Antimalarials (AMs), particularly hydroxychloroquine (HCQ) and chloroquine (CQ), are the cornerstone of the treatment for both systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus ...(CLE). HCQ and CQ are recommended as first‐line oral agents in all CLE guidelines. Initially thought to have potential therapeutic effects against COVID‐19, HCQ has drawn significant attention in recent years, highlighting concerns over its potential toxicity among patients and physicians. This review aims to consolidate current evidence on the efficacy of AMs in CLE. Our focus will be on optimizing therapeutic strategies, such as switching from HCQ to CQ, adding quinacrine to either HCQ or CQ, or adjusting HCQ dose based on blood concentration. Additionally, we will explore the potential for HCQ dose reduction or discontinuation in cases of CLE or SLE remission. Our review will focus on the existing evidence regarding adverse events linked to AM usage, with a specific emphasis on severe events and those of particular interest to dermatologists. Last, we will discuss the optimal HCQ dose and the balance between preventing CLE or SLE flares and minimizing toxicity.
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterised by the presence of autoantibodies towards nuclear antigens, immune complex deposition, and chronic inflammation ...at classic target organs such as skin, joints, and kidneys. Despite substantial advances in the diagnosis and management of SLE, the burden of disease remains high. It is important to appreciate the typical presentations and the diagnostic process to facilitate early referral and diagnosis for patients. In most patients, constitutional, mucocutaneous, and musculoskeletal symptoms represent the earliest complaints; these symptoms can include fatigue, lupus-specific rash, mouth ulcers, alopecia, joint pain, and myalgia. In this Seminar we will discuss a diagnostic approach to symptoms in light of the latest classification criteria, which include a systematic evaluation of clinical manifestations (weighted within each domain) and autoantibody profiles (such as anti-double-stranded DNA, anti-Sm, hypocomplementaemia, or antiphospholipid antibodies). Non-pharmacotherapy management is tailored to the individual, with specific lifestyle interventions and patient education to improve quality of life and medication (such as hydroxychloroquine or immunosuppressant) adherence. In the last decade, there have been a few major breakthroughs in approved treatments for SLE and lupus nephritis, such as belimumab, anifrolumab, and voclosporin. However the disease course remains variable and mortality unacceptably high. Access to these expensive medications has also been restricted across different regions of the world. Nonetheless, understanding of treatment goals and strategies has improved. We recognise that the main goal of treatment is the achievement of remission or low disease activity. Comorbidities due to both disease activity and treatment adverse effects, especially infections, osteoporosis, and cardiovascular disease, necessitate vigilant prevention and management strategies. Tailoring treatment options to achieve remission, while balancing treatment-related comorbidities, are priority areas of SLE management.
The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, ...detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ’s effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.
Ice is a highly transparent material in the visible. According to the most widely used database (IA2008; Warren and Brandt, 2008), the ice absorption coefficient reaches values lower than 10−3 m−1 ...around 400 nm. These values were obtained from a vertical profile of spectral radiance measured in a single snow layer at Dome C in Antarctica. We reproduced this experiment using an optical fiber inserted in the snow to record 56 profiles from which 70 homogeneous layers were identified. Applying the same estimation method on every layer yields 70 ice absorption spectra. They present a significant variability but absorption coefficients are overall larger than IA2008 by 1 order of magnitude at 400–450 nm. We devised another estimation method based on Bayesian inference that treats all the profiles simultaneously. It reduces the statistical variability and confirms the higher absorption, around 2 × 10−2 m−1 near the minimum at 440 nm. We explore potential instrumental artifacts by developing a 3-D radiative transfer model able to explicitly account for the presence of the fiber in the snow. The simulation shows that the radiance profile is indeed perturbed by the fiber intrusion, but the error on the ice absorption estimate is not larger than a factor of 2. This is insufficient to explain the difference between our new estimate and IA2008. The same conclusion applies regarding the plausible contamination by black carbon or dust, concentrations reported in the literature are insufficient. Considering the large number of profiles acquired for this study and other estimates from the Antarctic Muon and Neutrino Detector Array (AMANDA), we nevertheless estimate that ice absorption values around 10−2 m−1 at the minimum are more likely than under 10−3 m−1. A new estimate in the range 400–600 nm is provided for future modeling of snow, cloud, and sea-ice optical properties. Most importantly, we recommend that modeling studies take into account the large uncertainty of the ice absorption coefficient in the visible and that future estimations of the ice absorption coefficient should also thoroughly account for the impact of the measurement method.
Basal depth hoar that forms in Arctic snowpacks often has a low thermal conductivity, strongly contributing to the snowpack thermal insulance and impacting the permafrost thermal regime. At Ward Hunt ...Island (Canadian high Arctic, 83°05′N, 74°07′W) almost no depth hoar was observed in spring 2016 despite favorable thermal conditions. We hypothesize that depth hoar formation was impeded by the combination of two factors (1) strong winds in fall that formed hard dense wind slabs where water vapor transport was slow and (2) low soil moisture that led to rapid ground cooling with no zero-curtain period, which reduced soil temperature and the temperature gradient in the snowpack. Comparisons with detailed data from the subsequent winter at Ward Hunt and from Bylot Island (73°09′N, 80°00′W) and with data from Barrow and Alert indicate that both high wind speeds after snow onset and low soil moisture are necessary to prevent Arctic depth hoar formation. The role of convection to form depth hoar is discussed. A simple preliminary strategy to parameterize depth hoar thermal conductivity in snow schemes is proposed based on wind speed and soil moisture. Finally, warming-induced vegetation growth and soil moisture increase should reduce depth hoar thermal conductivity, potentially affecting permafrost temperature.
