Journal Club-2021.11.19
Lancet. 2021 Oct 30;398(10311):1581-1592. doi: 10.1016/S0140-6736(21)01256-3.Epub 2021 Oct 28.
Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study
Emmanuel Gonzales 1, Winita Hardikar 2, Michael Stormon 3, Alastair Baker 4, Loreto Hierro 5, Dorota Gliwicz 6, Florence Lacaille 7, Alain Lachaux 8, Ekkehard Sturm 9, Kenneth D R Setchell 10, Ciara Kennedy 11, Alejandro Dorenbaum 12, Jana Steinmetz 13, Nirav K Desai 14, Andrew J Wardle 15, Will Garner 15, Pamela Vig 15, Thomas Jaecklin 16, Etienne M Sokal 17, Emmanuel Jacquemin 18Affiliations expand
- PMID: 34755627
- DOI: 10.1016/S0140-6736(21)01256-3
Abstract
Background: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.
Methods: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.
Findings: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.
Interpretation: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.
Funding: Mirum Pharmaceuticals.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Journal club 2021-05-21
Nat Commun 2021 Apr 12;12(1):2185. doi: 10.1038/s41467-021-22479-4.
Therapeutic B-cell depletion reverses progression of Alzheimer’s disease
Ki Kim # 1, Xin Wang # 1, Emeline Ragonnaud # 1, Monica Bodogai # 1, Tomer Illouz 2 3 4, Marisa DeLuca 1, Ross A McDevitt 5, Fedor Gusev 6, Eitan Okun 2 3 4, Evgeny Rogaev 6 7 8 9, Arya Biragyn 10
- PMID: 33846335
- PMCID: PMC8042032
- DOI: 10.1038/s41467-021-22479-4
Abstract
The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ+ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.
Journal club 2021-05-13
Nat Commun. 2020 Dec 11;11(1):6363. doi: 10.1038/s41467-020-19931-2.
Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system
Grégoire Chevalier 1, Eleni Siopi 2, Laure Guenin-Macé 3, Maud Pascal 1 2, Thomas Laval 3, Aline Rifflet 4, Ivo Gomperts Boneca 4, Caroline Demangel 3, Benoit Colsch 5, Alain Pruvost 5, Emeline Chu-Van 5, Aurélie Messager 5, François Leulier 6, Gabriel Lepousez 2, Gérard Eberl 7, Pierre-Marie Lledo 8
- PMID: 33311466
- PMCID: PMC7732982
- DOI: 10.1038/s41467-020-19931-2
Abstract
Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.
Journal club 2021.05.07
Br J Dermatol. 2018 Sep;179(3):669-678. doi: 10.1111/bjd.16498.Epub 2018 Jun 21.
Itch in dermatomyositis: the role of increased skin interleukin-31
H J Kim 1 2 3, M Zeidi 1 2, D Bonciani 1 2 4, S M Pena 2, J Tiao 1 2, S Sahu 1 2, V P Werth 1 2
- PMID: 29494763
- PMCID: PMC6119520
- DOI: 10.1111/bjd.16498
Abstract
Background: Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch.
Objectives: To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch.
Methods: Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM.
Results: Among 191 patients with DM, 50·8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0·34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0·67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31-producing cells, and CD4+ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells.
Conclusions: Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM.
Journal Club 2021.04.02
Transl Psychiatry. 2019 Aug 5;9(1):189. doi: 10.1038/s41398-019-0525-3.
Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice
Jing Sun 1, Jingxuan Xu 2, Yi Ling 1, Fangyan Wang 3, Tianyu Gong 4, Changwei Yang 4, Shiqing Ye 4, Keyue Ye 4, Dianhui Wei 4, Ziqing Song 4, Danna Chen 4, Jiaming Liu 5 6
- PMID: 31383855
- PMCID: PMC6683152
- DOI: 10.1038/s41398-019-0525-3
Abstract
Alzheimer’s disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.
Journal Club – 2021.03.26
The influence of adolescent nicotine exposure on ethanol intake and brain gene expression
PLoS One . 2018 Jun 18;13(6):e0198935. doi: 10.1371/journal.pone.0198935. eCollection 2018.
