Persistent Flares Research Articles

De-intensifying treatment in established rheumatoid arthritis (RA): Why, how, when and in whom can DMARDs be tapered?

As more patients with established rheumatoid arthritis (RA) achieve remission or low disease activity, strategies such as tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) are being investigated. In several trials, DMARD discontinuation was associated with a higher risk of relapse, ranging from 56% to 87% at 1 year. Tapering, either by dose reduction or by injection spacing, may limit the risk of relapse. Half-dose etanercept (ETN) versus full-dose continuation was not associated with an increased relapse risk at 1 year in two trials. Progressive antitumor necrosis factor injection spacing was shown to be equivalent to full regimen continuation in terms of persistent flare and disease activity at 18 months in one trial, but not in another one. Reintroduction of a DMARD at previous dose/regimen was usually associated with remission re-induction. The risk of relevant structural damage progression was not increased. Safety improvement has not yet been demonstrated. The annual cost reduction when tapering biologic DMARDs (bDMARDs) was 3500-6000 €/patient. Research questions to be addressed include defining flare that requires reinitiation of treatment, such that patients facilitate the maintenance of remission during tapering by timely communication with their rheumatology team.

SIMULTANEOUS MULTIWAVELENGTH OBSERVATIONS OF MAGNETIC ACTIVITY IN ULTRACOOL DWARFS. IV. THE ACTIVE, YOUNG BINARY NLTT 33370 AB (= 2MASS J13142039+1320011)

We present multi-epoch simultaneous radio, optical, H{\alpha}, UV, and X-ray observations of the active, young, low-mass binary NLTT 33370 AB (blended spectral type M7e). This system is remarkable for its extreme levels of magnetic activity: it is the most radio-luminous ultracool dwarf (UCD) known, and here we show that it is also one of the most X-ray luminous UCDs known. We detect the system in all bands and find a complex phenomenology of both flaring and periodic variability. Analysis of the optical light curve reveals the simultaneous presence of two periodicities, 3.7859 $\pm$ 0.0001 and 3.7130 $\pm$ 0.0002 hr. While these differ by only ~2%, studies of differential rotation in the UCD regime suggest that it cannot be responsible for the two signals. The system's radio emission consists of at least three components: rapid 100% polarized flares, bright emission modulating periodically in phase with the optical emission, and an additional periodic component that appears only in the 2013 observational campaign. We interpret the last of these as a gyrosynchrotron feature associated with large-scale magnetic fields and a cool, equatorial plasma torus. However, the persistent rapid flares at all rotational phases imply that small-scale magnetic loops are also present and reconnect nearly continuously. We present an SED of the blended system spanning more than 9 orders of magnitude in wavelength. The significant magnetism present in NLTT 33370 AB will affect its fundamental parameters, with the components' radii and temperatures potentially altered by ~+20% and ~-10%, respectively. Finally, we suggest spatially resolved observations that could clarify many aspects of this system's nature.

Magnetar activity mediated by plastic deformations of neutron star crust

We advance a "Solar flare" model of magnetar activity, whereas a slow evolution of the magnetic field in the upper crust, driven by electron MHD (EMHD) flows, twists the external magnetic flux tubes, producing persistent emission, bursts and flares. At the same time the neutron star crust plastically relieves the imposed magnetic field stress, limiting the strain $ \epsilon_t $ to values well below the critical strain $ \epsilon_{crit}$ of a brittle fracture, $ \epsilon_t \sim 10^{-2}\epsilon_{crit} $. Magnetar-like behavior, occurring near the magnetic equator, takes place in all neutron stars, but to a different extent. The persistent luminosity is proportional to cubic power of the magnetic field (at a given age), and hence is hardly observable in most rotationally powered neutron stars. Giant flares can occur only if the magnetic field exceeds some threshold value, while smaller bursts and flares may take place in relatively small magnetic fields. Bursts and flares are magnetospheric reconnection events that launch Alfven shocks which convert into high frequency whistlers upon hitting the neutron star surface. The resulting whistler pulse induces a strain that increases with depth both due to the increasing electron density (and the resulting slowing of the waves), and due to the increasing coherence of a whistler pulse with depth. The whistler pulse is dissipated on a time scale of approximately a day at shallow depths corresponding to $\rho \sim 10^{10} {\rm g cm}^{-3}$; this energy is detected as enhanced post-flare surface emission.

Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

Down-titration and discontinuation strategies of tumor necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

A30: Assessment of Construct and Discriminative Validity of the 3‐Variable JADAS in Relation of Parent‐Reported Outcomes

Background/Purpose:An established approach to the measurement of disease activity in juvenile idiopathic arthritis (JIA) is based on the Juvenile Arthritis Disease Activity Score (JADAS). The feasibility of the JADAS for use in standard clinical practice might be enhanced by implementing of a 3‐variable version, which does not include the acute phase reactant. Recently, the 3‐variable JADAS was found to correlate closely with the original tool. However, the validity of this simplified version of the JADAS in the clinical setting is still insufficiently documented. Aim of the study was to further validate the 3‐variable version of the JADAS, hence named clinical JADAS (cJADAS), by assessing its relationship with parent‐reported outcomes (excluding the parent's rating of overall well‐being, which is included in the JADAS).Methods:The study was conducted in a cohort of 175 newly‐diagnosed consecutive JIA patients, first seen between 2007–2011 and then followed for 2 years. Clinical assessments were made at baseline and then at 6, 12, 18 and 24 months. At each visit, all parent reported outcomes included in the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) were assessed by a parent of each patient. Construct validity of the cJADAS was computed by calculating its Spearman's correlation with pain visual analog scale (VAS) and disease activity VAS. Discriminative validity was evaluated, by means of the non‐parametric analysis of variance (Kruskal‐Wallis test) or Mann‐Whitney U test, by examining the ability of cJADAS to discriminate between: 1) different categories of disease state (remission, persistent activity or flare), rated subjectively by the parents; 2) different categories of disease course (improved, stable or worsened), rated subjectively by the parents; 3) visit in which parents declared themselves as satisfied or not satisfied with the outcome of the illness; 4) different duration of morning stiffness.Results:The cJADAS was strongly correlated with pain VAS (r=0.71) and disease activity VAS (r=0.77). The cJADAS was significantly lower in patients rated as being in remission than in patients rated as being in persistent activity or flare (p < 0.0001), in patients rated as improved or stable than in patients rated as worsened (p < 0001), and in patients whose parents were satisfied with illness outcome than in those who were not (p < 0.0001). The cJADAS was proportionally greater in parallel with the progressive increase in morning stiffness (p < 0001).Conclusion:The cJADAS was strongly associated with all parent‐reported outcomes, which indicates that it reflects well the parent perception of the child's disease status and course.

Dose REduction strategy of subcutaneous TNF inhibitors in rheumatoid arthritis: design of a pragmatic randomised non inferiority trial, the DRESS study

BackgroundPreliminary, mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control. However, long term safety, cost effectiveness and feasibility in clinical practice remain uncertain.Methods/DesignThis study is a 18-months pragmatic, non-inferiority, cost minimalisation, randomized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor (TNF) blockers adalimumab and etanercept in RA patients with low disease activity. 180 RA patients with low disease activity (DAS28 < 3.2 or clinical judgment of the rheumatologist) are randomized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker, and usual care. Implementation is done in routine daily care, using treat to target and feedback implementation in both treatment arms. The primary outcome is non-inferiority (NI margin 20%) in cumulative incidence of persistent (> 3 months) RA flare, according to a recently validated DAS28 based flare criterion (DAS28 change > 1.2, or DAS28 increase of 0.6 and current DAS28 ≥ 3.2). Secondary outcomes include mean disease activity, function, radiographic progression, safety and cost effectiveness. Cost per quality adjusted life year (QALY) differences between groups are expressed as a decremental cost effectiveness ratio (DCER), i.e. saved costs divided by (possible) loss in QALY.DiscussionThe design of this study targeted several clinical and methodological issues on TNF blocker dose de-escalation, including how to taper the TNF blockers, the satisfactory control condition, how to define flare, implementation in clinical practice, and the choice of the non-inferiority margin. Pragmatic cost minimalisation studies using non-inferiority designs and DCERs will become more mainstream as cost effectiveness in healthcare gains importance.Trial registrationDutch Trial Register NTR3216, The study has received ethical review board approval (number NL37704.091.11)

Cranial ultrasonography and transfontanellar Doppler in premature neonates (24–32 weeks of gestation): Dynamic evolution and association with a severe adverse neurological outcome at hospital discharge in the Aquitaine cohort, 2003–2005

