IMPACT Study: Preliminary results of a trial with a biologic to prevent preeclampsia in women with antiphospholipid syndrome

BackgroundPregnant women with antiphospholipid antibodies and/or lupus have higher rates of adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The presence of lupus anticoagulant (LAC) is the strongest predictor of an APO. At present, there is no effective treatment for women with these high-risk pregnancies, but in an animal model that mimics this human condition we found that TNF-α was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-α blockade normalized placentation and spiral artery remodeling, and rescued pregnancies. We sought to determine whether TNF-α blockade during pregnancy, added to a regimen of heparin and low dose aspirin, reduces the rate of APOs in women with clinical APS and LAC.MethodsThe IMPACT Study (IMProve Pregnancy in APS with Certolizumab Therapy) is an open label single-stage Phase II trial to evaluate the effect of certolizumab, a TNF-α inhibitor that does not cross the placenta and has been shown to be well tolerated in pregnancy, to reduce the risk of adverse outcomes in this population. Patients with APS and LAC are referred to IMPACT by their physicians, consented and screened remotely by a study investigator, and medication is sent to the patient. They are treated with certolizumab from gestational week 8 through 28. Investigators contact patients every 2 weeks and receive medical reports and research blood samples monthly. The primary outcome is a composite of two APOs associated with poor placentation: fetal death >10 WG or severe preeclampsia/placental insufficiency requiring delivery prior to 34 weeks gestation. The target sample size is 45 evaluable subjects. We hypothesize that the rate of the primary outcome in these pregnancies will be reduced from ~40% based on historical data to 20% with certolizumab.ResultsSince May 2017 and despite the COVID-19 pandemic, we have enrolled 41 patients from ten states and 1 Canadian province. Characteristics: 56% previous PE or PI <34 weeks requiring delivery, 83% previous fetal death >10 weeks;61% thrombosis and/or stroke and 24% SLE in addition to APS. During the trial, no new clinical manifestations of SLE have been observed in participants who did not carry the SLE diagnosis. There were no instances of new anti-DNA antibodies or increases in autoantibody titres in those patients who were anti-DNA antibody positive. ACL or anti-β2GPI antibody titres did not change during the trial. There have been no serious adverse events attributable to the study medication.ConclusionWe are successfully using a "rare disease study” approach to conduct the first trial of a biologic therapy to prevent pregnancy complications in women with APS and LAC. Certolizumab appears to be safe in this small trial. Certolizumab appears to be safe so far in this small trial. IMPACT must be completed before we can draw any conclusions about efficacy, and its results must be confirmed in a future study.AcknowledgementsNIAMS, Lupus Research institute, Lupus Foundation of AmericaClinicalTrials. gov Identifier: NCT03152058Lay SummaryPregnancies in patients with antiphospholipid syndrome who have a lupus anticoagulant in their blood have a high likelihood of ending in fetal death or very premature delivery because of poor placental development and preeclampsia. At present, there is no effective treatment for women with these high-risk pregnancies, but our work in an animal model that mimics this human condition shows that blockade of TNF-α, a pivotal mediator of inflammation, prevents adverse outcomes. Our study will determine whether treatment during pregnancy with certolizumab, a TNF-α inhibitor that does not cross the placenta, reduces the rate of poor pregnancy outcomes in women with clinical antiphospholipid syndrome;and, if successful, it will provide a new approach to protecting pregnancies in women with antiphospholipid syndrome and a rationale for trials of TNF-α blockade in women with other conditions, like SLE, who are a risk for preeclampsia or placental insufficiency.

Physician Electronic Health Record Usage as Affected by the COVID-19 Pandemic.

OBJECTIVES: To utilize metrics from physician action logs to analyze volume, physician efficiency and burden as impacted by telemedicine implementation during the COVID-19 (coronavirus disease 2019) pandemic, and physician characteristics such as gender, years since graduation, and specialty category. METHODS: We selected 11 metrics from Epic Signal, a functionality of the Epic electronic health record (EHR). Metrics measuring time spent in the EHR outside working hours were used as a correlate for burden. We performed an analysis of these metrics among active physicians at our institution across three time periods-prepandemic and telehealth implementation (August 2019), postimplementation of telehealth (May 2020), and follow-up (July 2020)-and correlated them with physician characteristics. RESULTS: Analysis of 495 physicians showed that after the start of the pandemic, physicians overall had fewer appointments per day, higher same day visit closure rates, and spent less time writing notes in the EHR outside 7 a.m. to 7 p.m. on patient scheduled days. Across all three time periods, male physicians had better EHR-defined "efficiency" measures and spent less time in the EHR outside working hours. Years since graduation only had modest associations with higher same day visit closure rates and appointments per day in May 2020. Specialty category was significantly associated with appointments per day and same day closure visit rates and also was a significant factor in the observed changes seen across the three time periods. CONCLUSION: Utilizing EHR-generated reports may provide a scalable and nonintrusive way to monitor trends in physician usage and experience to help guide health systems in increasing productivity and reducing burnout.

