Summary
Background
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
...Objectives
To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies.
Methods
In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
Results
At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%, and BREEZE‐AD2 N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
Conclusions
Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease.
What does this study add?
These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.
Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD.
Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
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Summary
Background
The relationship between atopic dermatitis (AD), anxiety and depression in the U.S. adult population is not well established.
Objectives
To determine the relationship of AD and its ...severity with symptoms and diagnosis of anxiety and depression in U.S. adults.
Methods
A cross‐sectional, population‐based study of 2893 adults was performed. AD was determined using modified U.K. Diagnostic Criteria.
Results
Adults with AD vs. those without AD had higher mean Hospital Anxiety and Depression Scale anxiety (HADS‐A) (7·7 vs. 5·6) and depression (HADS‐D) (6·0 vs. 4·3) scores and higher prevalences of abnormal (≥ 11) HADS‐A (28·6% vs. 15·5%) and HADS‐D (13·5% vs. 9·0%) scores. In multivariable linear and logistic regression models controlling for sociodemographics, AD was associated with significantly higher mean HADS‐A and HADS‐D scores (7·7 and 6·0) and higher odds of abnormal HADS‐A odds ratio (OR) 2·19, 95% confidence interval (CI) 1·65–2·91 and HADS‐D scores (OR 1·50, 95% CI 1·04–2·17) (P ≤ 0·03 for all). Mean and abnormal HADS‐A and HADS‐D scores were increased in moderate and severe/very severe self‐reported global AD severity, Patient‐Oriented Eczema Measure (POEM), Patient‐Oriented Scoring AD (PO‐SCORAD), PO‐SCORAD itch and sleep (P < 0·0001 for all). All respondents with severe PO‐SCORAD, POEM and PO‐SCORAD itch had borderline or abnormal HADS‐A and HADS‐D scores. Adults with AD vs. those without AD had higher prevalence of self‐reported healthcare‐diagnosed anxiety or depression in the past year (40·0% vs. 17·5%). Many adults with AD who had borderline and/or abnormal HADS‐A or HADS‐D scores reported no diagnosis of anxiety or depression.
Conclusions
AD is associated with significantly increased anxiety and depression, which may go undiagnosed.
What's already known about this topic?
Previous studies found higher rates of anxiety and depression in clinical cohorts of patients with atopic dermatitis.
What does this study add?
This study found dramatically higher rates of anxiety and depression among adults with atopic dermatitis in the U.S. population, which was primarily driven by atopic dermatitis severity.
Anxiety and depression often go undiagnosed in adults with atopic dermatitis.
Linked Comment: Nicholas and Drucker. Br J Dermatol 2019; 181:442–443.
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One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. ...However, published evidence of the protective effect of these antibodies is conflicting.
We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-1(42) and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-1(19) (responders versus nonresponders, 54%, 95% confidence interval CI 33%-68% and 18% 4%-30% relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2(FC27) 0.82, 95% CI 0.62-1.08, p = 0.16 and MSP-2(3D7) 0.92, 95% CI 0.75-1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens.
These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors' Summary.
We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML).
We recorded the clinical ...outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood.
Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio HR for death = 0.47, 95% confidence interval CI 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival.
The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.
Summary
Background
Structured patient‐reported outcomes of atopic dermatitis (AD) severity are not standardized in clinical practice.
Objectives
To determine the construct validity, internal ...consistency, cross‐cultural validity and floor or ceiling effects of multiple AD severity assessments.
Methods
This is a cross‐sectional, population‐based study of 2893 adults, including 602 adults who met a modified set of U.K. diagnostic criteria for AD. AD severity was assessed using self‐reported global AD severity, Patient‐Oriented Eczema Measure (POEM), Patient‐Oriented Scoring Atopic Dermatitis (PO‐SCORAD) and its objective and subjective components, and numerical rating scale (NRS)‐itch. Quality of life was assessed using Short‐Form (SF)‐12 mental and physical health scores, Short‐Form Six Dimensions (SF‐6D) health utility scores and Dermatology Life Quality Index (DLQI). Mental health was assessed with the Hospital Anxiety and Depression Scale (HADS).
