2x Upper Limit Of Normal Research Articles

Tissue transglutaminase immunoglobulin A exceeds endomysial antibody in specificity of celiac diagnosis at ≥10 times the upper limit of normal.

Serologic diagnosis using tissue transglutaminase immunoglobulin A (TTG-IgA) and endomysial antibody (EMA) is being integrated into the care of pediatric patients with positive screening for celiac disease. The purpose of this study was to assess the utility of EMA in pediatric patients being considered for serologic diagnosis. Patients with TTG-IgA testing performed between May 1, 2022 and April 30, 2023 and with subsequent duodenal biopsy within 6 months were included. TTG-IgA serum samples were frozen and sent for EMA testing and titer. EMA was evaluated for positivity and TTG-IgA (normal <15 u/mL) for elevation <10 times (10x) the upper limit of normal (ULN) and ≥10x ULN (≥150 u/mL). Sensitivity and specificity of EMA and TTG-IgA were calculated using biopsy histology as the gold standard. Four hundred and eighty-six patients were included. The sensitivity and specificity of TTG-IgA ≥15 u/mL was 87.5% and 95.4% while EMA was 77.5% and 97.3%. For patients with TTG-IgA ≥10x ULN the specificity was 99.3%. The positive predictive value of TTG-IgA at ≥10x ULN was 91.4% and for EMA was 83.6%. All three patients with false positive TTG-IgA ≥10x ULN also had false positive EMA, and two of these patients had type 1 diabetes mellitus. TTG-IgA has greater sensitivity at the screening threshold of ≥15 u/mL and greater specificity and positive predictive value at ≥10x ULN than EMA. TTG-IgA at ≥10x ULN is superior to EMA for the serologic diagnosis of celiac disease.

Use of Gynecologic Cancer Intergroup (GCIG) CA125 criteria to evaluate cell cycle checkpoint kinase 1 inhibitor (CHK1i) prexasertib response and disease progression (PD) in recurrent high-grade serous ovarian cancer (HGSOC).

e17536 Background: Data suggest discordance between serum biomarker CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) response and/or PD in chemotherapies and PARP inhibitors. Here, we investigated the impact of CA125 on prognosis and its relationship with RECIST response/PD in HGSOC patients treated with a CHK1i, prexasertib. Methods: All relapsed HGSOC patients in this post-hoc analysis were treated with prexasertib at 105 mg/m2 IV every 14 days in a 28-day cycle until RECIST v1.1 PD, unacceptable toxicity, or consent withdrawal (NCT02203513). CA125 was assessed every cycle and CT scans obtained every two cycles. GCIG CA125 response was defined as &gt;50% reduction confirmed after 28 days and PD as &gt; 2X upper limit of normal (ULN) if baseline was normal or doubling of nadir if baseline was elevated. Patients with baseline CA125 &lt; 2X ULN or nadir &gt; 750 units/mL were not eligible for analysis. Clinical benefit rate (CBR; CR + PR + SD ≥ 6 months) was analyzed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves and univariate (UV) and multivariate (MV) hazard ratios by Cox regression models. Positive predictive value (PPV) and negative predictive value (NPV) confidence intervals (CI) were estimated by the Wilson-Brown method. Results: Eighty-one patients received at least two cycles of prexasertib between January 2015 and November 2020, out of which 72 were evaluable by both RECIST and GCIG CA125 response criteria. CBR in the CA125 response (CA125-R) group (24/32; 75%) was significantly higher than the CA125 non-responder (CA125-N) group (12/40; 30%; p&lt;0.001). CA125 response tended to occur prior to RECIST response (median: 28 days; IQR: 28, 30). PFS was improved in CA125-R at 8.0 months vs. CA125-N at 3.5 months (UV HR: 0.34, 95% CI: 0.21-0.56; MV HR: 0.35, 95% CI: 0.20-0.59). OS was improved in CA125-R at 19.8 months vs. CA125-N at 10.3 months (HR: 0.43, 95% CI: 0.26-0.71; MV HR: 0.45, 95% CI: 0.27-0.75). No significant differences in PFS or OS were observed between subgroups by BRCA mutation status, platinum-sensitivity, FIGO stage, baseline CA125 value, or previous PARP inhibitor therapy in MV analysis. Out of 70 patients evaluable by RECIST and CA125 PD criteria, 43 patients had CA125 PD and 24 of those had RECIST PD occur within one cycle of CA125 PD (PPV: 59%; 95% CI: 43-72). Of the 27 patients without a CA125 PD, 9 patients also did not have a RECIST PD (NPV: 33%; 95% CI: 19-52). Conclusions: GCIG CA125 response is an independent predictor of response to CHK1i in HGSOC prior to the first restaging scans and is associated with a higher CBR and improved PFS and OS. However, GCIG CA125 PD has poor PPV and NPV within a one cycle window, indicating that CA125 alone is not sufficient in monitoring for PD in HGSOC treated with CHK1i.

