Dissecting neuron-specific functions of circadian genes using modified cell-specific CRISPR approaches.

Circadian behavioral rhythms in Drosophila melanogaster are regulated by about 75 pairs of brain neurons. They all express the core clock genes but have distinct functions and gene expression profiles. To understand the importance of these distinct molecular programs, neuron-specific gene manipulations are essential. Although RNAi based methods are standard to manipulate gene expression in a cell-specific manner, they are often ineffective, especially in assays involving smaller numbers of neurons or weaker Gal4 drivers. We and others recently exploited a neuron-specific CRISPR-based method to mutagenize genes within circadian neurons. Here, we further explore this approach to mutagenize three well-studied clock genes: the transcription factor gene vrille, the photoreceptor gene Cryptochrome (cry), and the neuropeptide gene Pdf (pigment dispersing factor). The CRISPR-based strategy not only reproduced their known phenotypes but also assigned cry function for different light-mediated phenotypes to discrete, different subsets of clock neurons. We further tested two recently published methods for temporal regulation in adult neurons, inducible Cas9 and the auxin-inducible gene expression system. The results were not identical, but both approaches successfully showed that the adult-specific knockout of the neuropeptide Pdf reproduces the canonical loss-of-function mutant phenotypes. In summary, a CRISPR-based strategy is a highly effective, reliable, and general method to temporally manipulate gene function in specific adult neurons.

Risk of atopic dermatitis and the atopic march paradigm in children of mothers with atopic illnesses: A birth cohort study from the United Kingdom.

BACKGROUND: Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring. OBJECTIVE: (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom. METHODS: We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI]). RESULTS: Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first. CONCLUSION: Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway.

Neuropsychiatric disorders in adults with atopic dermatitis: A population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) may be associated with an increased burden of neuropsychiatric outcomes such as anxiety and depression, but longitudinal data on the impact of AD severity is lacking, and a comprehensive assessment of neuropsychiatric disease in adults with AD is needed. OBJECTIVES: Determine risk of incident neuropsychiatric disease among adults with AD by severity. METHODS: A cohort study using electronic health records data from UK general practices from 1994 to 2015. Adults (≥18 years) with AD were matched on age, practice and index date to patients without AD. AD severity was categorized using treatments and dermatology referrals. Outcomes were incident anxiety, depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism, obsessive-compulsive disorder (OCD), suicidality and completed suicide. RESULTS: Comparing 625,083 adults with AD to 2,678,888 adults without AD, AD was associated with higher risk of anxiety [HR 1.14 (1.13-1.15)], depression [1.14 (1.13-1.15)] and OCD [1.48 (1.38-1.58)] across all severities. Mild or moderate AD was also associated with higher risk of autism, ADHD, bipolar disorder and suicidality. CONCLUSIONS: Atopic dermatitis is associated with a higher risk of multiple neuropsychiatric conditions, but these risks differ by specific condition and AD severity. Clinicians should inquire about mental health in patients with AD.

Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures.

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N-hydroxylase (KtzI) and N-N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with 15NH4Cl and applying 1H-15N heteronuclear multiple bond correlation (HMBC) along with 1H-15N heteronuclear single quantum coherence (HSQC) and 1H-15N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid (1), previously reported chloptosin (2) in group I, depsidomycin D (3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B (4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A (4) inhibited STAT3 activation and induced G2/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A (4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams.

