Publications by authors named "Daniel Shin"

150 Publications

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

J Am Acad Dermatol 2021 Feb 16. Epub 2021 Feb 16.

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.

Background: Patients with psoriatic disease may be more susceptible to methotrexate hepatotoxicity than those with rheumatoid arthritis (RA) but direct evidence is lacking.

Objective: To compare liver disease risk among patients with psoriasis (PsO), psoriatic arthritis (PsA), and RA receiving methotrexate METHODS: In a population-based cohort study, Danish individuals with PsO, PsA, or RA receiving methotrexate during 1997-2015 were compared with respect to four outcomes: mild liver disease, moderate-to-severe liver disease, cirrhosis, and cirrhosis-related hospitalization.

Results: Among 5,687, 6,520, and 28,030 individuals 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 to patients with RA, patients with PsO were 1.6-3.4 times more likely to develop one of the liver disease outcomes while those with PsA were 1.3-1.6 times more likely to develop mild liver disease and cirrhosis after adjustment for demographics, smoking, alcohol use, comorbidities, and methotrexate dose.

Limitations: Confounding by 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 PsO.
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http://dx.doi.org/10.1016/j.jaad.2021.02.019DOI Listing
February 2021

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

Qual Life Res 2021 Feb 4. Epub 2021 Feb 4.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

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.
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http://dx.doi.org/10.1007/s11136-021-02770-zDOI Listing
February 2021

Age-Appropriate Cancer Screening: A Cohort Study of Adults with Psoriasis Prescribed Biologics, Adults in the General Population, and Adults with Hypertension.

J Am Acad Dermatol 2020 Oct 23. Epub 2020 Oct 23.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA,. Electronic address:

Background: Psoriasis is associated with increased risk of developing and dying from cancer.

Objective: To evaluate whether psoriasis patients prescribed biologics receive the recommended screening for cervical, breast, and colon cancer.

Methods: We conducted a retrospective cohort study using the Optum® de-identified Electronic Health Record dataset. Incidence rates for cervical, breast and colon cancer screening were compared between psoriasis patients prescribed biologics and two matched comparator cohorts: (1) general patient population, and (2) patients being managed for hypertension. Multivariable Cox proportional-hazards regression was performed to assess for differences in the rates of cancer screening.

Results: Compared to those in the general population without psoriasis, psoriasis patients prescribed biologics had higher screening rates for cervical cancer (adjusted hazard ratio [aHR] 1.09; 95% CI 1.02-1.16) and colon cancer (aHR 1.10; 95% CI 1.02-1.18). Compared to those with hypertension, patients with psoriasis 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.
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http://dx.doi.org/10.1016/j.jaad.2020.10.045DOI Listing
October 2020

Utility of FDG-PET/CT in clinical psoriasis grading: the PET-PASI scoring system.

Am J Nucl Med Mol Imaging 2020 15;10(5):265-271. Epub 2020 Oct 15.

Department of Radiology, Hospital of The University of Pennsylvania Philadelphia, PA, USA.

Psoriatic skin lesions are metabolically active, which makes them candidates for imaging with 18-F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). The aim of our study was to correlate FDG-PET findings with Psoriasis Area and Severity Index (PASI) scores, the most widely-used grading system for psoriasis. Thirty-three subjects and a total of 84 FDG-PET/CT scans from a prospective clinical trial [NCT01553058] with >2 months moderate-to-severe psoriasis were included. Subjects underwent whole-body FDG-PET/CT imaging 60 min after intravenous FDG administration, prior to the start of treatment. Scans were repeated 12 weeks and 52 weeks after baseline scans were conducted and after treatment or placebo administration was initiated. Each subject and scan was graded by our "PET-PASI" scoring system, a qualitative review of multi-plane reconstructions for both attenuation-corrected (AC) and non-attenuation-corrected (NAC) PET images. PASI and PET-PASI scores were correlated using Spearman's rho analysis. Our study demonstrated a significant positive correlation between each subject's corresponding PET-PASI and PASI scores before and during treatment or placebo administration (r=0.53, P<0.001). We also found positive correlations between PET-PASI and PASI scores across different regions of the body (head and neck: r=0.22, upper extremities: r=0.26, trunk: r=0.48, and lower extremities: r=0.58). In conclusion, AC and NAC FDG-PET/CT images may be utilized to evaluate lesions in subjects with moderate-to-severe psoriasis. Our methodology could have future implications in the diagnosis and therapeutic management of psoriasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675113PMC
October 2020

Leucocytosis and Stroke in a Lung Cancer Patient.

