717. Susceptibility to Cryptococcosis in Bruton's Tyrosine Kinase Knockout Model

Abstract Background Patients receiving the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib have an increased likelihood of systemic and central nervous system (CNS) fungal infections. Previous work has shown that BTK knockout (KO) mice have more severe Aspergillus infection compared to wild-type (WT) mice. We sought to determine: 1) if blocking BTK impacted Cryptococcus infection; 2) if the effect was strain-dependent; and 3) if the blood-brain barrier was impaired in BTK KO mice. Methods BTK KO C57 breeding pairs were obtained from Dr. Lionakis (NIH) and expanded in the Duke Breeding Core. We collected 4 clinical C. neoformans isolates from patients who developed cryptococcosis on ibrutinib and used virulent and avirulent control strains (H99 and A1-35-8, respectively). The following doses were used for infection: 1) 5x104 yeast for intranasal (IN); 2) 5x104 for oropharyngeal aspiration (OPA); and 3) 0.1 mL of 5x105 CFU/mL for tail vein injection. Mice were sacrificed on day 7 (IN infection, 6 infection strains; N=35 WT, 80 KO) and day 14 post-infection (OPA infection H99 only; N=15 WT, 20 KO). Lung and brain tissues were collected for yeast census. For tail vein injection, mice were sacrificed 48 hours post-infection (H99 only; N=10 WT, 8 KO). Yeast census was measured by colony forming units (CFUs) per gram of tissue weight. Survival experiments through day 28 were performed for OPA infection with H99 (N=12 WT, 17 KO) and analyzed by Kaplan Meier Curve. Results We observed no difference in infection severity as measured by lung and brain yeast census at days 7 and 14 post-infection or difference in survival between BTK KO and WT mice (Figure 1). We also did not observe a distinct pattern based on Cryptococcus strain to suggest that infection severity was strain-dependent (Figure 1A-B). For tail vein infection, there was no difference in brain yeast census at 48 hours post-infection (Figure 1F). Figure 1. Yeast Census and Survival. A) Lung yeast census day 7 post-intranasal infection with 6 clinical strains and 2 control strains; B) Brain yeast census day 7 post-intranasal infection with 6 clinical strains and 2 control strains; C) Lung yeast census day 14 post infection by oropharyngeal aspiration with H99; D) Brain yeast census day 14 post infection by oropharyngeal aspiration with H99; E) 28 day survival post-infection by oropharyngeal aspiration with H99; F) Brain yeast census 48 hours post infection by tail vein injection. Conclusion Our results in mice suggest that Ibrutinib target BTK is not a major contributing factor for controlling Cryptococcus, and that human susceptibility to cryptococcosis and CNS infection may be due to an off-target effect of ibrutinib. Future work will focus on pharmacologic inhibition of BTK with ibrutinib to determine if the off-target effects of the drug increase risk for cryptococcosis. Disclosures Julia A. Messina, MD, MHS, MS, Uptodate (Other Financial or Material Support) Julia A. Messina, MD, MHS, MS, Uptodate (Individual(s) Involved: Self): Author, Other Financial or Material Support John R. Perfect, MD, Astellas Pharma, Inc. (Consultant, Grant/Research Support, Other Financial or Material Support, Honorarium)Basilea (Consultant, Grant/Research Support)Enzon (Consultant, Grant/Research Support)F2G (Consultant, Grant/Research Support)Merck (Consultant, Research Grant or Support)MethylGene (Consultant, Grant/Research Support)Pfizer, Inc. (Consultant, Grant/Research Support)Schering-Plough Corp. (Consultant, Grant/Research Support)

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290. Persistence of Long COVID in SARS-CoV-2 Confirmed Cases One-Year Post Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.492 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S252-S253

Author(s):

Harrison L Howe ◽

Danielle A Rankin ◽

Sean M Bloos ◽

Kailee N Fernandez ◽

Seifein Salib ◽

...