Abstract 7094: Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations

Abstract AZD4573 is a highly potent and selective Cyclin-Dependent Kinase 9 inhibitor. The AZD4573 First-in-Human (FIH) study revealed variable alanine transaminase (ALT) and/or bilirubin elevation and a clear correlation to dose or PK exposure could not be defined. While concurrent ALT elevation ≥3x upper limit of normal (ULN) and bilirubin elevation ≥2x ULN (potential Hy’s law) is a biochemical finding indicating potential drug-induced liver injury, quantitative modeling disconnected ALT and bilirubin elevation demonstrating that the observations were not Hy’s Law cases. Furthermore, we implemented a targeted metabolomics workflow to investigate the ALT and bilirubin elevation mechanism and identify predictive biomarkers to better understand and/or predict any hepatic stress liabilities associated with AZD4573 clinical development. We implemented an established metabolomics methodology to 359 samples from 15 patients yielding 47,000 total data points. Data was separated into 98 different dosing intervals from the 15 patients to identify the ALT and bilirubin-associated metabolic changes conserved across all patients while incorporating metabolic differences in individual patents with ALT and bilirubin elevation in only a fraction of multiple doses. Orthogonal Partial Least Squares modeling identified several metabolites and pathways altered as a function of maximum ALT or bilirubin levels. Post-dose conjugated bile acids were elevated when ALT and bilirubin were elevated. Pre-dose creatine levels were decreased when ALT and bilirubin elevation occurred, and pre-dose glutamate levels were elevated when ALT elevation occurred. Pre-dose decreased total carnitines and kynurenine pathway activation were observed when ALT and bilirubin elevation occurred, but the effect did not reach statistical significance. Elevated bile acids are an established characteristic of cholestasis and suggest cholestasis as a probable mechanism for AZD4573-induced reversible liver stress. Interestingly, decreased creatine, glutamate elevation, decreased total carnitine, and kynurenine pathway activation are all associated with some form of liver stress or disfunction which may explain the irregular ALT and bilirubin elevations observed in patients receiving AZD4573; while ALT itself is a biomarker of liver damage, these pre-dose biochemical changes may illuminate potential preceding liver stress. Dosing patients already experiencing higher liver stress levels may be more susceptible to drug-induced ALT and bilirubin elevation, and patients with increasing in-study liver stress may only present at later doses. This work demonstrates metabolomics utility to elucidate possible mechanisms of liver toxicity as well as to identify potential predictive biomarkers for further investigation to explore individual patient risk in clinical studies. Citation Format: John K. Meissen, Kevin Contrepois, Sophie Regan, Jennifer Tan, Alison J. Foster, Jiaqi Yuan, Shringi Sharma, Dominic Williams, Anton I. Rosenbaum. Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7094.

Prediction of Survival by IL-6 in a Randomized Placebo-Controlled Trial of Anakinra in COVID-19 Cytokine Storm.

(1) Background: Some severe COVID-19 patients develop hyperinflammatory cytokine storm syndrome (CSS). We assessed the efficacy of anakinra added to standard of care (SoC) in hospitalized COVID-19 CSS patients. (2) Methods: In this single-center, randomized, double-blind, placebo-controlled trial (NCT04362111), we recruited adult hospitalized patients with SARS-CoV-2 infection, evidence of pneumonia, new/increasing oxygen requirement, ferritin ≥ 700 ng/mL, and at least three of the following indicators: D-dimer ≥ 500 ng/mL, platelet count < 130,000/mm3, WBC < 3500/mm3 or lymphocyte count < 1000/mm3, AST or ALT > 2X the upper limit of normal (ULN), LDH > 2X ULN, C-reactive protein > 100 mg/L. Patients were randomized (1:1) to SoC plus anakinra (100 mg subcutaneously every 6 h for 10 days) or placebo. All received dexamethasone. The primary outcome was survival and hospital discharge without need for intubation/mechanical ventilation. The data were analyzed according to the modified intention-to-treat approach. (3) Results: Between August 2020 and January 2021, 32 patients were recruited, of which 15 were assigned to the anakinra group, and 17 to the placebo group. Two patients receiving the placebo withdrew within 48 h and were excluded. The mean age was 63 years (SD 10.3), 20 (67%) patients were men, and 20 (67%) were White. At Day 10, one (7%) patient receiving anakinra and two (13%) patients receiving the placebo had died (p = 1.0). At hospital discharge, four (27%) patients receiving anakinra and four (27%) patients receiving the placebo had died. The IL-6 level at enrollment was predictive of death (p < 0.01); anakinra use was associated with decreases in CXCL9 levels. (4) Conclusions: Anakinra added to dexamethasone did not significantly impact the survival of COVID-19 pneumonia patients with CSS. Additional studies are needed to assess patient selection and the efficacy, timing, and duration of anakinra treatment for COVID-19 CSS.

B-062 A Self-Imposed Gray Area? Analysis of Anti-Tissue Transglutaminase and Anti-Endomysial Antibody Discordance in a Celiac Disease Screening Serology Testing Algorithm