Eur J Case Rep Intern Med 2020 14;7(11):001872. Epub 2020 Aug 14.

Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, CA, USA.

Significant leucocytosis in the setting of an underlying malignancy may be attributed to several causes and is not uncommon; however, extreme leucocytosis (>50×10 cells/l) and hypereosinophilia is less common and may represent a paraneoplastic syndrome. The underlying mechanism is thought to be bone marrow stimulation by tumour-produced cytokines, most notably interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This paraneoplastic syndrome is likely reflective of extensive disease and dissemination, and options for treatment are limited but include tumour resection, corticosteroids and hydroxyurea. In this report, we discuss an unusual case of known stage III lung adenocarcinoma presenting with an ischaemic stroke and extreme leucocytosis and hypereosinophilia.

Learning Points: To illustrate an unusual presentation of progression of non-small-cell lung adenocarcinoma.To highlight the prognostic significance of extreme leucocytosis and hypereosinophilia in patients with an underlying malignancy.
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http://dx.doi.org/10.12890/2020_001872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655007PMC
August 2020

Association of Racial/Ethnic and Gender Concordance Between Patients and Physicians With Patient Experience Ratings.

JAMA Netw Open 2020 11 2;3(11):e2024583. Epub 2020 Nov 2.

Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Importance: The Press Ganey Outpatient Medical Practice Survey is used to measure the patient experience. An understanding of the patient- and physician-related determinants of the patient experience may help identify opportunities to improve health care delivery and physician ratings.

Objective: To evaluate the associations between the patient experience as measured by scores on the Press Ganey survey and patient-physician racial/ethnic and gender concordance.

Design, Setting, And Participants: A cross-sectional analysis of Press Ganey surveys returned for outpatient visits within the University of Pennsylvania Health System between 2014 and 2017 was performed. Participants included adult patient and physician dyads for whom surveys were returned. Data analysis was performed from January to June 2019.

Exposures: Patient-physician racial/ethnic and gender concordance.

Main Outcomes And Measures: The primary outcome was receipt of the maximum score for the "likelihood of your recommending this care provider to others" question in the Care Provider domain of the Press Ganey survey. Secondary outcomes included each of the remaining 9 questions in the Care Provider domain. Generalized estimating equations clustering on physicians with exchangeable intracluster correlations and cluster-robust standard errors were used to investigate associations between the outcomes and patient-physician racial/ethnic and gender concordance.

Results: In total, 117 589 surveys were evaluated, corresponding to 92 238 unique patients (mean [SD] age, 57.7 [15.6] years; 37 002 men [40.1%]; 75 307 White patients [81.6%]) and 747 unique physicians (mean [SD] age 45.5 [10.6] years; 472 men [63.2%]; 533 White physicians [71.4%]). Compared with racially/ethnically concordant patient-physician dyads, discordance was associated with a lower likelihood of physicians receiving the maximum score (adjusted odds ratio [OR], 0.88; 95% CI, 0.82-0.94; P < .001). Black (adjusted OR, 0.73; 95% CI, 0.68-0.78; P < .001) and Asian (adjusted OR, 0.55; 95% CI, 0.50-0.60; P < .001) patient race were both associated with lower patient experience ratings. Patient-physician gender concordance was not associated with Press Ganey scores (adjusted OR, 1.00; 95% CI, 0.96-1.04; P = .90).

Conclusions And Relevance: In this study, higher Press Ganey survey scores were associated with racial/ethnic concordance between patients and their physicians. Efforts to improve physician workforce diversity are imperative. Delivery of health care in a culturally mindful manner between racially/ethnically discordant patient-physician dyads is also essential. Furthermore, Press Ganey scores may differ by a physician's patient demographic mix; thus, care must be taken when publicly reporting or using Press Ganey scores to evaluate physicians on an individual level.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.24583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653497PMC
November 2020

Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.

Sci Transl Med 2020 10;12(565)

Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.

Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking or did not respond to ICB, whereas ACT was effective against tumors, but not tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16- tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT.
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http://dx.doi.org/10.1126/scitranslmed.abb0152DOI Listing
October 2020

Commentary.

J Am Acad Dermatol 2021 Mar 8;84(3):e161-e162. Epub 2020 Oct 8.