Keyword(s):

Post Infection ◽

Antibody Testing ◽

Research Support ◽

Material Support ◽

Future Studies ◽

Illness Onset ◽

One Year ◽

The One ◽

Support Research ◽

Research Grant

Abstract Background Regardless of severity of acute SARS-CoV-2 illness, adults infected with SARS-CoV-2 are at risk for post-acute sequelae of COVID-19. Long COVID is typically classified as symptoms lasting greater than four weeks post-infection. We aimed to evaluate the frequency of resolved and unresolved long COVID symptoms in adults residing in greater Nashville, TN. Methods We conducted a longitudinal cohort study of SARS-CoV-2-positive and exposed individuals from March 20 to May 15, 2020. Participants for this analysis were included if: 1) ≥18 years; 2) SARS-CoV-2 positive by molecular or antibody testing; and 3) completed a one-year visit. Demographic and illness information were collected at enrollment, and long COVID symptoms were systematically collected at the one-year survey. Long COVID symptoms are defined as an adult experiencing at least one of the following symptoms four weeks post-infection: fatigue, confusion, loss of smell or taste, shortness of breath, chest pain, cough, muscle aches, inability to exercise, or heart palpitations. Unresolved symptoms are defined as an individual with long COVID still experiencing symptoms at the one-year visit. Results A total of 115 adults enrolled and completed the one-year survey, of which 63 (54.8%) were SARS-CoV-2-positive, with one asymptomatic individual. Of SARS-CoV-2-positive symptomatic adults, 32 (51%) were female, 5 (88%) were of Hispanic ethnicity, and 58 (92%) were white. At the one-year visit, 33 (52%) reported having long COVID, of which 17 (52%) reported having unresolved symptoms. Fatigue (89%), headache (89%), muscle aches (79%), and cough (77%) were the most common symptoms reported at illness onset (Figure 1). Among 33 adults with long COVID, fatigue (42%), loss of smell (39%), and loss of taste (33%) were most common (Figure 2A). In the 17 individuals with unresolved symptoms, loss of smell (29%) and loss of taste (24%) were commonly reported (Figure 2B). Figure 1. COVID-19 symptoms reported at enrollment (n=62) Figure 2. Long COVID (symptoms lasting ≥ 4 weeks) (n=33) (A) and unresolved long COVID symptoms one-year post-infection (n=17) (B) reported on the one-year survey Conclusion Half of the adults in our cohort reported long COVID symptoms, with more than quarter of symptoms persisting one-year post-illness. Our findings support that prolonged symptoms up to year after SARS-CoV-2 exposure occur, and future studies should investigate the residual impacts of long COVID symptoms and conditions. Disclosures Natasha B. Halasa, MD, MPH, Genentech (Other Financial or Material Support, I receive an honorarium for lectures - it’s a education grant, supported by genetech)Quidel (Grant/Research Support, Other Financial or Material Support, Donation of supplies/kits)Sanofi (Grant/Research Support, Other Financial or Material Support, HAI/NAI testing) Natasha B. Halasa, MD, MPH, Genentech (Individual(s) Involved: Self): I receive an honorarium for lectures - it’s a education grant, supported by genetech, Other Financial or Material Support, Other Financial or Material Support; Sanofi (Individual(s) Involved: Self): Grant/Research Support, Research Grant or Support

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1104. Risk Factors and Outcomes of Refractory and/or Resistant Cytomegalovirus (CMV) Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1290 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S582-S583

Author(s):