The logical and effective discovery of macrolactams, structurally unique natural molecules with diverse biological activities, has been limited by a lack of targeted search methods. Herein, a targeted discovery method for natural macrolactams was devised by coupling genomic signature-based PCR screening of a bacterial DNA library with spectroscopic signature-based early identification of macrolactams. DNA library screening facilitated the efficient selection of 43 potential macrolactam-producing strains (3.6% of 1,188 strains screened). The PCR amplicons of the amine-deprotecting enzyme-coding genes were analyzed to predict the macrolactam type (α-methyl, α-alkyl, or ß-methyl) produced by the hit strains. 1H-15N HSQC-TOCSY NMR analysis of 15N-labeled culture extracts enabled macrolactam detection and structural type assignment without any purification steps. This method identified a high-titer Micromonospora strain producing salinilactam (1), a previously reported α-methyl macrolactam, and two Streptomyces strains producing new α-alkyl and ß-methyl macrolactams. Subsequent purification and spectroscopic analysis led to the structural revision of 1 and the discovery of muanlactam (2), an α-alkyl macrolactam with diene amide and tetraene chromophores, and concolactam (3), a ß-methyl macrolactam with a [16,6,6]-tricyclic skeleton. Detailed genomic analysis of the strains producing 1-3 identified putative biosynthetic gene clusters and pathways. Compound 2 displayed significant cytotoxicity against various cancer cell lines (IC50 = 1.58 µM against HCT116), whereas 3 showed inhibitory activity against Staphylococcus aureus sortase A. This genomic and spectroscopic signature-based method provides an efficient search strategy for new natural macrolactams and will be generally applicable for the discovery of nitrogen-bearing natural products.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Malignancy risk in patients with atopic dermatitis: a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is associated with immunological dysfunction, which may influence cancer development. Previous studies of AD and cancer demonstrate inconsistent results and few of these studies examined children or AD severity and treatment. OBJECTIVES: To determine malignancy risk among children and adults with AD. METHODS: We conducted a cohort study using electronic health records data from UK general practices in The Health Improvement Network between 1994 and 2015. Children (< 18 years old) and adults (≥ 18 years old) with AD were matched on age, practice and index date to patients without AD. AD was categorized as mild, moderate or severe using treatments and dermatology referrals as proxies. The primary outcome was any incident malignancy, including in situ malignancy, identified using diagnosis codes and categorized into haematological, skin and solid organ malignancies. Secondary outcomes included specific malignancies: leukaemia, lymphoma, melanoma, nonmelanoma skin cancer (NMSC) and common solid-organ cancers. RESULTS: Among 409 431 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) and 1 809 029 children without AD who had median follow-up of 5-7 years, the incidence rates of malignancy were 1.9-3.4 and 2.0 per 10 000 person-years (PY), respectively. The adjusted risk of malignancy overall did not differ with respect to AD [hazard ratio (HR) 1.02 (95% confidence interval 0.92-1.12)]. Severe AD was associated with increased lymphoma risk [HR 3.18 (1.41-7.16), excluding cutaneous T-cell lymphoma (CTCL)], and mild AD was associated with increased NMSC risk [1.55 (1.06-2.27)]. Among 625 083 adults with AD (65.7% mild, 31.4% moderate, 2.9% severe) and 2 678 888 adults without AD who had median follow-up of 5 years, incidence rates of malignancy were 97.4-125.3 per 10 000 PY and 103.7 per 10 000 PY, respectively. The adjusted risk of any malignancy did not differ with respect to AD [HR 1.00 (0.99-1.02)]. However, adults with severe AD had a twofold higher risk of non-CTCL lymphoma. AD was also associated with slightly higher skin cancer risk [HR 1.06 (1.04-1.08)] and slightly lower solid cancer risk [0.97 (0.96-0.98)] but results varied by specific cancers and AD severity. CONCLUSIONS: Epidemiological evidence does not support a strong overall malignancy risk in AD but lymphoma risk may be increased with severe AD.

In utero or early in life exposure to antibiotics and the risk of childhood atopic dermatitis, a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disease of the skin that begins early in life and can be lifelong. The purpose of our study was to evaluate whether fetal exposure and/or early life exposure of a child to antibiotics increases the risk of early onset AD. OBJECTIVE: We hypothesize that antibiotic exposure in utero or early in life (e.g., first 90 days) increases the likelihood that children develop AD. METHODS: Utilizing a large prospectively collected electronic medical records database, we studied the association of antibiotic exposure received in utero or very early in life and the relative risk of onset of AD in a population-based cohort study. Associations were estimated using proportional hazards models as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The risk of AD in childhood was increased after in utero or early life antibiotic exposure. For any in utero AB exposure the HR was 1.38 (1.36,1.39). However, penicillin demonstrated the strongest association with AD for both in utero exposure, 1.43 (1.41,1.44), and for childhood exposure, 1.81(1.79,1.82). HRs were higher in children born to mothers without AD than those with AD pointing to effect modification by maternal AD status. CONCLUSION: Children born to mothers exposed to antibiotics while in utero had, depending on the mother's history of AD, approximately a 20 to 40% increased risk of developing AD. Depending on the antibiotic, children who received antibiotics early-in-life had a 40 to 80% increased risk of developing AD. Our study, supports and refines the association between incident AD and antibiotic administration. It also adds population-based support to therapeutic attempts to treat AD by modifying skin microbiome.

Atopic dermatitis and risk of major neuropsychiatric disorders in children: A population-based cohort study.