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543884PMC
March 2021

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.

J Biol Chem 2020 Dec 7;295(50):17169-17186. Epub 2020 Oct 7.

Department of Surgery, VAGLAHS West Los Angeles and David Geffen School of Medicine at UCLA, Los Angeles, California, USA

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, Lys-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 G-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.
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http://dx.doi.org/10.1074/jbc.RA120.014048DOI Listing
December 2020

Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma.

Cancer Cell 2020 10 10;38(4):500-515.e3. Epub 2020 Sep 10.

Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address:

We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
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http://dx.doi.org/10.1016/j.ccell.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872287PMC
October 2020

Effect of anti-tumor necrosis factor therapy on the risk of respiratory tract infections and related symptoms in patients with psoriasis-A meta-estimate of pivotal phase 3 trials relevant to decision making during the COVID-19 pandemic.

J Am Acad Dermatol 2021 01 26;84(1):161-163. Epub 2020 Aug 26.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.08.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448776PMC
January 2021

In response to: "Reply to research letter".

J Am Acad Dermatol 2020 Dec 29;83(6):e445. Epub 2020 Jul 29.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387358PMC
December 2020

Validation of synthesized normal-resolution image data generated from high-resolution acquisitions on a commercial CT scanner.

Med Phys 2020 Oct 5;47(10):4775-4785. Epub 2020 Aug 5.

Department of Radiology, University of California Davis, Sacramento, CA, USA.

Purpose: To validate a normal-resolution (NR) simulation (NRsim) algorithm that uses high-resolution (HR) or super-high resolution (SHR) acquisitions on a commercial HR computed tomography (CT) scanner by comparing image quality between NRsim-generated images and actual NR images. NRsim is intended to allow direct comparison between normal-resolution CT and HR/SHR reconstructions in clinical investigations, without repeating exams.

Methods: The Aquilion Precision CT (Canon Medical Systems Corporation) HR CT scanner has three resolution modes resulting from detector binning in the channel (x-y) and row (z) directions. For NR, each detector element is 0.5 mm × 0.5 mm along the channel and row directions, 0.25 mm × 0.5 mm for HR, and 0.25 mm × 0.25 mm for SHR. The NRsim algorithm simulates NR acquisitions from HR or SHR acquisitions (termed NR and NR , respectively) by downsampling the pre-log raw data in the channel direction for the HR acquisitions and in the channel and row direction for the SHR acquisition. The downsampled data are then reconstructed using the same process as NR. The axial modulation transfer function (MTF), slice sensitivity profile (SSP), and CT number accuracy were measured using the Catphan 600 phantom, and the three-dimensional noise power spectrum (NPS) was measured in water-equivalent phantoms for standard protocols across a range of size-specific dose estimates (SSDE): head (6.2-29.8 mGy), lung (2.2-18.2 mGy), and body (5.6-19.4 mGy). The MTF and NPS measurements were combined to estimate low-contrast detectability (LCD) using a non-prewhitening model observer with an eye filter for a 5-mm disk with 10 HU contrast. All metrics were compared for NR, NR , and NR images reconstructed using filtered back projection (FBP) and an iterative reconstruction algorithm (AIDR3D). We chose a 15% error threshold as a reasonable definition of success for NRsim when compared against actual NR based on published studies showing that a just-noticeable difference in image noise level for human observers is typically <15%.

Results: The axial MTF and SSPs for NRsim were in good agreement with NR demonstrated by a maximum difference of 5.1% for the MTF at 10% and 50% across materials (air, Teflon, LDPE, and polystyrene) and a maximum SSP difference of 2.2%. Noise magnitude differences were within 15% across the SSDE levels with the exception of below 4.5 mGy for the lung protocol with FBP. The relative RMSE of normalized NPS comparisons were all <15%. Differences in CT numbers for NRsim reconstructions were within 2 HU of NR. LCD for NRsim was within 15% of NR with the exception of NR for the lung protocol SSDE levels below 3.7 mGy with FBP.

Conclusions: NRsim, an algorithm for simulating NR acquisitions using HR and SHR raw data, was introduced and shown to generate images with spatial resolution, noise, HU accuracy, and LCD largely equivalent to scans acquired using an actual NR acquisition. At SSDE levels below ~5 mGy for the lung protocol, differences in noise magnitude and LCD for NR were >15% which defines a region where NRsim degrades due to contributions from electronic noise.
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http://dx.doi.org/10.1002/mp.14395DOI Listing
October 2020

Structures and Biosynthetic Pathway of Pulvomycins B-D: 22-Membered Macrolides from an Estuarine sp.