Eleni Karantoni ◽

Yiqi Su ◽

Anat Stern ◽

Phaedon D Zavras ◽

Sergio Giralt ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

T Cell ◽

Panel Member ◽

Multivariable Model ◽

Research Support ◽

Review Panel ◽

Material Support ◽

Advisory Boards ◽

Research Grant

Abstract Background The epidemiology of CMV end-organ disease (EOD) after Hematopoietic Cell Transplant (HCT) in the era of preemptive therapy (PET) is defined. In contrast, less data exists on refractory and/or resistant (R/R) CMV. We report on 1) the incidence; 2) risk factors and outcomes of R/R CMV by 1-year post HCT. Methods Retrospective review of 167 CMV seropositive (R+) recipients of first marrow or peripheral blood HCT from 1/2014 - 12/2017 managed by PET. Refractory CMV was defined as failure to achieve >1 log10 decrease in CMV viral load (VL) and having VL >1,000 IU/mL after ≥14 day of PET. Resistant CMV required genotypic confirmation of resistance mutation(s) in UL54 and/or UL97 genes. End organ disease (EOD) was defined by standard criteria. Patients (pts) were followed through 1-year post HCT and were categorized in two mutually exclusive groups as R/R and no R/R. Demographics, clinical characteristics and outcomes were extracted from medical records and hospital databases. Univariable and multivariable logistic models were used to identify risk factors for R/R CMV. Results Of 167 PET recipients, 91 (54.5%) received ex vivo T cell depleted (TCD) HCT; 40 (24.0%) had mismatched donor; and 26 (15.6%) had multiple myeloma. 66/167 (39.5%) pts developed refractory CMV (6 pts also had resistant CMV). Time from HCT to CMV viremia was shorter in R/R group: median (IQR) 21.5 (17.2-27.8) days compared to no R/R group: 26 (19-32) days (p=0.031). Maximum VL was higher for R/R compared to no R/R: median (IQR) 9,118 (2,849-18,456) and 868 (474-1,908), respectively (p< 0.001). In multivariable model, risk factors for R/R included TCD HCT (p< 0.0001) and higher VL at PET initiation (p=0.0002). In contrast, CMV seropositive donor (p=0.035) was protective (Figure 1). CMV EOD developed in 28.2% of R/R and 16.2% of no R/R groups (p=0.085) (Figure 2). Overall survival at 1 year was 59.1% for R/R compared to 83.1% for no R/R group (p=0.00027) (Figure 3). Figure 1. Adjusted odds ratio (OR) and 95% confidence interval (CI) from multivariable model evaluating risk factors of refractory/resistant (R/R) CMV. Figure 2. Cumulative incidence curves of CMV end-organ disease (EOD) at 1-year post HCT Figure 3. Kaplan-Meier survival curves of overall survival (OS) at 1-year post HCT Conclusion 1) Refractory and/or resistant CMV occurred in 39,5% of PET recipients. 2) T-cell depletion and higher CMV VL at PET initiation were risk factors for R/R CMV in multivariable models. 3) R/R CMV was associated with more EOD and worse overall survival. Disclosures Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

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POS0330 NINTEDANIB (TYROSINE KINASE INHIBITOR) DOWNREGULATES THE TRANSITION OF CULTURED SYSTEMIC SCLEROSIS FIBROCYTES INTO MYOFIBROBLASTS AND THEIR PRO-FIBROTIC ACTIVITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2411 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 392.2-392

Author(s):

S. Soldano ◽

P. Montagna ◽

E. Gotelli ◽

S. Tardito ◽

S. Paolino ◽

...

Keyword(s):

Gene Expression ◽

Systemic Sclerosis ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Adherent Cells ◽