ObjectiveTo correlate the short-term neurological outcome of early cerebral abnormalities using cranial ultrasonography (US) in premature newborns at their hospital discharge. MethodsEach newborn born<33 weeks of gestational age (GA) included in a prospective cohort benefited of 3 US: two early in the first week of life (D3 and D8) and one later (Months 1–2) standardized US pulsed Doppler. A US abnormality was ≥one morphologic abnormality (moderate: intra-ventricular hemorrhage (IVH) grades 1–2; severe: IVH 3–4, periventricular leukomalacia, persistent flares). Correlates of having a severe adverse neurological outcome were analyzed using a stepwise backward logistic regression adjusted model with gestational age, early cerebral abnormality at Days 3–8, velocity and with variables with correlation probabilities with p<0.25 in the univariate analysis among occurring co-morbidity events previously defined. Two adjusted logistic regression analyses were conducted including or not velocity data because of missing information. ResultsAmong 452 premature included, 11.3% did not have an early US, 74.8% had a normal early US, 13.9% ≥one early morphological US abnormality (10.0% moderate, 3.9% severe). At hospital discharge, 40% were still alive with a normal late US, 33% alive with ≥one late morphological US abnormality (10% moderate, 23% severe), and 10% died. Adjusted correlates of a late US severe abnormality or a neurological related death at hospital discharge were: early US abnormality (aOR: 8.7, 95% CI: 2.3–33.6), GA<29 weeks (aOR: 2.8 95% CI: 1.4–5.4). ConclusionThis study shows that early US morphological abnormalities increase significantly when the GA decreases and is highly predictive of the occurrence of a further late US severe abnormality or neurological related death at hospital discharge.

Stability of Eyelid Height After Graded Anterior-Approach Lid Lowering for Dysthyroid Upper Lid Retraction

Objective: To investigate the outcome of a modified anterior approach surgical procedure for the correction of primary upper eyelid retraction in thyroid eye disease.Methods: A retrospective review of 52 consecutive cases (in 32 patients) of anterior-approach graded upper lid lowering for the treatment of primary eyelid retraction, carried out at Moorfields Eye Hospital between 2006–2009 was conducted. Measurements of upper margin-reflex distance (MRD), upper lid skin crease height and skin fold height were taken from clinical records and photographs. A comparison between pre-operative and both early and late post-operative measurements was conducted, with a maximal follow-up of 12 months. Surgery was considered successful when all of the following criteria were met; an upper lid margin covering 0.5–1.5 mm of the superior cornea in the 12 o’clock position, smooth eyelid contour, skin crease height within 6–10 mm or upper lid skin fold within 2–5 mm of the lid margin, symmetry of lid position (difference in MRD of <1 mm between both eyes) and patient satisfaction.Results: A successful outcome was achieved in 86.5% (45/52) of lids with a single procedure. For the whole group, the mean MRD was 7.0 mm pre-operatively and 3.6 mm at 1 month after surgery. The corresponding values from photographic estimates were 6.5 mm and 3.6 mm, respectively. These values remained stable over the maximum follow-up period of 12 months. Under-correction occurred in 6/52 (11.5%) lids, one of which had persistent lateral flare, whereas over-correction occurred in 1/52 (2%).Conclusions: The described surgical approach produces reasonably predictable and stable outcome for upper eyelid lowering in patients with thyroid eye disease.

The Impact of Systemic Lupus Erythematosus on Women's Sexual Functioning

The effect of systemic lupus erythematosus (SLE) on women's sexual functioning has been rarely assessed. The aim of this study is to evaluate the impact of SLE on women's sexual functioning. A total of 302 consecutive female outpatients with SLE were provided with a questionnaire composed of the Female Sexual Function Index (FSFI), questions for sociodemographic characteristics and comorbidities. Similarly, 2,159 hospital female employees were assessed as the control group. In patients, data of SLE duration and Sjögren's syndrome were derived from the chart records and the disease activity was assessed using the SLE Disease Activity Index 2000. The FSFI scores were compared between the patients and the controls. Correlates of the FSFI scores were determined in the patients. Of 302 eligible patients, 92.4% (279/302) responded, in addition to 73.2% (1,580/2,159) of controls. Ninety-five percent (255/268) of the respondent patients were in no-to-mild SLE disease activity. Among the respondents, 171 (61.3%) patients and 930 (58.9%) controls were sexually active in the previous month, P = 0.446. Of the sexually active patients, 52.5% (85/162) had impaired sexual function (the FSFI total score < 26.55) and so did 47.1% (408/867) of the sexually active controls, P = 0.206. With adjustment of age group, marital status and education level, patients had lower FSFI scores than controls only in the domains of lubrication and pain. Significant risk factors for lower FSFI scores in the patients included persistent activity or flare of SLE, menstrual cycle disturbances, and vascular disease. With further adjustment of other risk factors, only vascular disease remained significant as a risk factor for impaired sexual function (odds ratio = 5.7; 95% confidence interval 1.6-20.1). When not in an exacerbation period, the impact of SLE on women's sexual functioning is not great and is related to vascular factors.