Org Lett 2020 07 6;22(14):5358-5362. Epub 2020 Jul 6.

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

Pulvomycins B-D (-) were discovered from an estuarine strain along with the known pulvomycin (). The 22-membered macrocyclic lactone structures of - were determined based on the interpretation of NMR, UV, and MS data, the modified Mosher's method, and Kishi's bidentate chiral solvent NMR spectroscopy. Genomic analysis of the bacterial strain revealed the biosynthetic gene cluster of pulvomycin and enabled us to propose the -acyltransferase polyketide biosynthetic pathway. Pulvomycin D displayed potent cytotoxic activity against various cancer cell lines.
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http://dx.doi.org/10.1021/acs.orglett.0c01249DOI Listing
July 2020

The risk of respiratory tract infections in patients with psoriasis treated with interleukin 23 pathway-inhibiting biologics: A meta-estimate of pivotal trials relevant to decision making during the COVID-19 pandemic.

J Am Acad Dermatol 2020 11 2;83(5):1523-1526. Epub 2020 Jul 2.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.06.1014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331500PMC
November 2020

Reply to: "Do IL-17 inhibitors increase risk of respiratory tract infections?"

J Am Acad Dermatol 2020 Oct 2;83(4):e305-e306. Epub 2020 Jul 2.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.06.1001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329655PMC
October 2020

The risk of respiratory tract infections and symptoms in psoriasis patients treated with interleukin 17 pathway-inhibiting biologics: A meta-estimate of pivotal trials relevant to decision making during the COVID-19 pandemic.

J Am Acad Dermatol 2020 08 19;83(2):677-679. Epub 2020 May 19.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.05.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235584PMC
August 2020

Association between atopic dermatitis and learning disability in children.

J Allergy Clin Immunol Pract 2020 Sep 26;8(8):2808-2810. Epub 2020 Apr 26.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.

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http://dx.doi.org/10.1016/j.jaip.2020.04.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483744PMC
September 2020

Structural Revision of Lydiamycin A by Reinvestigation of the Stereochemistry.

Org Lett 2020 05 24;22(10):3855-3859. Epub 2020 Apr 24.

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

Lydiamycin A () is a previously reported piperazic acid-bearing cyclic peptide from . The absolute configuration of lydiamycin A has not been fully determined despite the fact that multiple total syntheses have been reported. The absolute configuration of was reinvestigated by the advanced Marfey's method, chemical derivatization, and quantum-mechanics-based computational analysis, eventually resulting in a structural revision and establishment of the complete configuration. Lydiamycin A displayed weak antituberculosis activity in vitro.
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http://dx.doi.org/10.1021/acs.orglett.0c01110DOI Listing
May 2020

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

N Engl J Med 2020 06 10;382(24):2327-2336. Epub 2020 Apr 10.

