Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. METHODS: Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. RESULTS: Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). CONCLUSION: This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Epidemiology and treatment of children with hereditary angioedema in Germany: A retrospective database study.

BACKGROUND: Hereditary angioedema (HAE) is a potentially life-threatening inherited disease that causes recurrent, serious, and debilitating episodes of swelling. While evidence has improved in adult patients, data on the epidemiology and treatment of pediatric patients with HAE remain very limited. The aim of this study was to determine the incidence and prevalence of pediatric patients with HAE aged <12 years, as well as treatment patterns, co-medication, and specialties involved. METHODS: In this retrospective study (2016-2021), the German IQVIATM pharmacy claims (LRx) database was used to analyze prescriptions of HAE-specific treatments and co-medications. RESULTS: We found an HAE prevalence in pediatric patients aged <12 years of 2.51:100,000 and a 12-month prevalence of up to 1.02:100,000 between 2016 and 2021. Most HAE treatments were prescribed by outpatient clinics and pediatricians, with an increasing proportion of icatibant as an on-demand treatment and low rates of long-term prophylaxis (LTP). The prescription rate of analgesics as the most common co-medication decreased notably after HAE diagnosis. CONCLUSION: Our findings provide insights into the epidemiology and current pediatric HAE treatment landscape in Germany. The obtained HAE prevalence in pediatric patients aged <12 years was even higher than the previously reported average of overall cohorts, whereas the LTP rate was low, which might indicate an unmet need for newer LTP treatment options in pediatric patients.

Detrital Carbonate Minerals in Earth's Element Cycles.

We investigate if the commonly neglected riverine detrital carbonate fluxes might reconciliate several chemical mass balances of the global ocean. Particulate inorganic carbon (PIC) concentrations in riverine suspended sediments, that is, carbon contained by these detrital carbonate minerals, were quantified at the basin and global scale. Our approach is based on globally representative data sets of riverine suspended sediment composition, catchment properties, and a two-step regression procedure. The present-day global riverine PIC flux is estimated at 3.1 ± 0.3 Tmol C/y (13% of total inorganic carbon export and 4% of total carbon export) with a flux-weighted mean concentration of 0.26 ± 0.03 wt%. The flux prior to damming was 4.1 ± 0.5 Tmol C/y. PIC fluxes are concentrated in limestone-rich, rather dry and mountainous catchments of large rivers near Arabia, South East Asia, and Europe with 2.2 Tmol C/y (67.6%) discharged between 15°N and 45°N. Greenlandic and Antarctic meltwater discharge and ice-rafting additionally contribute 0.8 ± 0.3 Tmol C/y. This amount of detrital carbonate minerals annually discharged into the ocean implies a significant contribution of calcium (∼4.75 Tmol Ca/y) and alkalinity fluxes (∼10 Tmol (eq)/y) to marine mass balances and moderate inputs of strontium (∼5 Gmol Sr/y) based on undisturbed riverine and cryospheric inputs and a dolomite/calcite ratio of 0.1. Magnesium fluxes (∼0.25 Tmol Mg/y), mostly hosted by less-soluble dolomite, are rather negligible. These unaccounted fluxes help in elucidating respective marine mass balances and potentially alter conclusions based on these budgets.

Exploring Spatially Explicit Changes in Carbon Budgets of Global River Basins during the 20th Century.

Rivers play an important role in the global carbon (C) cycle. However, it remains unknown how long-term river C fluxes change because of climate, land-use, and other environmental changes. Here, we investigated the spatiotemporal variations in global freshwater C cycling in the 20th century using the mechanistic IMAGE-Dynamic Global Nutrient Model extended with the Dynamic In-Stream Chemistry Carbon module (DISC-CARBON) that couples river basin hydrology, environmental conditions, and C delivery with C flows from headwaters to mouths. The results show heterogeneous spatial distribution of dissolved inorganic carbon (DIC) concentrations in global inland waters with the lowest concentrations in the tropics and highest concentrations in the Arctic and semiarid and arid regions. Dissolved organic carbon (DOC) concentrations are less than 10 mg C/L in most global inland waters and are generally high in high-latitude basins. Increasing global C inputs, burial, and CO2 emissions reported in the literature are confirmed by DISC-CARBON. Global river C export to oceans has been stable around 0.9 Pg yr-1. The long-term changes and spatial patterns of concentrations and fluxes of different C forms in the global river network unfold the combined influence of the lithology, climate, and hydrology of river basins, terrestrial and biological C sources, in-stream C transformations, and human interferences such as damming.

Non-invasive Ventilation for Pediatric Hypoxic Acute Respiratory Failure Using a Simple Anesthetic Mask With 3D Printed Adaptor: A Case Report.

Non-invasive ventilation (NIV) is increasingly used in the supportive treatment of acute respiratory failure in children in the pediatric intensive care unit (PICU). However, finding an optimal fitting commercial available NIV face mask is one of the major challenges in daily practice, in particular for young children and those with specific facial features. Large air leaks and pressure-related skin injury due to suboptimal fit are important complications associated with NIV failure. Here, we describe a case of a 4-year old boy with cardiofaciocutaneous syndrome and rhinovirus-associated hypoxic acute respiratory failure who was successfully supported with NIV delivered by a simple anesthetic mask connected to a headgear by an in-house developed and 3D printed adaptor. This case is an example of the clinical challenge related to pediatric NIV masks in the PICU, but also shows the potential of alternative NIV interfaces e.g., by using a widely available and relatively cheap simple anesthetic mask. Further personalized strategies (e.g., by using 3D scanning and printing techniques) that optimize NIV mask fitting in children are warranted.