Evaluation of Immune Response and Disease Status in Systemic Lupus Erythematosus Patients Following SARS-CoV-2 Vaccination.

OBJECTIVE: To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE). METHODS: Ninety SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; interferon-γ (IFNγ) production was measured by enzyme-linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index. RESULTS: Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD compared to fully vaccinated controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-double-stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and correlated with antigen-specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre- and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe. CONCLUSION: In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID-19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination.

Evaluation of SARS-CoV-2 IgG antibody reactivity in a multi-racial/ethnic cohort of patients with systemic lupus erythematosus

1206 Figure 1SARS-CoV-2 IgG in SLE[Figure omitted. See PDF]ConclusionsMost patients with SLE and confirmed COVID-19 were able to produce a serologic response despite use of a variety of immunosuppressants. These findings provide reassurances regarding the efficacy of humoral immunity and possible reinfection protection in patients with SLE.AcknowledgmentsData presented on behalf of the NYU WARCOV investigators. We thank Leora Horwitz for her assistance with the ICD-10 query at NYU. We also acknowledge Tania Moin and Ranit Shriky for assistance in navigating regulatory matters.

Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus erythematosus: analysis of a multi-racial and multi-ethnic cohort.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. METHODS: For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. FINDINGS: 329 patients with SLE were included in this analysis, 146 from the WARCOV study and 183 from the NYU Lupus Cohort, and were tested for SARS-CoV-2 antibodies between April 29, 2020, and Feb 9, 2021. 309 (94%) were women and 91 (28%) were of Hispanic ethnicity. 51 (16%) of 329 patients had a positive SARS-CoV-2 IgG antibody test. Seropositive patients were more likely than seronegative patients to be Hispanic (24 [47%] of 51 vsz 67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. INTERPRETATION: Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. FUNDING: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

COVID-19-Induced Anosmia and Ageusia Are Associated With Younger Age and Lower Blood Eosinophil Counts.

BACKGROUND: Anosmia and ageusia are symptoms commonly associated with COVID-19, but the relationship with disease severity, onset and recovery are unclear. OBJECTIVE: To examine factors associated with anosmia and ageusia and the recovery from these symptoms in an ethnically diverse cohort. METHODS: Individuals tested for SARS-CoV-2 between March and April 2020 were eligible for the study. Randomly selected participants answered a telephone questionnaire on COVID-19 symptoms with a focus on anosmia and ageusia. Additionally, relevant past medical history and data on the COVID-19 clinical course were obtained from electronic medical records. 486 patients were in the COVID-19 group and 103 were COVID-19-negative. RESULTS: Patients who were younger were more likely to report anosmia and/or ageusia (odds ratio (OR) for anosmia per 1-year increase in age: 0·98, 95%CI:0-97-0·99, p = 0·003; for ageusia: 0·98, 95%CI:0·97-0·99, p = 0·005) as were patients with lower eosinophil counts (OR for anosmia per 0.1-K/µL increase in eosinophils: 0·02, 95%CI:0·001-0·46, p = 0·01, for ageusia 0·10, 95%CI:0·01-0·97, p = 0·047). Male gender was independently associated with a lower probability of ageusia (OR:0·56, 95%CI:0·38-0·82, p = 0·003) and earlier sense of taste recovery (HR:1·44, 95%CI:1·05-1·98, p = 0·02). Latinos showed earlier sense of taste recovery than white patients (HR:1·82, 95%CI:1·05-3·18, p = 0·03). CONCLUSION: Anosmia and ageusia were more common among younger patients and those with lower blood eosinophil counts. Ageusia was less commonly reported among men, and time to taste recovery was earlier among both men and Latinos.

Pandemics, Protests, and Feminist Politics of Resistance

The article explores the journal's publication of inquiries into social work settings and the role of anticarceral feminisms in enacting and preserving a carceral system in the U.S. as of 2021. Topics covered include exposing the divides of social work, and strengthening a critical feminist politics of resistance and liberation. Also noted is the journal's aim to continuously provide critical feminist scholarship amid the coronavirus pandemic.

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation.

BACKGROUND: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. METHODS: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies. RESULTS: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. CONCLUSIONS: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.

Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth.

OBJECTIVE: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity. STUDY DESIGN: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut. RESULTS: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 109 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity. CONCLUSIONS: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management.

Leveraging the United States Epicenter to Provide Insights on COVID-19 in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID-19) and to analyze associations of comorbidities and medications on infection outcomes. METHODS: Patients with SLE and reverse transcriptase-polymerase chain reaction-confirmed COVID-19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. RESULTS: A total of 226 SLE patients were included: 41 with confirmed COVID-19, 19 who tested negative for COVID-19, 42 with COVID-19-like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID-19, hospitalization was required in 24 (59%) and intensive care unit-level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION: In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.