From Cedars-Sinai Medical Center, Los Angeles (J.G.), El Camino Hospital, Mountain View (D.S., D. Chelliah), Sutter Santa Rosa Regional Hospital, Santa Rosa (G.G.), Regional Medical Center (A.S., J.R.) and Good Samaritan Hospital (S.M.), San Jose, John Muir Health, Walnut Creek (J.B.), UC Davis Health, Sacramento (S.H.C.), NorthBay Medical Center, Fairfield (S.I.), and Gilead Sciences, Foster City (A.O.O., A.D., Y.Z., L.Z., A. Chokkalingam, E.E., L. Telep, L. Timbs, I.H., S.S., H.C., S.K.T., L.W., P.D., R.M., A.G., R.P.M., D.M.B.) - all in California; the National Center for Global Health and Medicine, Tokyo (N.O.), Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu City (R.O.), Hiratsuka City Hospital, Hiratsuka (K.Y.), Yokohama City University Hospital, Yokohama (H.K.), Gunma University Hospital, Gunma (T.M.), and Tosei General Hospital, Seto (Y.M.) - all in Japan; Providence Regional Medical Center Everett, Everett (G.D.), and University of Washington Medical Center-Northwest (M.L.G.) and Virginia Mason Medical Center (S. Chihara), Seattle - all in Washington; Fondazione IRCCS Policlinico San Matteo, Pavia (E.A.), IRCCS, San Raffaele Scientific Institute (A. Castagna) and Azienda Socio Sanitaria Territoriale Spedali (ASST) Santi Paolo e Carlo, Department of Health Services, University of Milan (A.D.M.), Milan, National Institute for Infectious Diseases, IRCCS, L. Spallanzani, Rome (E.N.), Università degli Study of Brescia, ASST Civili di Brescia, Brescia (E.Q.-R.), San Gerardo Hospital, ASST Monza, University of Milan-Bicocca, Monza (G.L.), and Azienda Unite Sanitarie Locali-IRCCS, Reggio Emilia (M.M.) - all in Italy; Universitätsklinikum Düsseldorf, Düsseldorf, Germany (T. Feldt); Université de Paris, Infection, Antimicrobiens, Modélisation, Evolution (IAME), INSERM, and Assistance Publique-Hôpitaux de Paris, Department of Infectious Diseases, Bichat Hospital, Paris (F.-X.L.), Centre Hospitalier Régional et Universitaire de Brest-La Cavale Blanche, Brest (E.L.), and Division of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux (D.N.) - all in France; St. Alexius Medical Center, Hoffman Estates, IL (S.A.); Mackenzie Health, Richmond Hill, ON, Canada (D. Chen); Columbia University Irving Medical Center, New York (J.C.); Hospital Universitario La Paz-Carlos III, Instituto de Investigación Hospital Universitario La Paz, Madrid (M.M.-R.); Bernhoven Hospital, Uden, the Netherlands (E.V.); Kaiser Franz Josef Hospital, Vienna (A.Z.); the U.S. Public Health Service Commissioned Corps, Washington, DC (R.C.); and Miriam Hospital, Providence, RI (T. Flanigan).

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.).
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http://dx.doi.org/10.1056/NEJMoa2007016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169476PMC
June 2020

Opioid prescribing in adults with and without psoriasis.

J Am Acad Dermatol 2020 Dec 1;83(6):1777-1779. Epub 2020 Apr 1.

Department of Dermatology, University of Pennsylvania, Philadelphia; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1016/j.jaad.2020.03.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529723PMC
December 2020

Evaluation of the Frequency of "Not Relevant" Responses on the Dermatology Life Quality Index by Sociodemographic Characteristics of Patients With Psoriasis.

JAMA Dermatol 2020 04;156(4):446-450

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Importance: "Not relevant" responses (NRRs) on the Dermatology Life Quality Index (DLQI) are common among patients with psoriasis and may be associated with an underestimation of disease severity.

Objective: To evaluate the associations between (1) patient sociodemographic characteristics and the frequency of NRRs on the DLQI and (2) NRR frequency and treatment satisfaction.

Design, Setting, And Participants: This cross-sectional study using data from the Dermatology Clinical Effectiveness Research Network from February 2010 to June 2011 assessed the responses on the DLQI of 1733 patients with psoriasis.

Main Outcomes And Measures: Differences in the frequency of NRRs by sex, race/ethnicity, insurance type, income, educational attainment, marital status, and employment status were evaluated using the 2-tailed χ2 test. Multivariable logistic regression analysis was used to evaluate the associations between sociodemographic characteristics and having at least 1 NRR. Multivariable linear regression analysis was used to evaluate the association between having a DLQI score reclassified from 10 or less to more than 10 using the DLQI-Relevant scoring modification and the scores on the Treatment Satisfaction Questionnaire for Medication. Data were analyzed between July 2019 and November 2019.

Results: Of 1733 patients with psoriasis, 879 (50.7%) were female, and 1470 (84.8%) were non-Hispanic white individuals. The DLQI items 6 (sport, 223 patients [12.9%]), 9 (sexual difficulties, 214 patients [12.3%]), and 7 (work or study, 126 patients [7.3%]) had the greatest frequency of NRRs. In multivariable logistic regression analysis, male sex (odds ratio [OR], 0.63; 95% CI, 0.48-0.82) and income of more than $100 000 (OR, 0.45; 95% CI, 0.26-0.79) were associated with decreased odds of NRRs. By contrast, single (OR, 1.85; 95% CI, 1.31-2.61) or widowed or divorced (OR, 2.60; 95% CI, 1.80-3.74) marital status and unemployed or disabled employment status (OR, 1.98; 95% CI, 1.35-2.89) were associated with increased odds of NRRs. Having a DLQI score that would be reclassified from 10 or less to more than 10 using the DLQI-Relevant scoring modification was associated with lower global satisfaction scores on the Treatment Satisfaction Questionnaire for Medication (coefficient, -9.8; 95% CI, -16.3 to -3.4).