Constanza P Silva 1, William J Horton 2, Michael J Caruso 1, Aswathy Sebastian 3, Laura C Klein 1, Istvan Albert 3, Helen M Kamens 1
- PMID: 29912970
- PMCID: PMC6005571
- DOI: 10.1371/journal.pone.0198935
Abstract
Nicotine and alcohol are often co-abused. Adolescence is a vulnerable period for the initiation of both nicotine and alcohol use, which can lead to subsequent neurodevelopmental and behavioral alterations. It is possible that during this vulnerable period, use of one drug leads to neurobiological alterations that affect subsequent consumption of the other drug. The aim of the present study was to determine the effect of nicotine exposure during adolescence on ethanol intake, and the effect of these substances on brain gene expression. Forty-three adolescent female C57BL/6J mice were assigned to four groups. In the first phase of the experiment, adolescent mice (PND 36-41 days) were exposed to three bottles filled with water or nicotine (200 μg/ml) for 22 h a day and a single bottle of water 2 h a day for six days. In the second phase (PND 42-45 days), the 4-day Drinking-in-the-Dark paradigm consisting of access to 20% v/v ethanol or water for 2h or 4h (the last day) was overlaid during the time when the mice did not have nicotine available. Ethanol consumption (g/kg) and blood ethanol concentrations (BEC, mg %) were measured on the final day and whole brains including the cerebellum, were dissected for RNA sequencing. Differentially expressed genes (DEG) were detected with CuffDiff and gene networks were built using WGCNA. Prior nicotine exposure increased ethanol consumption and resulting BEC. Significant DEG and biological pathways found in the group exposed to both nicotine and ethanol included genes important in stress-related neuropeptide signaling, hypothalamic-pituitary-adrenal (HPA) axis activity, glutamate release, GABA signaling, and dopamine release. These results replicate our earlier findings that nicotine exposure during adolescence increases ethanol consumption and extends this work by examining gene expression differences which could mediate these behavioral effects.
Crotamiton, an Anti-Scabies Agent, Suppresses Histamine- and Chloroquine-Induced Itch Pathways in Sensory Neurons and Alleviates Scratching in Mice
2019-05-24 Journal Club
Pruritus in ordinary scabies: IL-31 from macrophages induced by overexpression of TSLP and periostin.
Author information
Abstract
BACKGROUND:
Scabies is a common contagious skin disease caused by an infestation of the skin by Sarcoptes scabiei var. hominis. A hallmark symptom of scabies is severe itch.
METHODS:
We sought to determine the generation of a pruritogenic cytokine, interleukin (IL)-31, together with immune profiles in skin lesions of ordinary scabies through immunohistochemical and immunofluorescent studies. To elucidate the pathological mechanisms of IL-31 generation, murine peritoneal macrophages were stimulated with various T helper 2 (Th2) cytokines and proteins ex vivo.
RESULTS:
A large number of CCR4(+) Th2 cells, eosinophils, and basophils infiltrated in scabies lesions. Increased generation of IL-31, TSLP, and periostin was also observed. A major population of IL-31(+) cells were Arginase-1(+)/CD163(+) M2 macrophages. Murine peritoneal macrophages showed an M2 phenotype and generated IL-31 when stimulated with TSLP and periostin.
CONCLUSION:
IL-31 appeared to be largely generated by M2 macrophages in ordinary scabies lesions. This IL-31 induction was mediated by TSLP and periostin. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS:
TSLP ; IL-31; macrophage; periostin; scabies
2019.05.03
TRPV1 mediates inflammation and hyperplasia in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice.
Author information
Abstract
BACKGROUND:
Transient Receptor Potential Vanilloid 1 (TRPV1) is known to mediate itch and neurogenic inflammation, but the role of TRPV1 in psoriasiform dermal inflammation is poorly understood.
OBJECTIVE:
To investigate the function of TRPV1 in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice.
METHODS:
Following daily treatment of topical IMQ cream for consecutive 5 days in C57BL/6 wide-type (WT) and TRPV1 gene knockout (KO) mice, we assessed the psoriasis severity index (PSI) scores, transepidermal water loss (TEWL), dermal inflammatory infiltrates, as well as gene expression levels for psoriasis related genes in mouse skin lesions.
RESULTS:
Compared with WT mice, the clinical and TEWL scores, the extent of skin hyperplasia, the area of Munro microabscesses (MM) and angiogenesis of psoriasis were all significantly decreased in TRPV1 KO mice triggered with IMQ, suggesting a reduction in skin inflammation and barrier defects. In addition, the infiltration of CD45+ leukocytes, mast cells as well as CD3+ T cells was all reduced in the IMQ-treated skin of TRPV1 KO mice. Quantitative Real-time PCR (RT-qPCR) revealed that expression levels of IL-1β, IL-6, IL-23, S100A8 were decreased while IL-10 was increased in TRPV1 KO mice.
CONCLUSIONS:
In summary, key markers of psoriatic inflammation and epidermal hyperplasia are reduced in TRPV1 KO mice, indicating the involvement of TRPV1 in the psoriasiform inflammation and suggesting its potential as a therapeutic target.
Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
KEYWORDS:
Itch; Pain neuroinflammation; Psoriasis
- PMID:
- 30527377
- DOI:
- 10.1016/j.jdermsci.2018.11.009