BACKGROUND: Paediatric atopic dermatitis (AD) has been linked to neuropsychiatric comorbidities such as depression, anxiety and attention-deficit/hyperactivity disorder (ADHD). However, longitudinal data are limited, and the effect of AD severity on neuropsychiatric outcomes requires further characterization. OBJECTIVES: To determine the risk of several major neuropsychiatric conditions in children with AD. METHODS: We analysed UK health records data in a population-based cohort study. Each patient <18 years old with AD was matched to up to five unaffected patients on age, practice and index date. Treatments served as proxies for AD severity, which was analysed in a time-updated manner. Outcomes were incident anxiety, depression, bipolar disorder, schizophrenia, ADHD, autism, obsessive-compulsive disorder (OCD), suicidal ideation or attempt, and completed suicide. RESULTS: A total of 409,431 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) were compared to 1,809,029 children without AD. In Cox regression models adjusted for age, sex, socioeconomic status and other atopic comorbidities, no statistically significant relationships were observed between AD and incident anxiety (HR 1.01, 95% CI 0.99-1.03), ADHD (1.02, 0.97-1.06), autism (1.02, 0.98-1.06), bipolar disorder (1.08, 0.85-1.36), suicidal ideation/attempt (0.98, 0.95-1.01) or completed suicide (0.85, 0.64-1.14). Children with AD were less likely to develop depression (0.93, 0.91-0.95) or schizophrenia (0.72, 0.54-0.95) but more likely to develop OCD (1.26, 1.16-1.37). However, there was substantial variation by AD severity and age in both the direction and magnitude of effect for many of the neuropsychiatric conditions examined. CONCLUSIONS: The was no substantial impact of AD on the overall risk of many neuropsychiatric conditions in children, but disease severity and age may be important modifying factors. Additional research is needed to further dissect the complex relationship between paediatric AD and neuropsychiatric comorbidities.

Glycosylated and Succinylated Macrocyclic Lactones with Amyloid-ß-Aggregation-Regulating Activity from a Marine Bacillus sp.

Two new glycosylated and succinylated macrocyclic lactones, succinyl glyco-oxydifficidin (1) and succinyl macrolactin O (2), were isolated from a Bacillus strain collected from an intertidal mudflat on Anmyeon Island in Korea. The planar structures of 1 and 2 were proposed using mass spectrometric analysis and NMR spectroscopic data. The absolute configurations of 1 and 2 were determined by optical rotation, J-based configuration analysis, chemical derivatizations, including the modified Mosher's method, and quantum-mechanics-based calculation. Biological evaluation of 1 and 2 revealed that succinyl glyco-oxydifficidin (1) inhibited/dissociated amyloid ß (Aß) aggregation, whereas succinyl macrolactin O (2) inhibited Aß aggregation, indicating their therapeutic potential for disassembling and removing Aß aggregation.

Does biologic therapy impact the development of PsA among patients with psoriasis?

OBJECTIVE: To examine the association of biologic therapy use for psoriasis with incident psoriatic arthritis (PsA) diagnosis. METHODS: A retrospective cohort study was conducted in the OptumInsights Electronic Health Record Database between 2006 and 2017 among patients with psoriasis between the ages of 16 and 90 initiating a therapy for psoriasis (oral, biologic or phototherapy). The incidence of PsA was calculated within each therapy group. Multivariable Cox models were used to calculate the HR for biologic versus oral or phototherapy using biologics as a time-varying exposure and next in a propensity score-matched cohort. RESULTS: Among 1 93 709 patients with psoriasis without PsA, 14 569 biologic and 20 321 cumulative oral therapy and phototherapy initiations were identified. Mean age was lower among biologic initiators compared with oral/phototherapy initiators (45.9 vs 49.8). The incidence of PsA regardless of therapy exposure was 9.75 per 1000 person-years compared with 77.26 among biologic users, 61.99 among oral therapy users, 26.11 among phototherapy users and 5.85 among those without a prescription for one of the target therapies. Using a multivariable adjustment approach with time-varying exposure, adjusted HR (95% CI) for biologic users was 4.48 (4.23 to 4.75) compared with oral or phototherapy users. After propensity score matching, the HR (95% CI) was 2.14 (2.00 to 2.28). CONCLUSIONS: In this retrospective cohort study, biologic use was associated with the development of PsA among patients with psoriasis. This may be related to confounding by indication and protopathic bias. Prospective studies are needed to address this important question.

Body surface area affected by psoriasis and the risk for psoriatic arthritis: a prospective population-based cohort study.