Conclusions And Relevance: There were sociodemographic differences in the frequency of NRRs on the DLQI among this cohort of patients with psoriasis. These differences may be associated with an underestimation of disease burden and treatment disparities owing to subsequent undertreatment among certain sociodemographic groups. Further study is needed to optimize the quality-of-life assessment among patients with psoriasis or other inflammatory skin diseases in diverse settings.
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http://dx.doi.org/10.1001/jamadermatol.2019.4659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142381PMC
April 2020

A Randomized Placebo-Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate-to-Severe Plaque Psoriasis (VIP-S).

J Invest Dermatol 2020 Sep 21;140(9):1784-1793.e2. Epub 2020 Feb 21.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has reported high efficacy with a favorable safety profile in various psoriatic disease manifestations. Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, patients with moderate-to-severe psoriasis received secukinumab for 40 weeks. Vascular inflammation using F-2-fluorodeoxyglucose-positron emission tomography/computed tomography imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. The difference in change in aortic inflammation from baseline to week 12 for secukinumab (n = 46) versus placebo (n = 45) was -0.053 (95% confidence interval = -0.169 to 0.064; P= 0.37). Small increases in total cholesterol, low-density lipoprotein, and low-density lipoprotein particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At week 52, reductions in TNF-α (P= 0.0063) and ferritin (P= 0.0354), and an increase in fetuin-A (P= 0.0024), were observed with secukinumab treatment compared with baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared with baseline. Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment.
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http://dx.doi.org/10.1016/j.jid.2020.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434644PMC
September 2020

Association of Race/Ethnicity and Sex With Differences in Health Care Use and Treatment for Acne.

JAMA Dermatol 2020 03;156(3):312-319

Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Importance: Our understanding of potential racial/ethnic, sex, and other differences in health care use and treatment for acne is limited.

Objective: To identify potential disparities in acne care by evaluating factors associated with health care use and specific treatments for acne.

Design, Setting, And Participants: This retrospective cohort study used the Optum deidentified electronic health record data set to identify patients treated for acne from January 1, 2007, to June 30, 2017. Patients had at least 1 International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code for acne and at least 1 year of continuous enrollment after the first diagnosis of acne. Data analysis was performed from September 1, 2019, to November 20, 2019.

Main Outcomes And Measures: Multivariable regression was used to quantify associations between basic patient demographic and socioeconomic characteristics and the outcomes of health care use and treatment for acne during 1 year of follow-up.

Results: A total of 29 928 patients (median [interquartile range] age, 20.2 [15.4-34.9] years; 19 127 [63.9%] female; 20 310 [67.9%] white) met the inclusion criteria for the study. Compared with non-Hispanic white patients, non-Hispanic black patients were more likely to be seen by a dermatologist (odds ratio [OR], 1.20; 95% CI, 1.09-1.31) but received fewer prescriptions for acne medications (incidence rate ratio, 0.89; 95% CI, 0.84-0.95). Of the acne treatment options, non-Hispanic black patients were more likely to receive prescriptions for topical retinoids (OR, 1.25; 95% CI, 1.14-1.38) and topical antibiotics (OR, 1.35; 95% CI, 1.21-1.52) and less likely to receive prescriptions for oral antibiotics (OR, 0.80; 95% CI, 0.72-0.87), spironolactone (OR, 0.68; 95% CI, 0.49-0.94), and isotretinoin (OR, 0.39; 95% CI, 0.23-0.65) than non-Hispanic white patients. Male patients were more likely to be prescribed isotretinoin than female patients (OR, 2.44; 95% CI, 2.01-2.95). Compared with patients with commercial insurance, those with Medicaid were less likely to see a dermatologist (OR, 0.46; 95% CI, 0.41-0.52) or to be prescribed topical retinoids (OR, 0.82; 95% CI, 0.73-0.92), oral antibiotics (OR, 0.87; 95% CI, 0.79-0.97), spironolactone (OR, 0.50; 95% CI, 0.31-0.80), and isotretinoin (OR, 0.43; 95% CI, 0.25-0.75).