Abstract Background Celiac disease (CD) is an autoimmune enteropathy affecting around 1% of the population. While occasionally asymptomatic, the disease can present in a variety of ways and can be triggered by dietary gluten at any age. CD serology, including anti-tissue transglutaminase (anti-tTG) IgA and/or IgG, anti-endomysial antibody IgA and/or IgG, and anti-deamidated gliadin peptide IgA and/or IgG, is a key tool for CD screening, diagnosis, and monitoring. Of these tests, the clinical utility of anti-EMA testing has been questioned due to its high cost and limited sensitivity: 5–10% of CD patients do not test positive for anti-EMA and a negative anti-EMA does not rule out CD. The objective of this study is to: 1) evaluate the concordance between anti-tTG and anti-EMA serology test results, and 2) assess the clinical validity of our current CD reflex testing algorithm in which every positive anti-tTG test result goes on for anti-EMA testing. Methods Using our laboratory’s information system, we conducted a retroactive study on patients who underwent CD serology testing at our institution. Query was performed for all patient data [pediatric (&amp;lt;18 years) and adult (&amp;gt;18 years)] collected between April 2020 and August 2022 for anti-tTG IgA performed on the BioPlex 2200 (BioRad Laboratories Inc., Hercules, CA) and anti-EMA IgA (Euroimmun, Germany) (N = 124 308). Vendor-supplied clinical sensitivity and specificity are as follows: anti-tTG IgA 94.3% sensitivity, 98.8% specificity; anti-EMA IgA 95.3% sensitivity and 98.0% specificity. Results From our data, we calculated a mean positive agreement between our anti-tTG IgA and anti-EMA test results of 53.2% (95% confidence interval (CI) 47.5–58.8%) for all anti-tTG IgA positive cases (N = 6691, 5.4% of total anti-tTG IgA test results). The agreement between anti-tTG IgA and anti-EMA test results is improved if multiples of the upper limit of normal (ULN) for anti-tTG IgA is applied. The mean positive agreement between anti-tTG IgA and anti-EMA test results when the anti-tTG result is &amp;gt;10x ULN is 98.4% (95% CI 97.7–99.2%). However, if an anti-tTG IgA cutoff of &amp;lt;10x ULN is employed a mean positive agreement of 32.3% (95% CI 25.8–38.7%) is observed. At an anti-tTG IgA cutoff of &amp;lt;3x ULN, the mean positive agreement is just 11.8% (95% CI 8.2–15.4%). These findings are consistent in both pediatric (N = 29 381) and adult (N = 94 961) populations and are problematic as 45.4% of our positive anti-tTG IgA test results are accompanied by a negative anti-EMA. Conclusion The agreement between anti-tTG IgA and anti-EMA is dependent on the value of anti-tTG IgA with greater agreement observed with increasing anti-tTG IgA values. As all specimens at our institution with positive anti-tTG IgA test results are automatically reflexed for anti-EMA testing, has led to physician confusion as the majority of patients are falling into a gray area with conflicting CD serology test results. Our algorithm is also out of line with most CD screening guidelines that suggest an initial positive anti-tTG test result is followed up with biopsy. Finally, discontinuing anti-EMA reflex testing could result in cost savings of approximately $120 000 CAD per year.

Safety and tolerability of isoniazid preventive therapy for tuberculosis for persons with HIV with and without alcohol use: a single arm trial.

Isoniazid (INH) preventive therapy is recommended to prevent tuberculosis (TB) disease for persons with HIV (PWH), except for those with regular and heavy alcohol consumption, due to hepatotoxicity concerns. We aimed to quantify the incidence of severe INH-related toxicity among PWH with and without recent alcohol consumption. Prospective study of PWH receiving INH. We included PWH in southwest Uganda with recent (prior three months) (n = 200) or no (prior year) self-reported alcohol consumption (n = 101), on antiretroviral therapy, TB infected (≥5 mm on tuberculin skin test), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2x the upper limit of normal (ULN). Grade 3+ INH-related toxicity was ALT or AST ≥5x the ULN or severe symptoms; we stopped IPT upon detection. Grade 2 INH-related toxicity was ALT or AST 2-5x the ULN or moderate symptoms. The cumulative incidence of Grade 3+ INH-related toxicity was 8.3% (95% CI: 5.7-12.0); all resolved after INH cessation. Incidence was 6.0% (95% CI: 3.1-10.2) among those reporting recent alcohol use and 12.9% (95% CI: 7.0-21.0) of those reporting no prior year alcohol use. We found no differences by baseline phosphatidylethanol-confirmed alcohol severity. The cumulative incidence of Grade 2 toxicities (without Grade 3+) was 21.7% (95% CI: 17.2-27.0); 25.0% (95% CI: 19.0-31.8) among those with recent alcohol use and 14.8% (95% CI: 8.1-23.9) among those with no prior year alcohol use. Alcohol use does not appear to increase risk for serious INH-related toxicity among PWH without significant liver enzyme elevations at baseline (≤2x ULN).

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

A110 INCIDENCE AND PREDICTORS OF ASYMPTOMATIC ABNORMALITIES IN BIOCHEMICAL AND RADIOLOGIC PANCREATIC MARKERS FOLLOWING UNCOMPLICATED ERCP