Results
PO‐SCORAD, PO‐SCORAD objective and subjective subscores, NRS‐itch and POEM all had moderate‐to‐strong correlations with each other and DLQI, fair‐to‐moderate correlations with HADS‐anxiety and HADS‐depression, and inverse correlations with SF‐12 mental component score and SF‐6D (Pearson correlations, P < 0·001). All scores showed good criterion validity as judged by anova and receiver operator characteristics. PO‐SCORAD, PO‐SCORAD objective subscore and POEM had similarly good internal consistency (Cronbach's alpha = 0·84, 0·82 and 0·86); the PO‐SCORAD subjective subscore was less internally consistent (alpha = 0·57). All scores showed potentially poor cross‐cultural validity as demonstrated by uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity for multiple items. There were floor effects for POEM, but not for the other assessments.
Conclusions
PO‐SCORAD, PO‐SCORAD objective and subjective subscores, NRS‐itch and POEM appear to be valid for assessing AD severity in clinical practice.
What's already known about this topic?
Few studies have demonstrated the validity of the atopic dermatitis severity assessments Patient‐Oriented Scoring Atopic Dermatitis (PO‐SCORAD), PO‐SCORAD subscores, numerical rating scale (NRS)‐itch and Patient‐Oriented Eczema Measure (POEM).
What does this study add?
This study demonstrates that PO‐SCORAD, PO‐SCORAD subscores, NRS‐itch and POEM all had good construct validity in the assessment of atopic dermatitis severity in adults.
Only POEM demonstrated floor effects.
What are the clinical implications of this work?
PO‐SCORAD, PO‐SCORAD subscores, NRS‐itch and POEM all appear to have sufficient validity to be used as assessments of atopic dermatitis severity in clinical practice.
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Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were ...quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.
Summary
Background
In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical ...trials in atopic dermatitis (AD), including those supporting the recent approval of dupilumab.
Objectives
To evaluate the treatment effect of dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life.
Methods
LIBERTY AD SOLO 1 and 2 were two 16‐week, randomized, double‐blind trials enrolling adult patients with moderate‐to‐severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient‐Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769.
Results
At week 16, 278 of 449 dupilumab q2w‐treated patients (median age 36·0 years) and 396 of 443 placebo‐treated patients had IGA > 1. Among patients with IGA > 1 at week 16, dupilumab significantly improved several outcome measures compared with placebo: EASI (−48·9% vs. −11·3%, P < 0·001), pruritus NRS (−35·2% vs. −9·1%, P < 0·001), affected BSA (−23·1% vs. −4·5%, P < 0·001), POEM score ≥ 4‐point improvement (57·4% vs. 21·0%, P < 0·001) and DLQI score ≥ 4‐point improvement (59·3% vs. 24·4%, P < 0·001).
Conclusions
In patients with IGA > 1 at week 16, dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant dupilumab treatment effects.
What's already known about this topic?
An Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin) is considered the regulatory standard for treatment success in trials of patients with atopic dermatitis in the U.S.A.
It is currently unknown whether patients receiving dupilumab treatment for moderate‐to‐severe atopic dermatitis derive clinical and quality‐of‐life benefit even if they have an end‐of‐treatment IGA score > 1.
What's does this study add?
This post hoc analysis of patients with an end‐of‐treatment IGA score > 1 from two randomized, placebo‐controlled trials showed that after 16 weeks of treatment dupilumab significantly improved their outcome measures compared with placebo, including measures of signs, symptoms and quality of life.
These results show that the regulatory IGA ≤ 1 end point used in clinical trials significantly underestimates clinically relevant dupilumab treatment effects, underscoring potential limitations of the IGA scale.
Linked Comment: de Bruin‐Weller. Br J Dermatol 2019; 181:12–13.
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In endemic areas, pregnant women are highly susceptible to Plasmodium falciparum malaria characterized by the accumulation of parasitized red blood cells (pRBC) in the placenta. In subsequent ...pregnancies, women develop protective immunity to pregnancy-associated malaria and this has been hypothesized to be due to the acquisition of antibodies to the parasite variant surface antigen VAR2CSA. In this systematic review we provide the first synthesis of the association between antibodies to pregnancy-specific P. falciparum antigens and pregnancy and birth outcomes.