Research Support ◽

Fibrotic Process ◽

Circulating Fibrocytes

Background:Fibroblast-to-myofibroblast transition is one of the fundamental steps involved in the fibrotic process that characterise systemic sclerosis (SSc) [1]. Myofibroblasts are α-smooth muscle actin (αSMA) positive cells that contribute to fibrosis through the excessive synthesis and deposition of extracellular matrix (ECM) proteins, primarily fibronectin (FN) and type I collagen (COL1) [2].Among the cells involved in the fibrotic process of SSc, circulating fibrocytes seem to have an emerging role as an important source of fibroblasts and myofibroblasts [3].Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis that interferes with the signalling pathways involved in the pathogenesis of fibrosis (4). Nintedanib was recently demonstrated to have a beneficial effect in patients with interstitial lung disease (ILD) associated with SSc (5).Objectives:To investigate nintedanib effect in inhibiting the in vitro transition of circulating SSc fibrocytes into myofibroblasts and their pro-fibrotic activity.Methods:Circulating fibrocytes were obtained from 14 SSc patients (mean age 64±14 years), who fulfilled the 2013 ACR/EULAR criteria for SSc and that underwent complete disease staging in a day-hospital setting at the Rheumatology Division of Genoa University. Five age-matched healthy subjects (HSs) were also analysed. All SSc patients and HSs signed the informed consent and the local EC approved the study. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and plated on FN-coated dishes. After overnight culture, non-adherent cells were removed, and adherent cells were maintained in growth medium for 8 days (T8) to obtain fibrocytes [6]. T8-cultured SSc fibrocytes were maintained in growth medium (untreated cells) or treated with nintedanib 0.1μM and 1μM for 3 and 24 hours. Fibroblast specific protein-1 (S100A4) and αSMA, as markers of fibroblast/myofibroblast phenotype, together with COL1 and FN, were investigated by qRT-PCR and Western blotting. Non-parametric Mann-Whitney and Wilcoxon tests were used for the statistical analysis.Results:Significantly elevated gene and protein expressions of αSMA, S100A4, COL1 and FN were observed in SSc fibrocytes compared to HS fibrocytes (gene: αSMA p<0.001; others p<0.0001; protein: all p<0.05). In accordance with the antibody positivity for Scl70 and the presence or absence of ILD at CT scan, SSc patients were grouped as either Scl70 positive patients with ILD (Scl70+ILD+) or Scl70 negative patients without ILD (Scl70-ILD-). Significant αSMA, S100A4, COL1 and FN gene expressions were found in fibrocytes from Scl70+ILD+ compared to HS fibrocytes (αSMA p<0.001; others p<0.0001). Moreover, fibrocytes from Scl70+ILD+patients showed a more significant gene expression of fibroblasts/myofibroblasts markers compared to Scl70-ILD-patients (p<0.01 for S100A4), whereas no differences were observed for ECM gene expression.Nintedanib reduced the gene and protein expression of αSMA, COL1 and FN in SSc fibrocytes compared to untreated ones with different statistical significance.Noteworthy, nintedanib significantly downregulated αSMA, S100A4, COL1 and FN gene expression (all p<0.05) in Scl70+ILD+fibrocytes, whereas only that of S100A4 and FN was significantly downregulated (p<0.05) in Scl70-ILD- fibrocytes compared to untreated cells.Conclusion:Nintedanib seems to downregulate in vitro the transition of fibrocytes into myofibroblasts and their pro-fibrotic activity, particularly in cells isolated from Scl70+ILD+SSc patients.References:[1]Cutolo M et al. Exp Rev Clin Immunol. 2019;15:753-64.[2]Van Caam A et al. Front. Immunol. 2018;9:2452.doi:10.3389/fimmu.2018.02452.[3]Distler JH et al. Arthritis Rheumatol. 2017;69:257-67.[4]Distler O et al. New Eng J Med. 2019; 380:2518-28.[5]Maher TB et al. Arthritis Rheumatol.2020.doi:10.1002/art.41576.[6]Cutolo M et al. Arthritis Res Ther. 2018;20:157.doi:10.1186/s13075-018-1652-6.Acknowledgements:We thank Stefano-Lutz Willing for the scientific support through the study.Disclosure of Interests:Stefano Soldano: None declared, Paola Montagna: None declared, Emanuele Gotelli: None declared, Samuele Tardito: None declared, Sabrina Paolino: None declared, Claudio Corallo: None declared, Carmen Pizzorni: None declared, Alberto Sulli: None declared, Carlotta Schenone: None declared, Greta Pacini: None declared, Vanessa Smith: None declared, Maurizio Cutolo Grant/research support from: I received grant/research support from Bristol-Myers Squibb, Boehringer, Celgene

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24. Economic Burden of Herpes Zoster Among Individuals with Chronic Obstructive Pulmonary Disease: A Retrospective Cohort Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.069 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S35-S36

Author(s):

Parinaz Ghaswalla ◽

Philippe Thompson-Leduc ◽

Wendy Y Cheng ◽

Colin Kunzweiler ◽

Min-Jung Wang ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Cohort Study ◽

Herpes Zoster ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Chronic Obstructive ◽