Abstract Background Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is common. Its diagnosis relies on characteristic abdominal pain in addition to biochemical and/or radiographic evidence of pancreatic inflammation. Purpose Little is known regarding the frequency with which asymptomatic alterations in biochemical and/or imaging parameters occur following uncomplicated ERCP. We sought to assess the incidence and predictors of such alterations following uncomplicated ERCP. Method This study was an analysis of a prospectively maintained ERCP registry. All inpatients ³ 18 years old who underwent ERCP between 2018/09/01 and 2022/02/28 were identified. Patients with acute pancreatitis or abdominal pain following ERCP were excluded, as were patients with lipase levels ≥3x the upper limit of normal (ULN) within 7 days preceding ERCP. Primary outcomes were (1) asymptomatic lipase elevation within 48 hours of uncomplicated ERCP or (2) asymptomatic cross-sectional imaging findings of pancreatic inflammation within 14 days of ERCP.Descriptive statistics were presented as means with accompanying standard deviations (SD) and percentages by lipase categories and PEP, or by imaging categories. Multiple logistic regression was used to examine the associations of exposure variables with PEP or imaging findings. Result(s) A total of 646 patients were analyzed in the biochemical cohort, and 187 patients were analyzed in the radiologic cohort. In the biochemical cohort, 478 patients (74.0%) had no elevations in pancreatic enzymes, while 81 (12.5%) had elevations up to 2x ULN, 26 (4.0%) had elevations between 2-3x ULN, and 61 (9.4%) had elevations &amp;gt;3x ULN. In the radiologic cohort, 148 (79.1%) had no abnormalities on cross-sectional imaging within 14 days of ERCP, while 39 (20.9%) had one or more imaging finding typically associated with acute pancreatitis. Among these, 22 (11.8%) had peri-pancreatic fluid collections and 2.1-9.6% of patients had pancreatic findings that included edema, enlargement, inflammation, or fat-stranding. On multivariable analysis, predictors of lipasemia &amp;gt;3x ULN included balloon sphincteroplasty (odds ratio, OR, 2.29, 95% confidence intervals, CI, 1.08 to 4.85) and the placement of a common bile duct stent (OR 4.19, 95% CI 1.37 to 12.77), whereas cannulation of the pancreatic duct or performance of a pancreatogram were not significantly associated (OR 0.75, 95% CI 0.24 to 2.35 and OR 1.07, 95% CI 0.18 to 6.26, respectively). Conclusion(s) Over 25% of patients will have asymptomatic elevations in pancreatic enzymes following ERCP, while over 20% will have asymptomatic cross-sectional imaging findings suggestive of pancreatic inflammation. Clinical symptoms should guide post-ERCP care rather than biochemical or imaging parameters. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis.

Durvalumab is approved for the treatment of lung cancer, advanced biliary tract cancers, and is also being evaluated in many other solid organ tumors. The aim of our study is to define the incidence, etiology, and outcomes of liver injury in consecutive patients receiving durvalumab-based immunotherapy. Durvalumab treated patients between 1/2016 - 7/2020 were identified from the electronic medical record. Liver injury was defined as serum AST or ALT ≥ 5x upper limit of normal (ULN), ALP ≥ 2x ULN, bilirubin ≥ 2.5 mg/dl, or INR ≥ 1.5. Potential drug induced liver injury (DILI) cases were adjudicated using expert opinion scoring and confirmed with Roussel Uclaf Causality Assessment Method (RUCAM). Amongst 112 patients, 58 (52%) had non-small cell lung cancer, the median age was 65 years, and 60% were male. The 21 (19%) liver injury patients were significantly more likely to harbor hepatic metastases (52% vs 17%, p=<0.001), experience tumor progression (67% vs 32%, p=0.01) or die (48% vs 11%, p<0.001) during follow-up compared to the 91 without liver injury. Using multivariate regression analysis, the development of liver injury during treatment as well as baseline hepatic metastases were independently associated with mortality during follow-up. Six of the 21 (29%) liver injury cases were adjudicated as probable DILI with four attributed to durvalumab and two due to other drugs (paclitaxel, pembrolizumab). Durvalumab was permanently discontinued in two DILI patients, three received corticosteroids, and one was successfully rechallenged. Only one patient with DILI developed jaundice, and none required hospitalization. Liver biochemistries normalized in all 6 DILI cases, while they only normalized in 27% of the 15 non-DILI cases (p=0.002). The 6 DILI patients also had a trend towards improved survival compared to those with other causes of liver injury. Liver injury was observed in 19% of durvalumab-treated patients and is associated with a greater likelihood of tumor progression and death during follow-up. The four durvalumab DILI cases were mild and self-limited, highlighting the importance of causality assessment to determine the cause of liver injury in oncology patients receiving immunotherapy.

Comparing the associations between host and tumor factors with survival outcomes with anti-PD-1 immunotherapy in metastatic melanoma.

Anti-programmed death-1 (PD-1) immunotherapy has drastically improved survival for metastatic melanoma; however, 50% of patients have progression within 6months despite treatment. In this study, we investigated host, and tumor factors for metastatic melanoma patients treated with anti-PD-1 immunotherapy. Patients treated with the anti-PD-1 immunotherapy between 2014 and 2017 were identified in Alberta, Canada. All patients had Stage IV melanoma. Patient characteristics, investigations, treatment, and clinical outcomes were obtained from electronic medical records. We identified 174 patients treated with anti-PD-1 immunotherapy. At 37.1months median follow-up time 135 (77.6%) individuals had died and 150 (86.2%) had progressed. An elevated lactate dehydrogenase (LDH) had a response rate of 21.0% versus 41.0% for those with a normal LDH (p=0.017). Host factors associated with worse median progression-free survival (mPFS) and median overall survival (mOS) included liver metastases, >3 sites of disease, elevated LDH, thrombocytosis, neutrophilia, anemia, lymphocytopenia, and an elevated neutrophil/lymphocyte ratio. Primary ulcerated tumors had a worse mOS of 11.8 versus 19.3 months (p=0.042). We identified four prognostic subgroups in advanced melanoma patients treated with anti-PD-1 therapy. (1) Normal LDH with <3 visceral sites, (2) normal LDH with ≥3 visceral sites, (3) LDH 1-2x upper limit of normal (ULN), (4) LDH ≥2x ULN. The mPFS each group was 14.0, 6.5, 3.3, and 1.9months, while the mOS for each group was 33.3, 15.7, 7.9, and 3.4months. Our study reports that host factors measuring the general immune function, markers of systemic inflammation, and tumor burden and location are the most prognostic for survival.

