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Paradoxical Mucositis Associated With Anti-Tumor Necrosis Factor Therapy

Steuer, Alexa B; Bieber, Amy K; Lee, Kristen; Meehan, Shane A; Lo Sicco, Kristen
PMID: 31524852
ISSN: 1536-7355
CID: 4088952

COVID-19 Outbreak - New York City, February 29-June 1, 2020

Thompson, Corinne N; Baumgartner, Jennifer; Pichardo, Carolina; Toro, Brian; Li, Lan; Arciuolo, Robert; Chan, Pui Ying; Chen, Judy; Culp, Gretchen; Davidson, Alexander; Devinney, Katelynn; Dorsinville, Alan; Eddy, Meredith; English, Michele; Fireteanu, Ana Maria; Graf, Laura; Geevarughese, Anita; Greene, Sharon K; Guerra, Kevin; Huynh, Mary; Hwang, Christina; Iqbal, Maryam; Jessup, Jillian; Knorr, Jillian; Lall, Ramona; Latash, Julia; Lee, Ellen; Lee, Kristen; Li, Wenhui; Mathes, Robert; McGibbon, Emily; McIntosh, Natasha; Montesano, Matthew; Moore, Miranda S; Murray, Kenya; Ngai, Stephanie; Paladini, Marc; Paneth-Pollak, Rachel; Parton, Hilary; Peterson, Eric; Pouchet, Renee; Ramachandran, Jyotsna; Reilly, Kathleen; Sanderson Slutsker, Jennifer; Van Wye, Gretchen; Wahnich, Amanda; Winters, Ann; Layton, Marcelle; Jones, Lucretia; Reddy, Vasudha; Fine, Anne
New York City (NYC) was an epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States during spring 2020 (1). During March-May 2020, approximately 203,000 laboratory-confirmed COVID-19 cases were reported to the NYC Department of Health and Mental Hygiene (DOHMH). To obtain more complete data, DOHMH used supplementary information sources and relied on direct data importation and matching of patient identifiers for data on hospitalization status, the occurrence of death, race/ethnicity, and presence of underlying medical conditions. The highest rates of cases, hospitalizations, and deaths were concentrated in communities of color, high-poverty areas, and among persons aged ≥75 years or with underlying conditions. The crude fatality rate was 9.2% overall and 32.1% among hospitalized patients. Using these data to prevent additional infections among NYC residents during subsequent waves of the pandemic, particularly among those at highest risk for hospitalization and death, is critical. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalization and death is an urgent priority. Similar to NYC, other jurisdictions might find the use of supplementary information sources valuable in their efforts to prevent COVID-19 infections.
PMID: 33211680
ISSN: 1545-861x
CID: 5325092

Eczematous reaction to IVIG for the treatment of dermatomyositis

Berk-Krauss, J; Lee, K; Lo Sicco, K I; Liebman, T N
The use of high-dose intravenous immunoglobulin (IVIG) is an accepted therapy for patients with refractory dermatomyositis. Cases of eczematous reactions to IVIG have been reported in the literature, but to our knowledge, none in patients being treated for dermatomyositis. We report on the cases of two female patients with refractory dermatomyositis who developed pruritic, scaly pink plaques after receiving high-dose IVIG. This diffuse eczematous skin reaction to high-dose IVIG is a rare adverse event that most often occurs days after administration of therapy. Practitioners should be aware of this entity because the eczematous eruption may be extensive and can commonly worsen with subsequent re-exposure to IVIG.
PMID: 30175220
ISSN: 2352-6475
CID: 3272142

Comparison of dual-energy CT, ultrasound and surface measurement for assessing tophus dissolution during rapid urate debulking

Modjinou, Dodji V; Krasnokutsky, Svetlana; Gyftopoulos, Soterios; Pike, Virginia C; Karis, Elaine; Keenan, Robert T; Lee, Kristen; Crittenden, Daria B; Samuels, Jonathan; Pillinger, Michael H
Tophaceous gout is painful and impairs quality of life. The optimal modality for assessing tophus resolution in response to urate-lowering treatment remains poorly defined. Using pegloticase as a model system for resolving tophi, we compared multiple imaging and physical diagnostic strategies for assessing tophus resolution. A 32-year-old subject with chronic refractory tophaceous gout was enrolled and received 6 months of pegloticase treatment. Measurements of tophi using vernier calipers (monthly), photographs and musculoskeletal ultrasound (MSK-US; every 3 months), and dual-energy CT (DECT) were compared. Pegloticase persistently lowered the patient's sUA to <0.5 mg/dl. After 6 months, caliper measurements revealed 73, 60, and 61% reductions of three index tophi, while MSK-US revealed 47, 65, and 48% reductions. In contrast, DECT revealed 100% resolution of monosodium urate deposition in all three index tophi, and resolution or improvement of all other tophi identified. On caliper and MSK-US measurement, index tophus size fluctuated, with some lesions enlarging before ultimately contracting. Correlation between assessment modalities during tophus resolution may be poor. DECT identifies urate deposits invisible to physical exam and reveals that some urate deposits completely resolve even as their physically/sonographically measurable lesions persist. Recognition of urate resorption during the urate-lowering process may be confounded by fluctuating lesion volumes during initial tophus breakdown. While DECT was superior for identifying total (including occult) urate deposition, and assessing volume of deposits, other modalities may permit better assessment of non-urate tophus components.
PMID: 28623421
ISSN: 1434-9949
CID: 2595342