Research Support ◽

Obstructive Pulmonary Disease ◽

Material Support ◽

Analysis Group

Abstract Background Previous studies have evaluated the risk of developing herpes zoster (HZ) in patients with chronic obstructive pulmonary disease (COPD), but little is known about the impact of an acute HZ episode on healthcare resource utilization (HCRU) and costs among patients with COPD in the US. Methods A retrospective cohort study of individuals ≥50 years of age was conducted using administrative claims data from Optum Clinformatics for commercially insured and Medicare Advantage members (01/01/2013 – 12/31/2018). Two cohorts of patients with COPD, with (Cohort A) and without (Cohort B) HZ episodes, were identified (Fig.1). COPD and HZ were identified using ICD-9 and ICD-10 diagnosis codes. All-cause HCRU rates were compared between cohorts using adjusted incidence rate ratios (IRRs), calculated using generalized linear models assuming a negative binomial distribution. Differences in all-cause costs were estimated by fitting a two-part model with a logit model in the first part and a gamma distribution for the second part. Potential differences between cohorts were accounted for by propensity scores, calculated using patients’ demographics and clinical characteristics at baseline and included as a covariate in multivariable regression analyses. Results Among patients with COPD, 3,415 patients with HZ (mean age [standard deviation]=73.2 [9.0] years) and 35,360 without HZ (72.4 [9.4] years) were identified. Compared to patients with COPD but without HZ, patients with COPD and HZ had an increased rate of all-cause outpatient visits (adjusted IRR=1.18; 95% confidence interval [CI]=1.15–1.22; p< 0.001) and Emergency Department visits (1.28; 1.20–1.35; p< 0.001) as well as higher all-cause total costs (adjusted cost difference, per patient per month [PPPM]=$313; 95% CI=$110–536; p< 0.004), in the first year of the observation period. All-cause mean costs PPPM and differences between cohorts were higher closer to the date of HZ diagnosis (or an imputed date for Cohort B, Fig.2). Figure 2: All-cause monthly costs Conclusion HCRU and cost burden is higher in patients ≥50 years old with COPD and HZ vs. without HZ. HZ vaccination may potentially reduce this burden among patients with COPD. Funding GlaxoSmithKline Biologicals SA (GSK study identifier: HO-19-19749) Disclosures Parinaz Ghaswalla, PhD, ORCID: 0000-0002-2883-5590, GlaxoSmithKline (Employee, Shareholder) Philippe Thompson-Leduc, MSc, ORCID: 0000-0001-9047-3941, Analysis Group, Inc. (Employee) Wendy Y. Cheng, MPH, PhD, ORCID: 0000-0002-8281-2496, GlaxoSmithKline (Other Financial or Material Support, I am an employee of Analysis Group, a consulting company that received research fund to conduct this study.) Min-Jung Wang, ScD, ORCID: 0000-0003-4432-3330, Analysis Group, Inc. (Employee, Other Financial or Material Support, Analysis Group received grant/research support from GSK) Michael Bogart, PharmD, ORCID: 0000-0002-1681-9710, GlaxoSmithKline (Employee, Shareholder) Brandon J. Patterson, PharmD, PhD, GSK (Employee, Shareholder) Mei-Sheng Duh, MPH, ScD, ORCID: 0000-0001-5035-6687, GlaxoSmithKline (Grant/Research Support) Suna Park, MS, GSK (Other Financial or Material Support, Analysis Group, Inc., where I am an employee, received funding for this study) Barbara P. Yawn, MD, Msc, ORCID: 0000-0001-7278-5810, GSK (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)

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POS0198 EFFICACY AND SAFETY OF DEUCRAVACITINIB, AN ORAL, SELECTIVE TYROSINE KINASE 2 INHIBITOR, IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: RESULTS FROM A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2603 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 314.2-315

Author(s):

