plasma waves in the lower-middle chromosphere region of loop footpoints for the case when the plasma can be considered to be in a pre-flare state. It is shown that among the well-known semi-empirical models of the solar atmosphere, only the VAL (F) model together with a particular set of basic plasma parameters and amplitudes of the electric and magnetic fields supports generation of low-frequency wave instability. Our results show that it is possible to predict the onset of the flare process in the active region by using the interaction of kinetic Alfvén and kinetic ion-acoustic waves, which are solutions of the derived dispersion equation. The VAL (F) model allows situations when the main source of the aforementioned instability can be a sub-Dreicer electric field and drift plasma movements due to presence of spatial inhomogeneities. We also show that the generation of kinetic Alfvén and kinetic ion-acoustic waves can occur both, in plasma with a purely Coulomb conductivity and in the presence of small-scale Bernstein turbulence. The excitation of the small amplitude kinetic waves due to the development of low threshold instability in plasma with relatively low values of the magnetic field strength is also discussed.

Features of development of sustained fluxes of high-energy gamma-ray emission at different stages of solar flares

We have studied properties of sustained gamma fluxes having quantum energies of >100 MeV at different stages of flares with 1-min temporal resolution (Fermi/LAT). The most probable process of emergence of high-energy gamma-quanta during the impulsive phase of flares (6 events) has been confirmed. Acceleration of particles, produced by flare energy release (at dissipation of current sheet), occurs when they interact with a shock front of a coronal mass ejection (CME), which develops in the same active region at the same time. Nuclear interactions of accelerated protons (>500 MeV) with plasma ions lead further to the emergence of high-energy gamma-quanta. We have established that the interaction between a flare flux and a high-speed CME during the flare impulsive phase occurs within fairly limited periods — from 2 to 16 min. In the events considered, we have found a direct connection between maximum gamma flux F max (γ > 100 MeV) and CME velocity. High maximum values of gamma fluxes are typical of the flare impulsive phase: 3.5·10⁻⁴ cm⁻²s⁻¹ ≤ F max (γ > 100 MeV) ≤ 1.3·10⁻² cm⁻² s⁻¹. At the same time, the value F max (γ > 100 MeV) = 0.013 cm⁻²s⁻¹ was the highest for the events observed by Fermi/LAT from 2008 to 2017. During the development of CMEs moving with a supersonic speed, shock waves are formed which are the major power source of accelerated particles during the main phase of gradual flares. In some cases, however, the impact of shock waves on particle acceleration is the greatest in the short impulsive phase. To reveal parameters most effectively influencing the generation of high-energy gamma-ray emission, we have compared 17 flare events. The most significant parameter proved to be the time interval of joint action of flare process and CME shocks. We have established that during simultaneous development of flare process and CME attendant on the flare, the most efficient particle acceleration occurs which gives rise to maximum fluxes of high-energy gamma-quanta.

Features of development of sustained fluxes of high-energy gamma-ray emission at different stages of solar flares

We have studied properties of sustained gamma fluxes having quantum energies of >100 MeV at different stages of flares with 1-min temporal resolution (Fermi/LAT). The most probable process of emergence of high-energy gamma-quanta during the impulsive phase of flares (6 events) has been confirmed. Acceleration of particles, produced by flare energy release (at dissipation of current sheet), occurs when they interact with a shock front of a coronal mass ejection (CME), which develops in the same active region at the same time. Nuclear interactions of accelerated protons (>500 MeV) with plasma ions lead further to the emergence of high-energy gamma-quanta. We have established that the interaction between a flare flux and a high-speed CME during the flare impulsive phase occurs within fairly limited periods — from 2 to 16 min. In the events considered, we have found a direct connection between maximum gamma flux F max (γ > 100 MeV) and CME velocity. High maximum values of gamma fluxes are typical of the flare impulsive phase: 3.5·10⁻⁴ cm⁻²s⁻¹ ≤ F max (γ > 100 MeV) ≤ 1.3·10⁻² cm⁻² s⁻¹. At the same time, the value F max (γ > 100 MeV) = 0.013 cm⁻²s⁻¹ was the highest for the events observed by Fermi/LAT from 2008 to 2017. During the development of CMEs moving with a supersonic speed, shock waves are formed which are the major power source of accelerated particles during the main phase of gradual flares. In some cases, however, the impact of shock waves on particle acceleration is the greatest in the short impulsive phase. To reveal parameters most effectively influencing the generation of high-energy gamma-ray emission, we have compared 17 flare events. The most significant parameter proved to be the time interval of joint action of flare process and CME shocks. We have established that during simultaneous development of flare process and CME attendant on the flare, the most efficient particle acceleration occurs which gives rise to maximum fluxes of high-energy gamma-quanta.

Nonlinear force-free magnetic field extrapolation in AR 11158 by GPU-DBIE

A GPU-based acceleration for the direct boundary integral equation method (GPU-DBIE) to extrapolate solar coronal magnetic fields is developed, which is about 1000 times faster than the original DBIE. The 3-d coronal magnetic field is reconstructed for NOAA 11158 on 14-Feb-2011 with the SDO/HMI vector magnetogram as bottom boundary condition. The extrapolated results agree well with the projected SDO/AIA, EUV loops and the STEREO EUV sideviews, which verifies the correctness of our GPU-DBIE method. It is also found that the group of bright EUV loops along magnetic neutral lines agree well with current lines, which may have played an important role in the flare process of the active region.