We conducted a systematic review and meta-analysis of population-based studies (published up to 07 June 2019) of pregnant women living in P. falciparum endemic areas that examined antibody responses to pregnancy-specific P. falciparum antigens and outcomes including placental malaria, low birthweight, preterm birth, peripheral parasitaemia, maternal anaemia, and severe malaria.
We searched 6 databases and identified 33 studies (30 from Africa) that met predetermined inclusion and quality criteria: 16 studies contributed estimates in a format enabling inclusion in meta-analysis and 17 were included in narrative form only. Estimates were mostly from cross-sectional data (10 studies) and were heterogeneous in terms of magnitude and direction of effect. Included studies varied in terms of antigens tested, methodology used to measure antibody responses, and epidemiological setting. Antibody responses to pregnancy-specific pRBC and VAR2CSA antigens, measured at delivery, were associated with placental malaria (9 studies) and may therefore represent markers of infection, rather than correlates of protection. Antibody responses to pregnancy-specific pRBC, but not recombinant VAR2CSA antigens, were associated with trends towards protection from low birthweight (5 studies).
Whilst antibody responses to several antigens were positively associated with the presence of placental and peripheral infections, this review did not identify evidence that any specific antibody response is associated with protection from pregnancy-associated malaria across multiple populations. Further prospective cohort studies using standardized laboratory methods to examine responses to a broad range of antigens in different epidemiological settings and throughout the gestational period, will be necessary to identify and prioritize pregnancy-specific P. falciparum antigens to advance the development of vaccines and serosurveillance tools targeting pregnant women.
Photochemical smog, characterized by high concentrations of ozone (O3) and fine particles (PM2.5) in the atmosphere, has become one of the top environmental concerns in China. Volatile organic ...compounds (VOCs), one of the key precursors of O3 and secondary organic aerosol (SOA) (an important component of PM2.5), have a critical influence on atmospheric chemistry and subsequently affect regional and global climate. Thus, VOCs have been extensively studied in many cities and regions in China, especially in the North China Plain, the Yangtze River Delta and the Pearl River Delta regions where photochemical smog pollution has become increasingly worse over recent decades. This paper reviews the main studies conducted in China on the characteristics and sources of VOCs, their relationship with O3 and SOA, and their removal technology. This paper also provides an integrated literature review on the formulation and implementation of effective control strategies of VOCs and photochemical smog, as well as suggestions for future directions of VOCs study in China.
Display omitted
•Characteristics and sources of VOCs in China are reviewed.•Relationship of VOCs with O3 and SOA in China are reviewed.•Integrated literature review on the control strategies of VOCs and photochemical smog is provided.•Future directions of VOC study in China are suggested.
ABSTRACT Our Galaxy is known to contain a central boxy/peanut-shaped bulge, yet the importance of a classical, pressure-supported component within the central part of the Milky Way is still being ...debated. It should be most visible at low metallicity, a regime that has not yet been studied in detail. Using metallicity-sensitive narrow-band photometry, the Pristine Inner Galaxy Survey (PIGS) has collected a large sample of metal-poor ($\rm {Fe/H}\, \lt -1.0$) stars in the inner Galaxy to address this open question. We use PIGS to trace the metal-poor inner Galaxy kinematics as function of metallicity for the first time. We find that the rotational signal decreases with decreasing Fe/H , until it becomes negligible for the most metal-poor stars. Additionally, the velocity dispersion increases with decreasing metallicity for $-3.0 \lt \rm {Fe/H}\, \lt -0.5$, with a gradient of −44 ± 4 km s−1 dex−1. These observations may signal a transition between Galactic components of different metallicities and kinematics, a different mapping on to the boxy/peanut-shaped bulge for former disc stars of different metallicities and/or the secular dynamical and gravitational influence of the bar on the pressure-supported component. Our results provide strong constraints on models that attempt to explain the properties of the inner Galaxy.
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