P. J. Mease ◽

A. Deodhar ◽

D. Van der Heijde ◽

F. Behrens ◽

A. Kivitz ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Tyrosine Kinase ◽

Phase 2 ◽

Efficacy And Safety ◽

Research Support ◽

Double Blind ◽

Double Blind Placebo ◽

Phase 2 Trial ◽

Tyrosine Kinase 2 ◽

Sf 36

Background:Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates signaling by key cytokines involved in psoriatic arthritis (PsA) and plaque psoriasis (PsO) pathogenesis. Deucravacitinib is a novel oral agent that selectively inhibits TYK2 via an allosteric mechanism by binding to the nonconserved regulatory domain of the kinase. A previous Phase 2 trial in PsO had demonstrated that deucravacitinib was efficacious and well tolerated, with no laboratory abnormalities observed.Objectives:To evaluate the efficacy and safety of deucravacitinib in active PsA.Methods:This is an ongoing, 1-year, randomized, double-blind, placebo (PBO)-controlled (initial 16 weeks), multiregional, Phase 2 trial (NCT03881059). Eligible patients had a PsA diagnosis for ≥6 months, met CASPAR criteria, and had active disease with ≥3 tender and ≥3 swollen joints, C-reactive protein ≥3 mg/L (ULN, 5 mg/L), and ≥1 psoriatic lesion (≥2 cm). Patients had failed or were intolerant to ≥1 nonsteroidal anti-inflammatory drug, corticosteroid, conventional synthetic disease-modifying antirheumatic drug (csDMARD), and/or 1 TNF inhibitor (TNFi; ≤30%). Patients were randomized 1:1:1 to deucravacitinib 6 mg once daily (QD) or 12 mg QD, or PBO. The primary endpoint was achievement of ACR 20 response at Week 16. Additional endpoints included the proportion of patients achieving ACR 50/70 response, Health Assessment Questionnaire-Disability Index (HAQ-DI) response (≥0.35 improvement from baseline), enthesitis resolution (Leeds Index score of 0), minimal disease activity, change from baseline in SF-36 physical component score (SF-36 PCS) and mental component score (SF-36 MCS), Psoriasis Area and Severity Index (PASI) 75 response, adverse events (AEs), and laboratory parameters.Results:Of 203 patients randomized, 180 (89%) completed 16 weeks of treatment (deucravacitinib 6 mg QD, 63/70 [90%]; deucravacitinib 12 mg QD, 59/67 [88%]; PBO, 58/66 [88%]). Demographic and baseline disease characteristics were similar across groups. Mean age was 49.8 years, 51% of patients were female, median PsA duration was 4.5 years, 66% of patients used csDMARDs at baseline and throughout the study, and 15% had used a TNFi. This study met its primary endpoint, with deucravacitinib 6 mg and 12 mg QD demonstrating significantly higher ACR 20 responses versus PBO at Week 16 (Figure 1). Additional endpoints were also met with deucravacitinib versus PBO (Figure 1). Adjusted mean changes from baseline in SF-36 PCS and SF-36 MCS at Week 16, respectively, were significantly higher in the deucravacitinib 6 mg QD group (5.6 vs 2.3, P=0.0062; 3.6 vs 0.7, P=0.0211) and 12 mg QD group (5.8 vs 2.3, P=0.0042; 3.5 vs 0.7, P=0.0263) compared with PBO. PASI 75 responses were also significantly higher in the deucravacitinib groups (P≤0.0136 vs PBO). The most common AEs in the deucravacitinib 6 mg/12 mg/PBO groups, respectively, during the 16-week treatment period were nasopharyngitis (5.7%/17.9%/7.6%), sinusitis (0%/7.5%/0%), headache (7.1%/1.5%/4.5%), and rash (4.3%/6.0%/0%). No serious AEs, herpes zoster infections, opportunistic infections, or thrombotic events were reported in deucravacitinib-treated patients during this period. Additionally, no significant changes from baseline in hematologic parameters (lymphocytes, neutrophils, platelets, and hemoglobin) or serum lipids were observed with deucravacitinib treatment.Conclusion:Deucravacitinib was efficacious versus PBO over 16 weeks in patients with active PsA. Treatment was generally well tolerated and the safety and laboratory parameter profile of deucravacitinib was consistent with that observed in an earlier Phase 2 PsO trial.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma, UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma, UCB, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma, Frank Behrens Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche, Chugai, Bristol Myers Squibb, UCB Pharma, Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Roche, Alan Kivitz Shareholder of: Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc., Novartis, Paid Consultant: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc., Speakers bureau: Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion, AbbVie, Jonghyeon Kim Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shalabh Singhal Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Miroslawa Nowak Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

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tail vein injection

Laboratory Mouse Procedural Techniques ◽

10.1201/b17377-16 ◽

2010 ◽

pp. 37-38

Keyword(s):

Tail Vein ◽

Tail Vein Injection

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509. Clinical Characteristics and Outcomes in Patients Infected with SARS-CoV-2 Treated with Remdesivir, Tocilizumab, and/or Dexamethasone at a Mid-Atlantic Hospital Consortium

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.708 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S356-S357

Author(s):

Nellie Darling ◽

Kristen R Kent ◽

Gavin Clark ◽

Xue Geng ◽

Marybeth Kazanas ◽

...

Keyword(s):

