Faculty Bibliography

Background Patients with Systemic Lupus Erythematosus (SLE) represent a unique population at risk for COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. This study was initiated to evaluate for the presence of SARS-CoV-2 IgG antibodies in SLE patients with and without prior COVID-19-related symptoms or COVID-19 RT PCR testing. Methods A total of 329 patients with SLE from two cohorts, one serially monitored for COVID-19 in Spring 2020 (the Web-based Assesment of Autoimmune, Immune-Mediated and Rheumatic Patients (WARCOV) and one undergoing routine surveillance (NYU Lupus Cohort) were tested for SARS-CoV-2 IgG via commercially available immunoassays processed through hospital or outpatient laboratories between April 29, 2020 and February 9, 2021. Results Overall, 16% of 329 patients had a reactive SARSCoV- 2 IgG antibody test. Seropositive patients were more likely to be Hispanic. Other demographic variables, lupus-specific factors and immunosuppressant use were not associated with reactivity. Of the 29 patients with prior RT-PCR confirmed COVID-19, 83% developed an antibody response despite 62% being on immunosuppressants. Six percent of patients who had symptoms suspicious for COVID-19 but negative concurrent RT-PCR testing developed an antibody response. Twenty-three percent of patients who had COVID- 19-related symptoms but no RT-PCR testing and 5% of patients who had no symptoms of COVID-19 developed an antibody response. Among patients initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially. In COVID- 19-confirmed patients high percentages had antibody positivity beyond 30 weeks from disease onset, 88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks. Conclusions Most 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

OBJECTIVE:To characterize patients with Systemic Lupus Erythematosus (SLE) affected by COVID-19 and to analyze associations of comorbidities and medications on infection outcomes. METHODS:Patients with SLE and RT-PCR-confirmed COVID-19 were identified through an established New York University lupus cohort, query of two hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected from 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 patients with confirmed COVID-19; 19 patients who tested negative for COVID-19; 42 patients with COVID-19-like symptoms who did not get tested; and 124 patients who remained asymptomatic without testing. Of those SLE patients with COVID-19, 24 (59%) required hospitalization, four required intensive care unit-level of care, and four died. Hospitalized patients tended to be older, non-white, Hispanic, have higher BMI, history of nephritis, and at least one comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least one comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION/CONCLUSIONS: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.

Background/Purpose: Patients with systemic lupus erythematosus (SLE) represent a unique population in considering risk for coronavirus disease 2019 (COVID-19) with biologic, genetic, demographic, clinical and treatment issues all at play. By the nature of their chronic inflammatory autoimmune condition and regular use of immunosuppressive medications, these individuals would traditionally be considered at high risk of contracting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and having a worse prognosis. Accordingly, we aimed to characterize patients with SLE affected by COVID-19 in New York City (NYC) and analyze associations of comorbidities and medications on outcomes.
Method(s): Patients with SLE and COVID-19 (confirmed by RT-PCR testing), were identified through a longitudinal survey of an established NYU lupus cohort, query of New York University Langone Health and Bellevue Hospitals systems and referrals from rheumatologists at those institutions. All patients were age 18 or older and met SLE classification criteria or carried a rheumatologist's diagnosis of SLE. Only English-, Spanish- or Mandarin-speaking patients were included in the study. Data were prospectively collected via a web-based questionnaire and review of electronic medical records. Baseline characteristics and medications were compared between the hospitalized and ambulatory patients with COVID-19. A logistic regression analysis was performed to identify independent predictors of hospital admission.
Result(s): A total of 41 SLE patients were confirmed COVID-19 positive by RT-PCR. The patients were predominantly female and encompassed the major racial/ethnic demographics seen in NYC. The most common symptoms of COVID-19+ patients were cough (78.4%), fever (64.9%), and shortness of breath (64.9%). Of those SLE patients with COVID-19, 24 (59%) were hospitalized, 4 required ICU level of care, and 4 died, all of hypoxic respiratory failure, Table 1. Hospitalized patients tended to be older, non-white, Hispanic, and have higher BMI, antiphospholipid syndrome, a history of lupus nephritis and at least one medical comorbidity, Table 2. There was no difference between the groups in use of hydroxychloroquine, systemic steroids or immunosuppressants. Logistic regression analysis identified the following independent predictors of being hospitalized with COVID-19: race (OR = 7.78 for non-white vs. white; 95% CI: 1.13 to 53.58; p=0.037), the presence of at least one comorbidity (OR=4.66; 95% CI: 1.02 to 21.20; p=0.047), and BMI (OR = 1.08 per increase in kg/m2; 95% CI: 0.99 to 1.18; p=0.096).
Conclusion(s): Patients with SLE and COVID-19 have a high rate of hospitalization but similar mortality rate to the general population in NYC. Risk factors such as non-white race, higher BMI, and the presence of one or more comorbidities were identified as independent predictors of hospitalization in SLE patients who develop COVID-19. The use of hydroxychloroquine and immunosuppressants did not appear to influence the outcomes of patients with SLE in the setting of COVID-19. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE

Background/Purpose: Patients with systemic lupus erythematosus (SLE) are at increased risk of premature atherosclerosis and thrombosis. Hydroxychloroquine (HCQ) is widely used in the treatment of SLE and has been considered of benefit for overall vascular health albeit studies to address this benefit at the cellular level have been limited. Accordingly, this study was initiated to investigate the relationship between HCQ use and dose with platelet activity, the platelet transcriptome, and vascular functional readouts.
Method(s): Patients fulfilling ACR or SLICC criteria for SLE were consecutively recruited for platelet evaluation with the only exclusion being on nonsteroidal anti-inflammatory medications, aspirin or anticoagulants. At enrollment, blood was collected for hematology analysis using the Sysmex XN-1000 analyzer, platelet aggregation via the Helena AggRAMTM system, and platelet RNA isolation and storage. Microvascular function was assessed via sublingual sidestream darkfield imaging. Brachial artery reactivity testing was used to evaluate large vessel function. Stored platelet RNA was isolated and analyzed by RNA sequencing (Illumina HiSeq4000 Sequencing).
Result(s): Among 132 SLE subjects, 108 were on HCQ. Mean age was 39.9 +/- 13.0 and 97% were female. Lupus disease activity at the time of blood draw assessed by the SELENA-SLEDAI activity index was 3.44 (range 0-20). Demographics and SLE disease activity did not differ between those on versus off HCQ (Table 1). Platelet count and size were not different between groups (Figure 1A). Platelet aggregation in response to submaximal ADP at multiple concentrations was lower in participants on HCQ (Figure 1B). Consistently, there was an inverse relationship between HCQ dosing and platelet aggregation in response to ADP (2uM: R=-0.213, P=0.037; 1uM: R=-0.310, P=0.0025; 0.4uM: R=-0.376, P=0.00018; Figure 1C). Since no subjects were on aspirin (or any other antiplatelet therapy at enrollment), aggregation in response to arachidonic acid (AA) was robust and similar between groups. However, after incubating platelets with aspirin (3mM) in vitro, platelet aggregation in response to AA was lower in the HCQ group compared to non-HCQ group (P=0.035, Figure 1B). To investigate the potential mechanisms of HCQ induced lower platelet aggregation, we evaluated platelet RNA sequencing in 49 subjects (8 no HCQ, 41 on HCQ). Positive regulation of pathways related to platelet activation (and in particular, P-selectin expression) was inversely related to HCQ, especially with higher doses (Figure 1E). In terms of vascular function, subjects on HCQ had improved microvascular function as noted by an increased proportion of sublingual capillaries filled with RBCs (P=0.011) and smaller perfused boundary region (PBR, P=0.010). HCQ dosing correlated with PBR (R=-0.599, P=0.002, Figure 1H) and RBC Filling (R=-0.592, P=0.002, Figure 1I). BART also trended positively with HCQ dose (R=0.385, P=0.094; Figure 1J).
Conclusion(s): These findings suggest that HCQ may provide benefit for vascular health in SLE as supported by ex vivo experiments demonstrating decreased platelet aggregation and downregulation of platelet functional pathways as well as improved vascular readouts