Lysosomotropic beta blockers induce oxidative stress and IL23A production in Langerhans cells.

Oxidative stress and Th17 cytokines are important mediators of inflammation. Treatment with beta-adrenoceptor (ADRB) antagonists (beta-blockers) is associated with induction or aggravation of psoriasis-like skin inflammation, yet the underlying mechanisms are poorly understood. Herein, we identify lysosomotropic beta-blockers as critical inducers of IL23A in human monocyte-derived Langerhans-like cells under sterile-inflammatory conditions. Cytokine release was not mediated by cAMP, suggesting the involvement of ADRB-independent pathways. NFKB/NF-κB and MAPK14/p38 activation was required for propranolol-induced IL23A secretion whereas the NLRP3 inflammasome was dispensable. MAPK14 regulated recruitment of RELB to IL23A promoter regions. Without affecting the ubiquitin-proteasome pathway, propranolol increased lysosomal pH and induced a late-stage block in macroautophagy/autophagy. Propranolol specifically induced reactive oxygen species production, which was critical for IL23A secretion, in Langerhans-like cells. Our findings provide insight into a potentially crucial immunoregulatory mechanism in cutaneous dendritic cells that may explain how lysosomotropic drugs regulate inflammatory responses. ABBREVIATIONS: ATF: activating transcription factor; DC: dendritic cell; ChIP: chromatin immunoprecipitation; gDNA: genomic DNA; IL: interleukin; LAMP1: lysosomal associated membrane protein 1; LC: Langerhans cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MoDC: monocyte-derived DC; MoLC: monocyte-derived Langerhans-like cell; mtDNA: mitochondrial DNA; NAC: N-acetyl-L-cysteine; NLRP3: NLR family pyrin domain containing 3; PBMC: peripheral blood mononuclear cell; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6; TNF: tumor necrosis factor; Ub: ubiquitin.

Characterization of reconstructed human skin containing Langerhans cells to monitor molecular events in skin sensitization.

Human cell-based approaches to assess defined key events in allergic contact dermatitis (ACD) are well-established, but lack cutaneous penetration and biotransformation as well as cellular cross-talk. Herein, we integrated in vitro-generated immature MUTZ-3-derived Langerhans-like cells (MUTZ-LCs) or monocyte-derived LC-like cells (MoLCs) into reconstructed human skin (RHS), consistent of a stratified epidermis formed by primary keratinocytes on a dermal compartment with collagen-embedded primary fibroblasts. LC-like cells were mainly localized in the epidermal compartment and distributed homogenously in accordance with native human skin. Topical application of the strong contact sensitizer 2,4-dinitrochlorobenzene (DNCB) induced IL-6 and IL-8 secretion in RHS with LC-like cells, whereas no change was observed in reference models. Increased gene expression of CD83, PD-L1, and CXCR4 in the dermal compartment indicated LC maturation. Importantly, exposure to DNCB enhanced mobility of the LC-like cells from epidermal to dermal compartments. In response to the moderate sensitizer isoeugenol and irritant sodium dodecyl sulphate, the obtained response was less pronounced. In summary, we integrated immature and functional MUTZ-LCs and MoLCs into RHS and provide a unique comparative experimental setting to monitor early events during skin sensitization.

Inflammatory conditions distinctively alter immunological functions of Langerhans-like cells and dendritic cells in vitro.

The specific function of human skin-resident dendritic cell (DC) subsets in the regulation of immunity or tolerance is still a matter of debate. Langerhans cells (LC) induce anti-viral immune responses but, conversely to dermal DC, maintain tolerance to bacteria. However, the definite function of epidermal LC and cutaneous DC appears even more complex under inflammatory conditions. Here we investigated the immune responses of human immature monocyte-derived DC (MoDC) and LC-like cells (MoLC) upon stimulation with different Toll-like receptor ligands in the presence or absence of pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). In MoDC, bacterial antigens selectively up-regulated CD83 and CD86 expression and induced the release of T helper type 1 (Th1) and Th17 cytokines and led to a higher CCR7-dependent migratory capacity compared with a low responsiveness of MoLC. Importantly, MoLC activation with lipopolysaccharide under inflammatory conditions strongly enhanced a phenotypically mature state, increased IL-12p70, IL-23 and IL-6 production and Th1 cytokine secretion by CD4(+) T cells. Treatment with poly(I:C) specifically up-regulated surface expression of co-stimulatory molecules and increased release of IL-12p70 in MoLC and co-stimulation with TNF-α and IL-1ß further elevated Th1 and Th17 cytokine production. Poly(I:C)-induced up-regulation of type I interferon mRNA levels in MoLC and MoDC was Toll-like receptor 3-dependent but not, or only weakly, modulated by pro-inflammatory cytokines. Our results indicate that inflammatory conditions greatly facilitate recognition of bacteria by MoLC. Furthermore, we suggest a critical involvement of both subsets in innate defence against viruses, whereas inflammatory skin environments additionally favour MoLC as potent inducers of Th1 and Th17 cytokines.

Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells.

Recent studies suggest a role for autophagy in the secretion of IL-1 cytokines regulating the development of inflammatory diseases. The antimalarial drug and autophagy/lysosome inhibitor chloroquine (CHQ) is considered as potential trigger of drug-induced or drug-aggravated psoriasis, in which Th17 cells sustain a persistent inflammation. In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1ß. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4(+) T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late autophagy inhibitors, whereas PI3K inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.