Summary
Background
Interleukin (IL)‐31 affects the inflammatory response, is involved in epidermal barrier disruption in atopic dermatitis (AD) and plays a key role in pruritus. Nemolizumab, a ...humanized monoclonal antibody against IL‐31 receptor A, reduced pruritus in patients with AD after a 16‐week administration period.
Objectives
To examine the long‐term effectiveness and safety of nemolizumab in patients aged ≥ 13 years with AD and inadequately controlled moderate‐to‐severe pruritus.
Methods
In two long‐term phase III studies, nemolizumab 60 mg every 4 weeks (Q4W) was administered subcutaneously, concomitantly with topical treatments. Study‐JP01 patients received double‐blind nemolizumab or placebo for 16 weeks, and then entered a 52‐week extension period in which all patients received nemolizumab (nemolizumab/nemolizumab and placebo/nemolizumab groups). Study‐JP02 patients received nemolizumab for 52 weeks. Both studies included an 8‐week follow‐up period.
Results
Study‐JP01 nemolizumab/nemolizumab and placebo/nemolizumab, and Study‐JP02 nemolizumab groups comprised 143, 72 and 88 patients, respectively. In the nemolizumab/nemolizumab group, there were clinically meaningful improvements from the start of treatment to week 68 in the pruritus visual analogue scale (66% decrease) and Eczema Area and Severity Index (78% decrease). Quality of life (QoL) indicators improved after the first nemolizumab dose; improvements were maintained during the follow‐up period. The long‐term safety profile was consistent with previous studies, with no unexpected late‐onset adverse events.
Conclusions
Nemolizumab 60 mg Q4W with concomitant topical treatments in patients with AD and inadequately controlled moderate‐to‐severe pruritus produced a continuous improvement in pruritus, signs of AD, and QoL for up to 68 weeks, with a favourable safety profile.
What is already known about this topic?
Pruritus, a characteristic symptom of atopic dermatitis (AD), causes distress to patients, reducing quality of life and affecting sleep and daily activities.
Nemolizumab (plus topical agents) has previously been shown to reduce pruritus associated with AD to a greater extent than placebo over 16 weeks.
As patients with AD suffer from repeated phases of relapse and remission, it is important to extend the periods of relief from pruritus and rash.
What does this study add?
Data from two long‐term (≥ 52 weeks) phase III studies confirmed that nemolizumab plus topical agents increased or maintained effectiveness through the study duration, with continuous improvement after week 16.
Acute itchiness or flare of AD were rarely observed during the 8‐week follow‐up period.
The results support the long‐term use of nemolizumab with concomitant topical agents in patients with AD and inadequately controlled moderate‐to‐severe pruritus.
Linked Comment: S. Barbarot. Br J Dermatol 2022; 186:608.
Plain language summary available online
Plants respond and adapt to drought, cold and high-salinity stresses in order to survive. In this study, we applied Arabidopsis Affymetrix tiling arrays to study the whole genome transcriptome under ...drought, cold, high-salinity and ABA treatment conditions. The bioinformatic analysis using the tiling array data showed that 7,719 non-AGI transcriptional units (TUs) exist in the unannotated 'intergenic' regions of Arabidopsis genome. These include 1,275 and 181 TUs that are induced and downregulated, respectively, by the stress or ABA treatments. Most of the non-AGI TUs are hypothetical non-protein-coding RNAs. About 80% of the non-AGI TUs belong to pairs of the fully overlapping sense-antisense transcripts (fSATs). Significant linear correlation between the expression ratios (treated/untreated) of the sense TUs and the ratios of the antisense TUs was observed in the SATs of AGI code/non-AGI TU. We studied the biogenesis mechanisms of the stress- or ABA-inducible antisense RNAs and found that the expression of sense TUs is necessary for the stress- or ABA-inducible expression of the antisense TUs in the fSATs (AGI code/non-AGI TU).
Noninvasive measurement of the distribution and oxygenation state of hemoglobin (Hb) inside the tissue is strongly required to analyze the tumor-associated vasculatures. We developed a photoacoustic ...imaging (PAI) system with a hemispherical-shaped detector array (HDA). Here, we show that PAI system with HDA revealed finer vasculature, more detailed blood-vessel branching structures, and more detailed morphological vessel characteristics compared with MRI by the use of breast shape deformation of MRI to PAI and their fused image. Morphologically abnormal peritumoral blood vessel features, including centripetal photoacoustic signals and disruption or narrowing of vessel signals, were observed and intratumoral signals were detected by PAI in breast cancer tissues as a result of the clinical study of 22 malignant cases. Interestingly, it was also possible to analyze anticancer treatment-driven changes in vascular morphological features and function, such as improvement of intratumoral blood perfusion and relevant changes in intravascular hemoglobin saturation of oxygen. This clinical study indicated that PAI appears to be a promising tool for noninvasive analysis of human blood vessels and may contribute to improve cancer diagnosis.