Clinical Trials ◽

Length Of Stay ◽

Ventilatory Support ◽

Combination Group ◽

Delivery Device ◽

Research Support ◽

Material Support ◽

Treatment Groups ◽

Treatment Regimens ◽

All Treatment

Abstract Background Treatment strategies for COVID-19 have evolved based on clinical trials. We performed a retrospective analysis to determine treatment outcomes for Remdesivir (RDV), Tocilizumab (TOCI), and/or Dexamethasone (DEX) in a representative population from the Mid-Atlantic region. Methods A retrospective chart review was performed for patients admitted to MedStar hospitals within the D.C./Baltimore corridor from 03/01/2020 to 12/31/2020, and diagnosed with COVID-19 using a NP SARS-CoV-2 RT PCR assay. The MedStar Pharmacy Database was utilized to stratify based on any combination of RDV, TOCI, DEX treatment. Our primary endpoints included O2 delivery device, length of stay (LOS), and mortality. Results A total of 2488 patients were included. Overall, the average age of patients was 62yrs, 53% male, and the majority of patients were of Black (54%) or White (27%) race. The average length of stay was 11 days (SD = 12) with a mortality of 14%. Using univariate analyses, all combinations of RDV, TOCI, and DEX treatment regimens were evaluated. Patients who received DEX required the most ventilatory support on Day 1 (5%, p< 0.001) compared to all other groups. These same patients, however, did not go on to have higher ventilatory needs (17%, p< 0.001) compared to the group which ultimately required the most ventilatory support, TOCI plus DEX (94%, p< 0.001) at Day 28 of treatment. TOCI use alone was associated with a 4% to 63% (p< 0.001) increase in need for ventilatory support over the course of 28 days (Figure 1). The shortest LOS was seen in those treated with DEX alone (9.5 days, p< 0.001). Longer LOS outcomes were associated with all treatment groups which included TOCI use (19 to 22 days, p< 0.001, Figure 2). Mortality was similarly higher among all treatment groups which contained TOCI (30% to 62.5%, p< 0.001, Figure 3) when compared to those with RDV and/or DEX use alone (10% to 14%, p< 0.001). Barplot of Oxygen Delivery Device at Admission and within 28 Days among Treatments Figure 1. Largest increase in ventilatory support from Day 1 of treatment (left) to Day 28 of treatment (right) was seen among TOCI and DEX (0% to 93.8%), RDV and TOCI (0% to 72.2%) and TOCI alone (3.7% to 63.4%). Figure 2. LOS was higher among all treatments containing TOCI (p<0.001), with the highest being the combination group of RDV, TOCI, and DEX (22.4 days, p<0.001). Figure 3. Treatment regimens containing TOCI accounted for the highest mortality rates as seen in TOCI and DEX use (62.5%), RDV and TOCI (44.4%), and TOCI use alone (30.4%). Conclusion Our study demonstrates that “real-world” clinical outcomes for patients with COVID-19 treated with Remdesivir, Tocilizumab, and Dexamethasone are consistent with what has been reported in clinical trials. The higher mortality associated with Tocilizumab treatment may reflect the use of this agent in critically ill patients with COVID-19. Disclosures Princy N. Kumar, MD, AMGEN (Other Financial or Material Support, Honoraria)Eli Lilly (Grant/Research Support)Gilead (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)GSK (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)Merck & Co., Inc. (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)

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1598. Clinical implications of azole-resistant vs. azole-susceptible invasive aspergillosis in hematological malignancy (CLARITY) – a multicenter study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1778 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S795-S796

Author(s):

Danila Seidel ◽

Oliver Cornely ◽

Marouan Zarrouk ◽

Philipp Koehler ◽

Jacques F Meis ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Invasive Aspergillosis ◽