Can Lupus Flares be Associated with Tuberculosis Infection?

Systemic lupus erythematosus (SLE) is an autoimmune disease that frequently requires treatment with high doses of corticosteroids and immunosuppressive drugs. Primary defects in the innate immunity also contribute to an increased susceptibility to infections. Patients with SLE are at an increased risk for infections with several pathogens, among them Mycobacterium tuberculosis, which is a significant cause of morbidity and mortality, especially in endemic regions. TB infection requires awareness for several reasons: first, TB infection thrives under conditions of immunosuppression, may it be secondary to the disease itself or its treatment. Second, shared antigens by mycobacteria and autoantigens have been described, which may be targets for autoantibodies. We present four Brazilian patients, in whom a diagnosis of tuberculosis was determined during or following persistent flares of their disease. The association of SLE and TB is discussed, as well as different aspects of the tuberculosis infection in this selected population, and its possible role in the course of SLE.

Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study

Objectives:In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is...

Influence of gestational age on the type of brain injury and neuromotor outcome in high-risk neonates

This study was an investigation of a possible correlation between either the gestational age (GA) and type of brain injury or between the gestational age and type, distribution and severity of cerebral palsy (CP). Four hundred sixty-one children with a birthweight > or = 1250 g and GA > or = 30 weeks with a complicated neonatal period and/or brain injury on serial cerebral ultrasound were selectively followed at the regional Center for Developmental Disorders. The children were divided into a preterm and term group. There were 40 children with cerebral palsy in the preterm group and 38 children with cerebral palsy in the term group. Various types of brain injury diagnosed by echography were nosologically classified. The type, distribution and severity of cerebral palsy were also registered. The type of brain injury most frequently occurring in the term group was hypoxic-ischemic injury to the basal ganglia (39%), focal ischemia (18%), subcortical hemorrhage (13%) and parasagittal cerebral injury (10%). In the preterm group 39% of the children with cerebral palsy had periventricular leukomalacia, 24% intraventricular hemorrhage and 18% persistent flares. There was a significant correlation between the GA and type of brain injury (P < 0.001; Cramer's V = 0.76) and between the GA and type (P = 0.004; Cramer's V = 0.47) and distribution (P < 0.001; Cramer's V = 0.55) of CP. There was no significant correlation between the GA and severity of CP. The type of brain injury detected by serial ultrasound during the neonatal period, as well as the type and location of CP detected during later childhood, are all GA-dependent in at-risk newborn infants with a birthweight of > or = 1,250 g and GA > or = 30 weeks.

Pre-S Deletion and Complex Mutations of Hepatitis B Virus Related to Advanced Liver Disease in HBeAg-Negative Patients

This longitudinal study investigated the interactions and roles of hepatitis B virus (HBV) genotypes, pre-S deletions, and core promoter and precore mutations on the progression of liver disease in hepatitis B e antigen (HBeAg)-negative patients. A total of 141 HBeAg-negative patients without liver cirrhosis or hepatocellular carcinoma at study entry were recruited for this study, including 45 inactive HBV carriers and 96 patients with HBeAg-negative chronic hepatitis B. The HBV genotypes and the sequences of pre-S, core promoter, and precore regions were determined. Compared with patients without developing liver cirrhosis, patients with the development of liver cirrhosis had higher rates of genotype C; pre-S deletions; C or G1753, T1762/A1764, T1766, and/or A1768 mutants; and G1799 variant. Cox regression analysis showed that older age, higher total bilirubin and HBV DNA levels, pre-S deletions, and T1766 and/or A1768 mutants were significantly associated with the development of liver cirrhosis. HBV with a complex mutation pattern (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutants) rather than a single mutation was associated with the development of liver cirrhosis, and the patterns of mutation combinations differed between HBV genotype B and C. Moreover, pre-S deletion was a significant risk factor for hepatocellular carcinoma. This study indicated that pre-S deletion and combined mutations of HBV are useful molecular markers for predicting the clinical outcomes of HBeAg-negative patients.