Ceramides are major constituents of stratum corneum (SC) intercellular lipids involved in skin barrier function. The ratio of molecular species of ceramides and their correlation with disease ...severity was examined in patients with atopic dermatitis (AD). Thirty‐eight patients with AD and 32 healthy controls (HCs) were assessed for transepidermal water loss, SC collection and clinical assessment. The ceramide content of different molecular species in the samples was quantified using high‐performance liquid chromatography coupled with tandem mass spectrometry. Unsaturated acyl chains of both covalently bound and free ceramides EOS were higher in AD lesional skin than those in AD non‐lesional or normal HC skin. The proportion of unsaturated acyl chains (C30:1, C32:1 and C34:1) was higher than other ceramide molecular species among covalently bound and free ceramides EOS in patients with AD. The proportion of unsaturated acyl chains in covalently bound ceramides was positively correlated with transepidermal water loss (r = 0.600) when considering the total number of non‐lesional and lesional skin. Additionally, thymus and activation‐regulated chemokine (TARC) showed a positive correlation with unsaturated acyl chains proportion in AD non‐lesional (r = 0.676) and lesional (r = 0.503) skin. Our study is the first to show the increase in unsaturated acyl chains of both covalently bound and free ceramides EOS in lesional and non‐lesional skin in AD for each molecular species. This increase is associated with dryness and impaired barrier function, which correlates with TARC levels, a marker for the degree of type 2 inflammation. We speculate that type 2 inflammation exacerbation leads to abnormal epidermal lipid metabolism in the skin of patients with AD.
Summary
Background
Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin‐4 and interleukin‐13. International phase II and III studies have evaluated the efficacy and ...safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported.
Objectives
To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate‐to‐severe AD.
Methods
We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16‐week, phase IIb dose‐finding trial (AD‐1021; NCT01859988); a 16‐week, phase III, placebo‐controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52‐week, phase III, placebo‐controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986).
Results
Twenty‐seven, 106 and 117 Japanese patients were enrolled in AD‐1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection‐site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation‐regulated chemokine and gradual IgE reductions.
Conclusions
Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate‐to‐severe AD.
What's already known about this topic?
Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T‐cell activation profiles have been observed.
International clinical studies in adults with moderate‐to‐severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin‐4 and interleukin‐13, key molecules in type 2 inflammation.
The effects of dupilumab in Japanese patients specifically have not yet been reported.
What does this study add?
Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate‐to‐severe AD.
The effects were comparable with those observed in the overall study population.
Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.
Plain language summary available online
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Bipolar segmental clavicle fractures are simultaneous clavicle fractures of both proximal and distal ends. Few case reports describing these fractures have been published, and the management of these ...injuries have remained controversial. Non-operative treatment is likely to result in poor shoulder function due to the instability of the fracture in patients with high physical demands. In contrast, surgical treatment with fixation of both proximal and distal ends of the clavicle possibly may cause life-threatening complications. We present a 74-year old female farmer who had injured her left shoulder and was diagnosed with a bipolar segmental clavicle fracture. Taking the fracture mechanism into consideration, we surgically treated only the distal end of the clavicle fracture with a locking plate. The proximal end of the clavicle fracture was treated without surgical intervention. Both fracture sites achieved bony union after four months and she returned to her activities as a farmer. Quick DASH score was 5.0 with excellent results at three years after operation.
Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance ...phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients.
Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association ...studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.
The faecal microbiota of 166 healthy Japanese newborns was analysed periodically from day 1 after birth until the age of 3 years by using the reverse transcription-quantitative PCR. Faecal pH and the ...organic acid concentration were also examined. Colonisation by both facultative anaerobes and strict anaerobes was confirmed in 95% of the meconium tested. Bifidobacterium-predominant microbiota was established subsequently in most of the infants by 3 months after birth. Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium catenulatum group and Bifidobacterium bifidum were the species mainly detected. Intergroup correlation analysis revealed that the bifidobacterial population levels, but not other strict anaerobe groups, were found to be negatively correlated with those of the Enterobacteriaceae from 7 days until 3 months after birth. Faecal pH was maintained at about 6 until 6 months after birth and reached 6.6 at 3 years after birth. The initial concentration of faecal organic acids (19 μM/g of faeces) just after birth increased until 3 years after birth to the level of 111 μM/g of faeces. Early start of feeding formula milk promoted colonisation by obligate anaerobes such as the Clostridium coccoides group, the Clostridium leptum subgroup, Prevotella, and Atopobium cluster during the 3 months after birth. Population levels of the bifidobacteria until 1 month after birth and those of the Bacteroides fragilis group until 6 months after birth were lower in infants delivered by Caesarean section than in those delivered normally. The results suggested that both earlier start of feeding of formula milk and the mode of infant delivery were found to be important in the development of intestinal microbiota in early infancy.
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