Stress Responses ◽

Hematological Malignancy ◽

Clinical Implications ◽

Azole Resistance ◽

Research Support ◽

Material Support ◽

Travel Grant

Abstract Background Advances in the survival of patients with invasive aspergillosis (IA) are jeopardized by the emergence of azole resistance in Aspergillus fumigatus, which has been associated with high probability of azole treatment failure. The clinical implications of azole-resistant IA compared to azole-susceptible IA remain unclear. Thus, we seek to describe the epidemiology and to determine the efficacy of antifungal therapy in patients with documented azole-resistant IA compared to azole-susceptible IA in patients with hematological malignancy. Methods For proven and probable IA (EORTC/MSG 2019) caused by A. fumigatus in patients with hematological malignancies retrospective data were documented, comprising demographics, diagnosis, treatment, response, and outcome. Sites provided susceptibility results or respective isolates for analysis in a central laboratory. Results Sites in 16 countries worldwide enrolled 187 cases diagnosed with IA between 2010 and 2019; 31 (16.6%) were resistant to at least one of the clinical azoles. Fungal isolates were available from 42 cases. A mixed fungal infection was reported for 32 patients (17.1%), most were related to non-fumigatus Aspergillus and non-Aspergillus molds (n=22, 69%). Most patients were male (66.8%) and overall the majority of patients were in the age groups between 50 and 89 years (71%). Amphotericin B was used for treatment in 24 (77%) patients with azole-resistant IA, compared to 76 (49%) in the azole-susceptible group (lipid-based formulation in 98%); only five (16%) patients with azole-resistant IA were treated with an azole alone vs. 57 (36%) of those with azole-susceptible IA. Overall, all-cause mortality rate was higher for patients with azole-resistant compared to azole-susceptible IA (74.2% vs. 53.8%, log rank P=0.004), the 8 patients with an azole-resistant IA treated in the intensive care unit died within 1 month (Figure 1). Details on underlying disease and survival are given in Table 1. Table 1. Underlying hematological malignancy and clinical outcome of patients with azole-resistant and azole-susceptible invasive aspergillosis Figure 1. Intensive care unit 1-year survival probability for patients with azole-resistant and azole-susceptible invasive aspergillosis Conclusion Azole-resistance in IA is associated with worse outcome, especially in critically ill patients. Susceptibility testing should be considered in patients with a suspected azole-resistant IA to support treatment decisions. Disclosures Danila Seidel, PhD, Basilea (Other Financial or Material Support, travel grant) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Philipp Koehler, MD, Akademie für Infektionsmedizin e.V., (Other Financial or Material Support, Personal fees)Astellas Pharma GmbH (Other Financial or Material Support, Personal fees)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany (Other Financial or Material Support, Other)Gilead Sciences GmbH (Other Financial or Material Support, Personal fees)GPR Academy Ruesselsheim (Speaker’s Bureau)Miltenyi Biotec GmbH (Other Financial or Material Support, Non-financial support)MSD Sharp & Dohme GmbH (Other Financial or Material Support, Personal fees)Noxxon N.V. (Speaker’s Bureau)University Hospital, LMU Munich (Other Financial or Material Support, Personal fees) Katrien Lagrou, n/a, FUJIFILM WAKO (Speaker’s Bureau)Gilead (Consultant, Speaker’s Bureau)MSD (Consultant, Speaker’s Bureau, Other Financial or Material Support, travel grant)Pfizer (Speaker’s Bureau, travel grant)SMB Laboratoires Brussels (Consultant) Zdenek Racil, n/a, Astellas (Grant/Research Support, Speaker’s Bureau, travel grant) Blandine Rammaert, n/a, Gilead (Speaker’s Bureau, Other Financial or Material Support, travel grant)Merck/MSD (Speaker’s Bureau)Pfizer (Other Financial or Material Support, travel grant) Nikolay Klimko, n/a, Astellas (Speaker’s Bureau)Gilead (Speaker’s Bureau)Merck/MSD (Speaker’s Bureau)Pfizer (Speaker’s Bureau) Sung-Yeon Cho, MD, Gilead (Grant/Research Support, Speaker’s Bureau)Merck Sharp & Dohme (Grant/Research Support, Speaker’s Bureau)Pfizer (Grant/Research Support, Speaker’s Bureau)

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Sa1705 The Introduction of Mast Cells by Tail Vein Injection Enhances Biliary Proliferation and Fibrosis in Cholestatic HDC−/- Mice

Gastroenterology ◽

10.1016/s0016-5085(15)33473-9 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-1016

Author(s):

Laura Hargrove ◽

Lindsey Kennedy ◽

Allyson B. Graf ◽

Fanyin Meng ◽

Jennifer Owens ◽

...

Keyword(s):

Mast Cells ◽

Tail Vein ◽

Tail Vein Injection

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Impact assessment of tail-vein injection in mice using a modified anaesthesia induction chamber versus a common restrainer without anaesthesia

Laboratory Animals ◽

10.1177/0023677218786982 ◽

2018 ◽

Vol 53 (2) ◽

pp. 190-201 ◽

Cited By ~ 4

Author(s):

Marlene Resch ◽

Tania Neels ◽

Alexander Tichy ◽

Rupert Palme ◽

Thomas Rülicke

Keyword(s):

Body Weight ◽

The Body ◽

Anaesthesia Induction ◽

Temporary Reduction ◽

Isoflurane Anaesthesia ◽

Tail Vein ◽

Tail Vein Injection ◽

Nesting Behaviour ◽

The Common ◽

Corticosterone Metabolites

Intravenous (IV) administration in mice is predominantly performed via the lateral tail veins. The technique requires adequate training before it can be used safely and routinely. A novel anaesthesia induction chamber has been developed to simplify the treatment and to facilitate IV injection in mice, particularly for untrained personnel. We have assessed the benefits of the chamber in refining IV injection in isoflurane-anaesthetized mice in direct comparison with the common restrainer method on conscious animals. The body weight, nesting behaviour and concentrations of faecal corticosterone metabolites were taken as indicative of distress induced by the various procedures. The results suggest that both methods of tail-vein injection induce similar levels of momentary stress in the animals, revealed by a short-term increase in the levels of stress hormone metabolites in faeces. A temporary reduction of body weight was observed after IV injection under isoflurane anaesthesia but not for conscious mice injected in the common restrainer. We conclude that the severity of tail-vein injection in mice is ‘mild’ for both methods. There was no evidence that refining the procedure by using isoflurane anaesthesia in the induction chamber was associated with any benefit.

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