Abstract
Objective
The Physician Global Assessment (PGA) is a visual analogue score that reflects the clinician’s judgement of overall SLE disease activity. The aim of this systematic literature ...review is to describe and analyse the psychometric properties of the PGA.
Methods
This systematic literature review was conducted by two independent reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. All articles published through 1 July 2019 in PubMed were screened, with no limitation on year of publication, language or patients’ age. Psychometric properties data were analysed according to the OMERACT Filter methodology version 2.1.
Results
The literature search identified 91 studies. Face validity was reported in all the articles retrieved in which the PGA was used alone or as part of composite indices (Systemic Responder Index, Safety of Estrogen in Lupus Erythematosus National Assessment Flare Index, Lupus Low Disease Activity State, Definitions of Remission in Systemic Lupus Erythematosus criteria). Content validity was reported in 89 studies. Construct validity was demonstrated by a good correlation (r ≥ 0.50) between the PGA with the SLEDAI (12 studies), SLAM (4 studies), LAI, BILAG and ECLAM (2 studies each). Criterion validity was assessed exploring the PGA correlation with quality of life measurements, biomarker levels and treatment changes in 28 studies, while no study has evaluated correlation with damage. A good responsiveness for PGA was shown in eight studies. A high variability in scales was found, causing a wide range of reliability (intraclass correlation coefficient 0.67–0.98).
Conclusion
PGA is a valid, responsive and feasible instrument, though its reliability was impacted by the scale adopted, suggesting the major need for standardization of its scoring.
Ultra-lung-protective ventilation may be useful during veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe acute respiratory distress syndrome (ARDS) to minimize ventilator-induced ...lung injury and to facilitate lung recovery. The objective was to compare pulmonary and systemic biotrauma evaluated by numerous biomarkers of inflammation, epithelial, endothelial injuries, and lung repair according to two ventilator strategies on vv-ECMO.
This is a prospective randomized controlled study. Patients were randomized to receive during 48 h either ultra-lung-protective ventilation combining very low tidal volume (1-2 mL/kg of predicted body weight), low respiratory rate (5-10 cycles per minute), positive expiratory transpulmonary pressure, and 16 h of prone position or lung-protective-ventilation which followed the ECMO arm of the EOLIA trial (control group).
The primary outcome was the alveolar concentrations of interleukin-1-beta, interleukin-6, interleukin-8, surfactant protein D, and blood concentrations of serum advanced glycation end products and angiopoietin-2 48 h after randomization. Enrollment was stopped for futility after the inclusion of 39 patients. Tidal volume, respiratory rate, minute ventilation, plateau pressure, and mechanical power were significantly lower in the ultra-lung-protective group. None of the concentrations of the pre-specified biomarkers differed between the two groups 48 h after randomization. However, a trend to higher 60-day mortality was observed in the ultra-lung-protective group compared to the control group (45 vs 17%, p = 0.06).
Despite a significant reduction in the mechanical power, ultra-lung-protective ventilation during 48 h did not reduce biotrauma in patients with vv-ECMO-supported ARDS. The impact of this ventilation strategy on clinical outcomes warrants further investigation. Trial registration Clinical trial registered with www.
gov ( NCT03918603 ). Registered 17 April 2019.
We proposed a simple algorithm to retrieve the total ozone column and snow properties (spectral albedo and effective light absorption path) using the high spatial resolution single–view MSI/S-2 ...measurements over Antarctica. In addition, the algorithm allows the retrieval of the snow grain size on a scale of 10–20 m. This algorithm should be useful for the understanding of intra-pixel total ozone and snow albedo variability in complement to satellite observations performed on a much coarser spatial resolution scale (0.3–1 km and even larger spatial scales).
Abstract While our knowledge of the pathogenesis of Takayasu's arteritis (TA) has considerably improved during the last decade, the exact pathogenic sequence remains to be elucidated. It is now ...hypothesised that an unknown stimulus triggers the expression of the 65 kDa Heat-shock protein in the aortic tissue which, in turn, induces the Major Histocompatibility Class I Chain-Related A (MICA) on vascular cells. The γδ T cells and NK cells expressing NKG2D receptors recognize MICA on vascular smooth muscle cells and release perforin, resulting in acute vascular inflammation. Pro-inflammatory cytokines are released and increase the recruitment of mononuclear cells within the vascular wall. T cells infiltrate and recognize one or a few antigens presented by a shared epitope, which is associated with specific major Histocompatibility Complex alleles on the dendritic cells, these latter being activated through Toll-like receptors. Th1 lymphocytes drive the formation of giant cells through the production of interferon-γ, and activate macrophages with release of VEGF resulting in increased neovascularisation and PDGF, resulting in smooth muscle migration and intimal proliferation. Th17 cells induced by the IL-23 microenvironnement also contribute to vascular lesions through activation of infiltrating neutrophils. Although still controversial, dendritic cells may cooperate with B lymphocytes and trigger the production of anti-endothelial cell auto-antibodies resulting in complement-dependent cytotoxicity against endothelial cells. In a near future, novel drugs specifically designed to target some of the pathogenic mechanisms described above could be expanding the physician's therapeutic arsenal in Takayasu's arteritis.
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