Impact of SLCO1B1*5 on Flucloxacillin and Co-Amoxiclav-Related Liver Injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is a serious uncommon disease that may develop as a result of the intake of certain drugs such as the antimicrobials flucloxacillin and co-amoxiclav. The reported cases showed significant associations between DILI and various human leukocyte (HLA) markers. The solute carrier organic anion transporter 1B1 (SLCO1B1), a non-HLA candidate gene, was previously reported as a risk factor for liver injury induced by rifampin and methimazole. This study presumed that SLCO1B1 may play a general role in the DILI susceptibility and therefore investigated the association of rs4149056 (SLCO1B1*5, T521C) polymorphism with flucloxacillin- and co-amoxiclav–induced liver injury. Methodology: We recruited 155 and 165 DILI cases of white ancestral origin from various European countries but mainly from the United Kingdom owing to flucloxacillin and co-amoxiclav, respectively. Only adult patients (≥18 years) who were diagnosed with liver injury and who showed i) clinical jaundice or bilirubin >2x the upper limit of normal (ULN), ii) alanine aminotransferase (ALT) >5x ULN or iii) alkaline phosphatase (ALP) >2x ULN and bilirubin > ULN were selected. The population reference sample (POPRES), a European control group (n = 282), was used in comparison with the investigated cases. TaqMan SNP genotyping custom assay designed by Applied Biosystems was used to genotype both DILI cohorts for SLCO1B1 polymorphism (rs4149056). Allelic discrimination analysis was performed using a step one real-time PCR machine. Genotype differences between cases and controls were examined using Fisher’s exact test. GraphPad Prism version 5.0 was used to determine the p-value, odds ratio, and 95% confidence interval. Compliance of the control group with Hardy–Weinberg equilibrium was proven using a web-based calculator available at https://wpcalc.com/en/equilibrium-hardy-weinberg/. Results: A small number of cases failed genotyping in each cohort. Thus, only 149 flucloxacillin and 162 co-amoxiclav DILI cases were analyzed. Genotyping of both DILI cohorts did not show evidence of association with the variant rs4149056 (T521C) (OR = 0.71, 95% CI = 0.46–1.12; p = 0.17 for flucloxacillin cases and OR = 0.87, 95% CI = 0.56–1.33; p = 0.58 for co-amoxiclav), although slightly lower frequency (22.8%) of positive flucloxacillin cases was noticed than that of POPRES controls (29.4%). Conclusion: Carriage of the examined allele SLCO1B1*5 is not considered a risk factor for flucloxacillin DILI or co-amoxiclav DILI as presumed. Testing a different allele (SLCO1B1*1B) and another family member gene (SLCO1B3) may still be needed to provide a clearer role of SLCO1B drug transporters in DILI development–related to the chosen antimicrobials.

The prognostic value of cardiac troponin for 60 day mortality and major adverse events in COVID-19 patients

BackgroundThe variability of coronavirus disease 2019 (COVID-19) illness severity has puzzled clinicians and has sparked efforts to better predict who would benefit from rapid intervention. One promising biomarker for in-hospital morbidity and mortality is cardiac troponin (cTn). MethodsA retrospective study of 1331 adult patients with COVID-19 admitted to the Rush University System in Illinois, USA was performed. Patients without cTn measurement during their admission or a history of end stage renal disease or stage 5 chronic kidney disease were excluded. Using logistic regression adjusted for baseline characteristics, pre-existing comorbidities, and other laboratory markers of inflammation, cTn was assessed as a predictor of 60-day mortality and severe COVID-19 infection, consisting of a composite of 60-day mortality, need for intensive care unit, or requiring non-invasive positive pressure ventilation or intubation. ResultsA total of 772 patients met inclusion criteria. Of these, 69 (8.9%) had mild cTn elevation (> 1 to < 2x upper limit of normal (ULN)) and 46 (6.0%) had severe cTn elevation (≥ 2x ULN). Regardless of baseline characteristics, comorbidities, and initial c-reactive protein, lactate dehydrogenase, and ferritin, when compared to the normal cTn group, mild cTn elevation and severe cTn elevation were predictors of severe COVID-19 infection (adjusted OR [aOR] aOR 3.00 [CI: 1.51 – 6.29], P < 0.01; aOR 9.96 [CI: 2.75 – 64.23], P < 0.01, respectively); severe cTn elevation was a predictor of in-hospital mortality (aOR 2.42 [CI: 1.10 – 5.21], P < 0.05) and 60-day mortality (aOR 2.45 [CI: 1.13 – 5.25], P < 0.05). ConclusionIn our cohort, both mild and severe initial cTn elevation were predictors of severe COVID-19 infection, while only severe cTn elevation was predictive of 60-day mortality. First cTn value on hospitalization is a valuable longitudinal prognosticator for COVID-19 disease severity and mortality.