Role of DNA Methylation in Modulating Transcription Factor Occupancy

Maurano, Matthew T; Wang, Hao; John, Sam; Shafer, Anthony; Canfield, Theresa; Lee, Kristen; Stamatoyannopoulos, John A
Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.
PMID: 26257180
ISSN: 2211-1247
CID: 1744672

Platelet Activation and Endothelial Reactivity in the Pathogenesis of Tissue Inflammation/Injury in Systemic Lupus Erythematosus [Meeting Abstract]

Clancy, Robert; Nhek, Sokha; Newman, Jonathan; Nwaukoni, Janet; Rasmussen, Sara; Buyon, Jill P; Rubin, Maya; Lee, Kristen; Berger, Jeffrey
ISSN: 2326-5205
CID: 2029272


Reed, Joanne H; Jain, Manish; Lee, Kristen; Kandimalla, Ekambar R; Faridi, Mohd Hafeez; Buyon, Jill P; Gupta, Vineet; Clancy, Robert M
Toll-like receptor (TLR) signaling is an important component in the inflammatory response generated in diseases characterized by autoantibody reactivity to proteins such as SSA/Ro in complex with endogenous nucleic acids. Complement receptor 3 (CR3), a genetic variant of which has been identified as a risk factor in systemic lupus erythematosus, has been shown to induce tolerogenic responses in dendritic cells and suppress TLR4 responses in a murine sepsis model. Accordingly, this study addressed the hypothesis that activation of CR3, influenced by genotype of CD11b, negatively regulates TLR7/8-dependent effector function. Allosteric activation of CD11b via pretreatment with the small molecule, leukadhedrin 1 (LA1), significantly attenuated TLR7/8-induced (hY3 RNA, R848) secretion of TNFalpha in THP-1 cells and human macrophages isolated from donors homozygous for the ancestral common ITGAM allele at rs1143679. This inhibition was accompanied by profound degradation of the adaptor protein MyD88, an effect not observed with direct inhibition of TLR ligation by an antagonist oligonucleotide. In contrast, the addition of LA1 after incubation with the TLR agonists did not result in MyD88 degradation and subsequent attenuation of TNFalpha secretion. In TLR7/8-stimulated macrophages isolated from donors heterozygous for the CD11b variant, pretreatment with LA1 did not down-regulate TNFalpha release. These novel findings support a negative cross-talk between CR3 and TLR pathways likely to be induced by antibodies reactive with ribonucleoproteins and point to the development of CR3-specific agonists as potential therapeutics for diseases such as neonatal lupus.
PMID: 23386618
ISSN: 0021-9258
CID: 271242

ITGAM R77H: Genotype/Phenotype relationships in toll-like receptor 7 stimulated macrophages [Meeting Abstract]

Clancy, R; Reed, J R; Lee, K; Jain, M; Gupta, V; Buyon, J P
Introduction: This study explored the role of a novel CR3 agonist to attenuate pro-inflammatory signaling in subjects with common and variant ITGAM polymorphism, rs1143679. The mechanism underlying initiation and perpetuation of inflammation - with eventual end organ injury - in Systemic Lupus Erythemasosus (SLE) is not yet defined. Equally unclear are mechanisms to attenuate such inflammation. An important candidate for initiation and perpetuation of the inflammatory response may be the chronic stimulation of resident leukocytes through toll like receptors (TLR). Complement Receptor 3 (CR3), a heterodimeric receptor on the surface of various types of leucocytes, is known to decrease proinflammatory signals by dendritic cells when ligated to iC3b. The goal of this study was to evaluate whether a TLR-mediated pro-inflammatory stimulus is attenuated by a novel iC3b mimetic specific for CR3 - known as LA1 - on macrophages expressing CR3. ITGAM polymorphism rs1143679, encoding for a non-conserved R77H substitution CD11b alpha chain of CR3 is known to be associated with SLE across various ethnic groups. While the polymorphism is theorized to affect ligand binding to CR3 the functional significance of the polymorphism is unknown. A sub-goal was to evaluate if rs1143679 carrier status attenuated the effect of LA1. Patients and Methods: The effect of LA1 on basal and stimulated responses by macrophages of human subjects (twenty healthy donors) was evaluated. Rs1143679 carrier status of subjects was determined by allelic discrimination. Macrophages derived from CD14+ monocytes of healthy human donors were treated with R848 (a specific TLR7 ligand, 1 uM) and hY3 (2.5 ug), with and without LA1 (a recently described CR3 agonist, 15 uM). Quantification of TNFalpha secretion, the readout of TLR7 activation, was assessed by ELISA. Results: Treatment of macrophages with R848 significantly stimulated TNFalpha release compared with macrophages alone (1265 +/- 297 pg/ml versus 26 +/- 30 pg/ml, respectively, p = 0!
ISSN: 0961-2033
CID: 558112

Leukadherin 1, a CR3 Mimetic, Negatively Regulates Toll Like Receptor (TLR) Dependent Inflammatory Responses via Degradation of an Adaptor Protein [Meeting Abstract]

Lee, Kristen; Reed, Joanne H.; Gupta, Vineet; Patel, Tejaskumar; Buyon, Jill P.; Clancy, Robert M.
ISSN: 0004-3591
CID: 183982