OBJECTIVE: Increasing psoriasis severity has been associated with comorbidities including cardiovascular disease. The objective of this study was to examine the association of psoriasis severity with the development of PsA. METHODS: A prospective population-based cohort study was performed within The Health Improvement Network, a UK medical record database. Patients aged 25-60 years with a code for psoriasis were randomly selected between 2008 and 2011. Questionnaires were sent to their general practitioners to confirm the diagnosis of psoriasis and provide the patient's approximate body surface area (BSA). Incidence of PsA was calculated by BSA, and Cox proportional hazard ratios were used to examine the risk of developing PsA by BSA category after adjusting for other covariates. RESULTS: Among 10 474 questionnaires sent, 9987 (95%) were returned, 9069 (91%) had confirmed psoriasis, and BSA was provided for 8881 patients: 52% had mild psoriasis, 36% moderate psoriasis and 12% severe psoriasis. The mean age was 46, and 49% were female. Mean follow-up time was 4.2 years (s.d. 2.1); the incidence of PsA was 5.4 cases per 1000 person-years. After adjusting for age and sex, BSA >10% [hazard ratio (HR) 2.01, 95% CI: 1.29, 3.13], BSA 3-10% (HR 1.44, 95% CI: 1.02, 2.03), obesity (HR 1.64, 95% CI: 1.19, 2.26) and depression (HR 1.68, 95% CI: 1.21, 2.33) were associated with incident PsA. CONCLUSIONS: In this large prospective cohort study, BSA assessed by general practitioners was a strong predictor of developing PsA, and obesity and depression were additive risk factors.

Multiple functional neurosteroid binding sites on GABAA receptors.

Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry (MS), we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1ß3 GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 (labeled residues α1-N408, Y415) and ß3 (labeled residue ß3-Y442) subunits, adjacent to the extracellular domains (ECDs). An intersubunit site (labeled residues ß3-L294 and G308) in the interface between the ß3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies of receptors with mutations based on these predictions (α1-V227W, N408A/Y411F, and Q242L) indicate that both the α1 intrasubunit and ß3-α1 intersubunit sites are critical for neurosteroid action.

Taeanamides A and B, Nonribosomal Lipo-Decapeptides Isolated from an Intertidal-Mudflat-Derived Streptomyces sp.

Two new lipo-decapeptides, namely taeanamides A and B (1 and 2), were discovered from the Gram-positive bacterium Streptomyces sp. AMD43, which was isolated from a mudflat sample from Anmyeondo, Korea. The exact molecular masses of 1 and 2 were revealed by high-resolution mass spectrometry, and the planar structures of 1 and 2 were elucidated using NMR spectroscopy. The absolute configurations of 1 and 2 were determined using a combined analysis of 1H-1H coupling constants and ROESY correlations, the advanced Marfey's method, and bioinformatics. The putative nonribosomal peptide synthetase pathway for the taeanamides was identified by analyzing the full genome sequence data of Streptomyces sp. AMD43. We also found that taeanamide A exhibited mild anti-tuberculosis bioactivity, whereas taeanamide B showed significant bioactivity against several cancer cell lines.

Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer.

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.

Age-appropriate cancer screening: A cohort study of adults with psoriasis prescribed biologics, adults in the general population, and adults with hypertension.

BACKGROUND: Psoriasis is associated with increased risk of developing and dying from cancer. OBJECTIVE: To evaluate whether psoriasis patients who are prescribed biologics receive the recommended screening for cervical, breast, and colon cancer. METHODS: We conducted a retrospective cohort study using the Optum deidentified Electronic Health Record data set. Incidence rates for cervical, breast, and colon cancer screening were compared between psoriasis patients who were prescribed biologics and 2 matched comparator cohorts: general patient population and patients being managed for hypertension. Multivariable Cox proportional hazards regression was performed to assess for differences in the rates of cancer screening. RESULTS: Compared with those in the general population without psoriasis, psoriasis patients who were prescribed biologics had higher screening rates for cervical cancer (adjusted hazard ratio [aHR] 1.09; 95% confidence interval [CI] 1.02-1.16) and colon cancer (aHR 1.10; 95% CI 1.02-1.18). Compared with those with hypertension, patients with psoriasis who were prescribed biologics had lower screening rates for breast cancer (aHR 0.88; 95% CI 0.83-0.94) and colon cancer (aHR 0.89; 95% CI 0.83-0.95). CONCLUSIONS AND RELEVANCE: Patients with psoriasis who are prescribed biologic therapies may not be receiving adequate age-appropriate cancer screening, especially for breast and colon cancer.

Risk of liver disease in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis receiving methotrexate: A population-based study.