S1159 Hepatic Steatosis Is Associated With Elevated Alanine Aminotransferase (ALT) but Not Elevated Bilirubin or Hepatic Decompensation in Patients With Coronavirus Disease (COVID)-19

INTRODUCTION: COVID-19 is a global pandemic. However, the effects of underlying liver disease on COVID-19 in the United States is not well described. We investigated whether COVID-19 was associated with elevations in liver enzymes or hepatic decompensation in patients with underlying hepatic steatosis. METHODS: We retrospectively reviewed the charts of consecutive adults with RT-PCR positive for COVID-19 treated at Michigan Medicine between March 1 and April 30, 2020, who had ultrasound, computed tomography, or magnetic resonance imaging >30 days before COVID-19 diagnosis. Hepatic steatosis was defined based on imaging. Outcomes were: (1) peak ALT or bilirubin following COVID-19 diagnosis, (2) ALT >2 or 5 times upper limit of normal (ULN), defined as the higher of baseline ALT or 19 U/L in women and 30 U/L in men, (3) jaundice defined as bilirubin >2 or 4 mg/dl, and (4) new/worsening ascites or encephalopathy. We conducted regressions with the above outcomes as dependent variables and hepatic steatosis as the primary predictor, adjusting for age, sex, race, recent healthcare exposure, body mass index, hypertension, dyslipidemia, and diabetes. These regression models were logistic for outcomes of abnormal ALT or bilirubin, and linear for maximal ALT or bilirubin. RESULTS: Of patients with prior imaging, 80/159 (50.3%) had steatosis. Overall, 89% of patients were hospitalized, 51% were admitted to intensive care, and 16% died. 14% had chronic liver disease other than NAFLD, 5% had cirrhosis, and 2.7% had prior liver decompensation with ascites, variceal bleeding, or hepatic encephalopathy. Patients with steatosis were older, had higher body mass index, and were more often Black than those without steatosis (Table 1). Baseline ALT and total bilirubin were higher in the steatosis group (Table 1). Hepatic steatosis was associated with increased incidence of ALT >2x ULN (OR 2.93 [1.23–6.97]) or >5x ULN (OR 6.21 [1.45–26.62]), and with peak ALT (beta 39.7 [7.85–71.49]) (Table 2). Hepatic steatosis was not associated with increased bilirubin (Table 2). Rates of new/worsening ascites and encephalopathy were very low: 1.3% and 2.5%, respectively, with no difference based on NAFLD status (P > 0.4 for both). CONCLUSION: Hepatic steatosis is associated with acute hepatocellular injury with COVID-19 infection. Steatosis was not associated with jaundice. Rates of new/worsening ascites or hepatic encephalopathy were very low and unrelated to steatosis status.Table 1Table 2

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels

ObjectivesIn this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD). MethodsFrom the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121–140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease. ResultsAmong 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51–9.54), 3.78 (95% CI:2.27–6.28), 2.78 (95% CI:1.55–4.97), and 1.03 (95% CI:1.02–1.05), respectively. ConclusionEven in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.

MACITENTAN IN PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASE: REAL-WORLD EVIDENCE FROM THE COMBINED OPUS/ORPHEUS DATA SETS

MACITENTAN IN PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASE: REAL-WORLD EVIDENCE FROM THE COMBINED OPUS/ORPHEUS DATA SETS

P3674Patient characteristics and treatment patterns in the multicentre, retrospective chart review of first-time Opsumit (macitentan) users in the United States (OrPHeUS)

Abstract Introduction The OPsumit® Historical USers cohort (OrPHeUS) is a multicentre, US, retrospective medical chart review conducted to supplement the OPsumit® USers (OPUS) Registry to fulfil the FDA request to characterise the safety of macitentan in clinical practice. Purpose To describe patient characteristics, treatment patterns, hepatic safety and survival in patients with pulmonary hypertension (PH) newly treated with macitentan. Methods OrPHeUS (NCT03197688) aimed to include 2200 new users of macitentan, between October 2013 and March 2017, who were not enrolled in OPUS. Here we present patients with follow-up data, including characteristics and treatment patterns at macitentan initiation, hepatic adverse events (HAEs) identified using preferred terms in chart entries and pharmacovigilance reporting, hospitalisations and survival. Results OrPHeUS included 2982 patients newly treated with macitentan and with follow-up data; the reason for macitentan prescription was pulmonary arterial hypertension (PAH) in 2362 (79.3%) patients, other PH aetiologies in 612 (20.6%) patients and 8 patients with other/unknown reasons. At macitentan initiation, the median (Q1, Q3) age of the patients was 62 (51, 72) years and 73.9% were female. WHO functional class (FC) was documented in 654 (21.9%) patients, 35.6% of patients were in FC I/II and 64.4% in FC III/IV; median (Q1, Q3) 6-minute walk distance, documented in 411 (13.8%) patients, was 293 (200, 383) metres. At macitentan initiation, 41.5% (n=1239) of patients were not receiving PAH therapy, 46.3% (n=1382) were already receiving one PAH therapy and 11.9% (n=356) were already receiving two PAH therapies. The median (Q1, Q3) exposure to macitentan was 14.9 (5.6, 27.1) months; 57% and 43% of patients had exposures of &gt;12 and &gt;18 months. During the exposure period, 933 (31.3%) patients discontinued treatment, including 474 (15.9%) patients who discontinued due to an adverse event (AE), 6 (0.2%) due to a HAE, 449 (15.1%) for reasons other than an AE/HAE, and 4 (0.1%) for unknown reasons. There were 275 (9.2%) patients who experienced ≥1 HAE (incidence rate [IR]: 0.07 [95% CI, 0.06, 0.08] per 1 person-year); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of normal (ULN) were experienced by 113 (3.8%) patients (IR: 0.028 [95% CI, 0.023, 0.033] per 1 person-year); ALT/AST ≥x3 ULN and bilirubin ≥2x ULN was experienced by 33 (1.1%) patients (IR: 0.008 [95% CI, 0.006, 0.011] per 1 person-year). There were 1148 (38.5%) patients who experienced at least one hospitalisation (IR: 0.36 [95% CI, 0.34, 0.39] per 1 person-year). The 12-month Kaplan-Meier survival estimate was 92% (95% CI, 91, 93). Conclusion OrPHeUS provides additional real-world evidence in patients newly treated with macitentan, confirming the hepatic safety profile of macitentan. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