Iron lines from transient and persisting hot spots on AGN accretion disks

Aims. We model the X-ray reprocessing from a strong co-rotating flare above an accretion disk in active galactic nuclei. By performing detailed radiative transfer computations we explore the horizontal structure and evolution of the underlying hot spot. The main goal is to study how the resulting spectral features manifest themselves in short exposure time spectra. Methods. We analyze both the vertical and the horizontal spot structure and its dynamical reprocessed spectrum. To obtain the spectral evolution seen by a distant observer, we apply a general relativity ray-tracing technique. We concentrate on the energy band around the iron K-line, where the relativistic effects are most pronounced. Persistent flares lasting for a significant fraction of the orbital time scale and short, transient flares are considered. Results. In our time-resolved analysis, the spectra recorded by a distant observer depend on the position of the flare/spot with respect to the central black hole. If the flare duration significantly exceeds the light travel time across the spot, then the spot horizontal stratification is unimportant. On the other hand, if the flare duration is comparable to the light travel time across the spot radius, the lightcurves exhibit a typical asymmetry in their time profiles. The sequence of dynamical spectra proceeds from more strongly to less strongly ionized re-emission. At all locations within the spot the spectral intensity increases towards edge-on emission angles, revealing the limb brightening effect. Conclusions. Future X-ray observatories with significantly larger effective collecting areas will enable to spectroscopically map out the azimuthal irradiation structure of the accretion disk and to localize persistent flares. If the hot spot is not located too close to the marginally stable orbit of the black hole, it will be possible to probe the reflecting medium via the sub-structure of the iron K-line. Indications for transient flares will only be obtained from analyzing the observed lightcurves on the gravitational time scale of the accreting supermassive black hole.

Which nerve fibers mediate the axon reflex flare in human skin?

Axon reflex vasodilatation due to transcutaneous electrical stimulation in human skin was measured by laser Doppler imaging. Constant current pulses of 10 mA, 0.2 ms, delivered at 1 or 10 Hz for 2 min through a probe of 30 mm2 surface area did not induce a significant flare response, though this stimulus previously has been found supra-maximal for cutaneous polymodal (mechano-heat responsive) C-nociceptors in microneurography experiments. Pulses of the same strength from a pointed probe yielding a higher current density induced an extended and persistent flare. This type of stimulus previously has been proven to recruit mechano-insensitive C-units in microneurography experiments, in contrast to stimuli from the 30 mm2 probe. It is concluded that mechano-insensitive C-nociceptors and not polymodal C-units mediate the axon reflex flare in human skin.

Neonatal cerebral doppler flow velocity waveforms in the pre-term infant with cerebral pathology

In a longitudinal study of 217 infants delivering at < 37 completed weeks gestation, Doppler flow velocity waveforms were obtained, and resistance index (RI) values calculated from the middle (MCA) and anterior (ACA) cerebral arteries during the first 10 days of life. Sixty infants demonstrated ultrasound evidence of cerebral pathology, of which five cases were congenital, and an additional 13 cases were complicated by patent ductus arteriosus during the study period. The Doppler data obtained during the first week of life from the remaining 42 infants who developed cerebral pathology, and 15 infants who had evidence of metabolic acidosis at delivery without ultrasound evidence of cerebral pathology were compared with local reference data obtained from non-acidotic infants with normal cranial ultrasound from 24 h of age. In those infants who had evidence of minor periventricular haemorrhage alone (Grade I/II PVH), there was no significant difference between the ACA or MCA RI during the study period compared with the reference data. In those groups of infants who demonstrated major PVH (Grade III/IV) or persistent periventricular flares, the ACA and MCA RI was found to be consistently significantly higher than the reference group throughout the study period. In those infants who developed ultrasound evidence of periventricular cystic leukomalacia (PVCL), the MCA RI was significantly lower than the reference data between 48 and 72 h of age, there being no significant difference in the ACA RI. The Doppler findings in those infants with evidence of metabolic acidosis at delivery (umbilical arterial pH < 7.20; BD > 8 mmol/1) but with normal ultrasound findings were similar to those infants who developed PVCL, namely a significant fall in MCA RI between 48 and 72 h of life, with no significant difference in the ACA RI during the study period. These findings suggest that variable changes in cerebral vascular resistance occur with the evolution of, or as a consequence of the development of cerebral pathology in the pre-term infant, and these changes of increased and decreased vascular resistance are discussed. Further investigation of the changes occurring in the cerebral circulation in the early neonatal period of infants who develop PVCL is required to clarify the vascular changes taking place, but if the findings of this study are confirmed, this technique may provide a means of identifying infants at risk of developing ischaemic cerebral pathology at an early stage when it may be possible to initiate therapeutic intervention to limit the cerebral damage.