BACKGROUND: Patients with psoriatic disease may be more susceptible to methotrexate hepatotoxicity than those with rheumatoid arthritis (RA); however, direct evidence supporting this notion is lacking. OBJECTIVE: To compare liver disease risk among patients with psoriasis (PsO), psoriatic arthritis (PsA), or RA receiving methotrexate. METHODS: In a population-based cohort study, Danish individuals with PsO, PsA, or RA receiving methotrexate between 1997 and 2015 were compared according to 4 disease outcomes: mild liver disease, moderate-to-severe liver disease, cirrhosis, and cirrhosis-related hospitalization. RESULTS: Among 5687, 6520, and 28,030 patients with PsO, PsA, and RA, respectively, the incidence rate of any liver disease was greatest for PsO, followed by PsA, and lowest for RA. Compared with patients with RA, patients with PsO were 1.6-3.4 times more likely to develop at least one of the liver disease outcomes, whereas those with PsA were 1.3-1.6 times more likely to develop mild liver disease and cirrhosis after adjusting for demographics, smoking, alcohol use, comorbidities, and methotrexate dose. LIMITATIONS: Confounding due to unmeasured variables, misclassification, and surveillance bias. CONCLUSION: PsO, PsA, and RA differentially influence liver disease risk in the setting of methotrexate use independent of other major risk factors. More conservative monitoring should be considered in patients receiving methotrexate for psoriatic disease, particularly in PsO patients.

Frequency and influence of "not relevant" responses on the Dermatology Life Quality Index among adults with atopic dermatitis.

PURPOSE: "Not relevant" responses (NRRs) on the Dermatology Life Quality Index (DLQI) are common among adults with psoriasis and may be associated with underestimation of disease burden. Little is known about "not relevant" responses among adults with atopic dermatitis. We aimed to examine the frequency of NRRs on the DLQI and to determine whether NRRs are associated with underestimation of disease burden among adults with atopic dermatitis. METHODS: Adults with atopic dermatitis were identified and evaluated via online survey. We evaluated the frequency of NRRs on the DLQI, stratified by sociodemographic characteristics. To examine the association between NRRs and other measures of disease burden, Patient-Oriented Eczema Measure (POEM), Patient-Oriented SCORAD (PO-SCORAD), and Short-Form (SF)-12 scores were compared between those who responded "not relevant" versus "not at all". RESULTS: Among 764 adults with atopic dermatitis, most had mild disease. The median (interquartile range [IQR]) POEM, PO-SCORAD, and DLQI scores were 5 (2-10), 24 (14-34), and 2 (1-6), respectively. Most (55.2%) also had at least one NRR, and 17.9% had 4 or more "not relevant" responses, with differences across several sociodemographic characteristics. There were no substantial differences in SF-12, POEM, and PO-SCORAD scores between those who responded "not relevant" versus "not at all". CONCLUSION: NRRs on the DLQI are common among adults with atopic dermatitis and differ across sociodemographic characteristics, suggesting issues with content validity. There is not a clear association between NRRs and other measures of disease severity among adults with mostly mild atopic dermatitis.

Treatment utilization and drug survival of systemic medications among commercially insured children with psoriasis.

BACKGROUND/OBJECTIVES: Systemic medications and phototherapy are used to treat pediatric psoriasis, but real-world data on treatment utilization and persistence are limited. The study objective was to determine systemic and phototherapy treatment utilization and compare drug survival among systemics in pediatric psoriasis. METHODS: Using United States commercial insurance claims data, a cross-sectional analysis was conducted to describe the prevalence of systemic treatment and phototherapy use among patients <18 years old with psoriasis. We compared drug survival among new users of methotrexate, adalimumab, etanercept, and ustekinumab using a retrospective cohort design. RESULTS: Among 13 759 patients, 14.6% used systemic or phototherapy treatment during 2001-2016, with rising utilization of systemics over this period. Among 579 new users of methotrexate, adalimumab, etanercept, and ustekinumab, the median durations of the initial treatment course were 141 (IQR 59-314), 179 (79-339), 175 (90-419), and 216 (64-435) days, respectively (P = .04). Drug discontinuation was less likely among ustekinumab (HR 0.47 [95% CI 0.27-0.83]), etanercept (0.74 [0.59-0.92]), and adalimumab (0.75 [0.55-1.02]) initiators than methotrexate initiators after adjustment for sociodemographic factors and psoriatic arthritis. Drug survival differences were limited to systemic-naïve patients. Potential limitations include short follow-up and residual confounding. CONCLUSIONS: Utilization of systemic therapies for pediatric psoriasis is increasing, but differences in drug survival exist.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.

BACKGROUND: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. METHODS: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. RESULTS: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. CONCLUSIONS: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.