Contributing factors and outcomes of burn-associated cholestasis

Cholestasis often occurs after burn injuries. However, the prevalence of cholestasis and its effect on outcomes in patients with severe burn injuries are unknown. The aim of this study was to describe the course and the burden of cholestasis in a cohort of severely burned adult patients. We investigated the relationship between burn-associated cholestasis (BAC) and clinical outcomes in a retrospective cohort of patients admitted to our unit for severe burn injuries between 2012 and 2015. BAC was defined as an increased level of serum alkaline phosphatase (ALP) ≥1.5x the upper limit of normal (ULN) with an increased level of gamma-glutamyltransferase (GGT) ≥3x ULN, or as an increased level of total bilirubin ≥2x ULN. A total of 214 patients were included: 111 (52%) patients developed BAC after a median (IQR) stay of 9 (5-16) days. At 90 days, the mortality rate was 20%, including 34 and 9 patients with and without BAC (p <0.001), respectively, which corresponded to a 2.5-fold higher (95% CI 1.2-5.2, p = 0.012) risk of 90-day mortality for patients with BAC. After being adjusted for severity of illness, patients with BAC, hyperbilirubinemia and without elevated ALP and GGT levels had a hazard ratio of 4.51 (95% CI 1.87-10.87) for 90-day mortality. BAC was associated with the severity of the burn injury, shock and bacteraemia. BAC was present in 38 (51%) patients at discharge, and 7 (18%) patients had secondary sclerosing cholangitis. These patients maintained elevated levels of ALP and GGT that were 5.8x (1.7-15) the ULN and 11x the ULN (4.5-22), respectively, 20 months (3.5-35) after discharge. BAC is prevalent among patients with severe burn injuries and is associated with worse short-term outcomes, especially when total bilirubin levels were increased without elevated ALP and GGT levels. BAC survivors are at risk of developing sclerosing cholangitis. Cholestasis is common after burn injuries and is associated with burn severity, sepsis, organ failure and mortality. Patients with hyperbilirubinemia without elevated alkaline phosphatase and gamma-glutamyltransferase levels after the burn injury have a poor prognosis. Patients with burn-associated cholestasis may develop sclerosing cholangitis and secondary biliary cirrhosis.

SUN-357 Trial in Progress: A Multicenter, Dose-titration, Open-Label Phase 2b Study of Nevanimibe Hydrochloride, a Novel ACAT1 Inhibitor, for the Treatment of Classic Congenital Adrenal Hyperplasia

More than 90% of classic congenital adrenal hyperplasia (CAH) patients have defects in the cytochrome P450 enzyme steroid 21-hydroxylase, resulting in the inability to produce cortisol as well as the overproduction of androgens and androgen precursors such as 17-hydroxyprogesterone (17-OHP). Management of classic CAH can be challenging since patients are often unable to adequately balance the supraphysiologic doses of exogenous glucocorticoids required to suppress excess androgen production while avoiding the iatrogenic side effects of high dose glucocorticoids. Nevanimibe hydrochloride is a novel, orally-administered adrenal-specific acyl-CoA:cholesterol acyltransferase-1 (ACAT1) inhibitor. Nevanimibe inhibits adrenal steroidogenesis by decreasing cholesteryl esters, the substrate required for steroid synthesis. This inhibition of adrenocortical steroidogenesis at an early step results in impaired production across all pathways (i.e., mineralocorticoid, glucocorticoid and androgens). In a previous Phase 2 study in patients with classic CAH and elevated 17-OHP levels (NCT02804178), nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Millendo Therapeutics is now conducting a Phase 2b study to evaluate the efficacy and safety of nevanimibe in treating patients with classic CAH over a longer period (NCT03669549). At approximately 12 sites in the EU, Israel, and Brazil, 20-24 patients with classic CAH and elevated 17-OHP will be treated with nevanimibe at doses of 1000-2000 mg twice per day for 12 weeks. During the screening period, patients who are on a high glucocorticoid dose and have suppressed 17-OHP levels may undergo a slight reduction in their supraphysiologic glucocorticoid dose in order to allow their 17-OHP levels to increase to > 4x the upper limit of normal (ULN). All eligible patients will be started on nevanimibe 1000 mg BID, and nevanimibe doses will be titrated based on 17-OHP levels. The primary efficacy endpoint is the proportion of patients who are able to achieve a reduction of 17-OHP to ≤ 2x ULN. Safety endpoints include the incidence of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as values and changes from baseline in clinical laboratory tests, vital signs, physical examinations, and electrocardiogram parameters. Nevanimibe, an adrenal-specific ACAT1 inhibitor, presents a novel therapeutic approach to the treatment of classic CAH that may allow patients to more easily achieve balance between replacement glucocorticoid doses and control of hyperandrogenemia.