Conclusions And Relevance: The findings identify racial/ethnic, sex, and insurance-based differences in health care use and prescribing patterns for acne that are independent of other sociodemographic factors and suggest potential disparities in acne care. In particular, the study found underuse of systemic therapies among racial/ethnic minorities and isotretinoin among female patients with acne. Further study is needed to confirm and understand the reasons for these differences.
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http://dx.doi.org/10.1001/jamadermatol.2019.4818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042795PMC
March 2020

A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.

Cancer 2020 04 5;126(8):1668-1682. Epub 2020 Feb 5.

Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.

Background: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.

Methods: A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.

Results: Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.

Conclusions: The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.

Lay Summary: Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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http://dx.doi.org/10.1002/cncr.32644DOI Listing
April 2020

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

J Am Soc Nephrol 2020 02 2;31(2):435-446. Epub 2020 Jan 2.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1681/ASN.2019070676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003302PMC
February 2020

Global alteration of T-lymphocyte metabolism by PD-L1 checkpoint involves a block of de novo nucleoside phosphate synthesis.

Cell Discov 2019 26;5:62. Epub 2019 Nov 26.

2Department of Molecular, Cellular, and Integrative Physiology, University of California Los Angeles, Los Angeles, CA 90095 USA.

Metabolic obstacles of the tumor microenvironment remain a challenge to T-cell-mediated cancer immunotherapies. To better understand the interplay of immune checkpoint signaling and immune metabolism, this study developed and used an optimized metabolite extraction protocol for non-adherent primary human T-cells, to broadly profile in vitro metabolic changes effected by PD-1 signaling by mass spectrometry-based metabolomics and isotopomer analysis. Inhibitory signaling reduced aerobic glycolysis and glutaminolysis. A general scarcity across the panel of metabolites measured supported widespread metabolic regulation by PD-1. Glucose carbon fate analysis supported tricarboxylic acid cycle reliance on pyruvate carboxylation, catabolic-state fluxes into acetyl-CoA and succinyl-CoA, and a block in de novo nucleoside phosphate synthesis that was accompanied by reduced mTORC1 signaling. Nonetheless, exogenous administration of nucleosides was not sufficient to ameliorate proliferation of T-cells in the context of multiple metabolic insufficiencies due to PD-L1 treatment. Carbon fate analysis did not support the use of primarily glucose-derived carbons to fuel fatty acid beta oxidation, in contrast to reports on T-memory cells. These findings add to our understanding of metabolic dysregulation by PD-1 signaling and inform the effort to rationally develop metabolic interventions coupled with immune-checkpoint blockade for increased treatment efficacy.
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http://dx.doi.org/10.1038/s41421-019-0130-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877514PMC
November 2019

Mental health impairment among children with atopic dermatitis: A United States population-based cross-sectional study of the 2013-2017 National Health Interview Survey.

J Am Acad Dermatol 2020 Jun 15;82(6):1368-1375. Epub 2019 Oct 15.

Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: Atopic dermatitis (AD) is associated with mental health disorders, but its impact on global mental health symptoms is less clear.

Objective: To determine the association between pediatric AD and mental health impairment.

Methods: In a cross-sectional study using 2013-2017 United States National Health Interview Survey data, children with and without AD were assessed for mental disorder with impairment (MDI) using a validated behavioral screening questionnaire. Mental health services utilization was also reported.

Results: The prevalence of any MDI was 26.7% (95% confidence interval [CI], 25.1-28.3) among children with AD and 17.7% (95% CI, 17.2-18.2) among those without AD, with severe MDI being present in 10.9% (95% CI 9.9-12.1) and 6.2% (95% CI 5.9-6.5), respectively. Adjusted for sociodemographic factors, AD was associated with higher odds of MDI (odds ratio, 1.52; 95% CI, 1.39-1.67), including impairments in conduct, emotions, peer relationships, and attention. Among children with AD, 19.9% (95% CI, 16.6-23.8) and 53.5% (95% CI, 48.5-58.5) of those with mild or severe MDI, respectively, had seen a mental health professional in the last year.

Limitations: Misclassification bias may arise from self-reported data.

Conclusion: AD is associated with clinically significant mental health symptoms, but many affected children may not seek or receive care for their symptoms.
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http://dx.doi.org/10.1016/j.jaad.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156313PMC
June 2020