Donor Specific Antibodies are Associated with more Inflammation, More Fibrosis and Higher Expression of Rejection Associated Transcripts in Subclinically Rejected Liver Allografts

Background and Aims Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation and has a good medium-term prognosis even if left untreated. We recently found hints for an intrahepatic regulation of cytotoxic T cells by regulatory T cells (Treg) in SCR. However, the role of donor-specific anti-HLA antibodies (DSA) has not been investigated in this setting. Material and Methods We included all liver biopsies with SCR (rejection activity index (RAI)≥1+1+1; liver enzymes (ALT, AST, AP)≤2x upper limit of normal (ULN)) from virus negative patients in our program. Comparator cohorts consisted of biopsies with acute cellular rejection (ACR: RAI≥3; liver enzymes >2x ULN), and no histological rejection (NHR: RAI<2, normal liver enzymes). RT-PCR was performed from 77 liver biopsies with gene panels using 90 genes for rejection, endothelial cell activation, operational tolerance, T cell exhaustion and immune regulation. DSA were detected with bead assays. DSA positivity was analyzed using an MFI threshold of 1000 or more. Results and Discussion Graft gene expression in SCR biopsies broadly overlapped with the distinct expression pattern from ACR and NHR in a cluster analysis of RT-PCR results (p<0.05 and q<0.08). Thereby, SCR was characterized rather by an intermediate expression level of those genes and molecular pathways that were upregulated in ACR than by a unique set of genes or pathways. However, expression levels of GARP, a marker for activated Treg, but not of FOXP3, the Treg lineage marker, were higher in grafts with SCR compared ACR. Additionally, granzyme B, an effector molecule of cytotoxic lymphocytes, was downregulated in SCR compared to ACR, while CD8 was not significantly different in SCR and ACR. Next, the influence of DSA on the graft gene expression was evaluated, because the graft gene expression in SCR was inhomogeneous. DSAs were found in paired blood samples in 30% of SCR, 8% of NHR and 47% of ACR biopsies, while the overall DSAs frequency was 27% in our biopsy program. DSA+ SCR biopsies had significantly higher scores for lobular and portal inflammation, central perivenulitis and perisinusoidal fibrosis compared to DSA- SCR biopsies. Thereby, rejection associated transcripts were significantly overexpressed in DSA+ compared to DSA- SCR biopsies. No DSA+ liver biopsy showed a relevant C4d staining with our protocols. Nonetheless, eight SCR biopsies (10% of all SCR biopsies, 43% of DSA+ SCR biopsies) additionally fulfilled the 2016 Banff criteria for possible chronic antibody mediated rejection (cAMR). However, the biopsies numbers are still too low for prognostic evaluations. Conclusions SCR overlaps transcriptionally with NHR and ACR. Thereby, DSA seems to mark SCR biopsies with more inflammation and fibrosis. The combination of SCR in biopsies with DSA positivity might therefore identify patients with more pronounced graft inflammation, which might require a change in immunosuppression.

Overlap Syndrome of Autoimmune Hepatitis, Primary Biliary Cholangitis, and Primary Sclerosing Cholangitis in a Patient with Systemic Lupus Erythematosus: A Case Report of Complex Autoimmune Liver Disease

Introduction: Overlap syndrome is a spectrum of clinical manifestations between Autoimmune hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Overlap syndromes between AIH-PBC and AIH-PSC are well recognized. Overlap between PBC-PSC has only been reported in a few patients. To our knowledge, it is extremely rare for PBC, PSC and probable AIH overlap syndrome to occur in the same patient.Figure 1Figure 2Case report: The patient is a 48-year old Hispanic male with liver cirrhosis and SLE. His cirrhosis was complicated by esophageal varices, thrombocytopenia, coagulopathy, hypoalbuminemia, and chronic portal vein thrombosis. His biochemical profile revealed elevated ALT (2X upper limit of normal (ULN)) and AST (4X ULN), persistently elevated alkaline phosphatase (3X ULN) and elevated bilirubin (2X ULN). Investigations for etiology of cirrhosis included a detailed social history were done. Viral hepatitis serology, iron studies, celiac panel, ceruloplasmin and alpha-1 antitrypsin level were unremarkable. Anti-nuclear antibody (ANA) was positive with a titer of 1:320, anti-smooth muscle antibody (ASMA) was positive with a serum level of 20 (Normally < 20) and P-ANCA was positive. Anti-Soluble liver antigen (anti-SLA) and anti-liver kidney microsomal 1 antigen (Anti-LKM1) were negative. Gamma globulin level was elevated at 2501 mg/dL (normal range 694-1617). Anti-mitochondrial antibody (AMA) was positive with a level of 71.9 units (Normally < 20). The more specific antibody for PBC, AMA-M2, was also positive as well. He also had a positive anti-dsDNA. The patient met criteria for AIH-PBC overlap syndrome based on Paris Criteria. He was on prednisone for autoimmune thrombocytopenia and was started on oral Ursodeoxycholic acid. We also performed an ERCP with cholangiography which showed segmental irregularities of intrahepatic bile ducts with beaded appearance suggestive of sclerosing cholangitis. Based on patient's liver enzymes profile, autoimmune markers, and ERCP findings; he was diagnosed with AIH-PBC-PSC overlap syndrome. We wanted to obtain a liver biopsy, however it could not be done as patient deceased due to septic shock. Conclusion: We are presenting a case with complex clinical spectrum of autoimmune liver diseases which include AIH, PBC, and PSC. To our knowledge, this is only the second reported case of all these diseases overlapping in the same patient; and the first reported case in a patient with SLE.