Background/Purpose: Disparities have been reported during the coronavirus disease (COVID-19) outbreak. Systemic lupus erythematosus (SLE) patients represent a unique group that is affected by clinical, treatment, demographic, and socioeconomic (SES) risk factors for severe COVID-19 disease. The Neighborhood Deprivation Index has been associated with non-communicable disease as well as communicable disease outcomes. We conducted this study to identify neighborhood SES factors influencing SLE COVID-19 outcomes.
Method(s): Patients with SLE and COVID-19 (confirmed by RT-PCR testing), were identified through a longitudinal survey of an established NYU lupus cohort, query of NYU Langone Health and Bellevue Hospitals systems and referrals from rheumatologists at those institutions. All patients were age 18 or older and met SLE classification criteria or carried a clinical diagnosis of SLE. Baseline characteristics along with zip code neighborhood data including COVID-19 case rates and neighborhood characteristics were obtained using the Hopkins COVID database and the American Community Surveys (ACS 2014-2018) respectively. A principal component analysis was performed to identify contributory neighborhood characteristics. Then a logistic regression analysis identified predictors of testing positive for COVID-19 and COVID-19 hospitalization.
Result(s): A total of 59 SLE patients (41+ and 18-) were tested for COVID-19 by RT-PCR. The patients were predominantly female, aged 46+/-16, and racially/ethnically diverse. Roughly 140 neighborhood data points were recorded and categorized as follows: population density, race and ethnicity, household type, household size, education level, employment type and status, income and poverty, transportation method, and insurance status. COVID-19 positive patients tended to live in neighborhoods with more single parent households, households with >4 residents, higher unemployment rate, higher high school dropout rate, more public transit use, and more employment in retail, construction, and personal care services. These variables were directly proportional to principal component 1 (PC1) and accounted for 88% of the variance in neighborhood characteristics. A logistic regression model identified that PC1 (OR= 1.3; 95% CI: 1.0-1.8) and taking immune suppressants (IS) (taking vs not taking OR= 2.1; 95% CI: 1.5 to 23.3) independently correlated with having a positive COVID-19 test when controlling for hydroxychloroquine (HCQ), glucocorticoids (GC), and previous lupus nephritis (LN). Only PC1 independently correlated with COVID-19 hospitalization (OR= 1.4; 95% CI: 1.1-1.9) upon controlling for taking IS, HCQ, GCs, and LN. PC1 associated with African American (AA) or Hispanic patient race/ethnicity (OR= 1.6, 95% CI: 1.2-2.2).
Conclusion(s): In addition to SLE disease, neighborhood characteristics and SES are important risk factors both for contracting COVID-19 and developing severe disease. Neighborhood deprivation may mediate the reported relationship between AA and Hispanic race/ethnicity and COVID-19. Given that a plurality of SLE patients are of AA and/or Hispanic backgrounds, care teams must formulate strategies to address socioeconomic stress in our patients

Background/Purpose : SLE diagnostic criteria are important for reliable epidemiologic data. The prevalence of SLE in West Africa is falsely low due to barriers including limited access to both resource and labor-intensive diagnostic testing. Recently, the ACR and EULAR have proposed a weighted classification tool which is thought to improve diagnostic sensitivity and specificity compared to the established ACR and SLICC criteria. Here we aim to investigate the performance of each classification criteria in two West African cohorts--Korle bu Teaching Hospital, Accra Ghana (GH); and Lagos University Teaching Hospital, Lagos, Nigeria (N)--compared to an NYU Langone-African American (AA) cohort. Methods : We collected data on a total of 355 SLE patients: AA: n=151, GH: n=110, and N: n=94, diagnosed by expert clinicians. Clinical information including demographics, SLE criteria, SLEDAI scores, SLICC damage indexes, vital signs, and laboratory values as available was obtained at the initial patient encounter. Longitudinal data was collected over the course of at least 1 year at 6 month intervals during routine clinical visits. Where necessary, clinical charts were retrospectively reviewed, and the proportion of patients in each cohort meeting ACR, SLICC and the ACR/EULAR classification criteria was calculated. Results : The demographics per cohort were as follows: Age (in yrs): AA=43.1, GH=32.4yrs, N=35.5; percent female: AA=90, GH=100, N=97; Mean SLE disease duration (yrs): AA=14.3, GH=2.2, N=4.4. In each cohort, the percentage of patients meeting ACR, SLICC, and ACR/EULAR criteria were AA=96%, 96%, and 95%; GH=85%, 84%, 62%; N=90%, 87%, 61%. This discrepancy was largely due to missing laboratory data particularly with regard to immunologic and hematologic studies. ANA was missing in 0% of the AA cohort, 26% of the GH cohort, and 33% of the N cohort respectively. Compared to the GH and N cohorts, the reference AA cohort was more likely to meet ACR, SLICC, and ACR/EULAR criteria with likelihood ratios (LR) of GH=10.2 p< 0.001 and N=3.0 p=0.08; GH=11.5, p< 0.001 and N=6.3, p=0.01; and GH=46.1 P< 0.001 and N=44.9, p< 0.001 respectively. On average, the mean number of ACR/EULAR points by cohort was AA: 26.1+/-11.8, GH: 21.3+/-8.1, and N: 19.0+/-6.2. While the ANA entry criteria greatly diminished the new ACR/EULAR diagnostic utility in the GH and N cohorts, the weighted point system performed better than either of the ACR or SLICC criteria with 96% of the AA cohort, 92%of the GH, and 95% of the N cohort meeting criteria (LR: AA vs GH=1.9, p=0.2; AA vs N=0.23, p=0.6). Conclusion : Due to a relative lack of resources, supportive laboratory assays including an ANA may be more difficult to attain in developing nations. SLE is a clinical syndrome that may be efficiently diagnosed using the new weighted ACR/EULAR criteria. The entry criteria of ANA 1:80 greatly diminished the diagnostic utility of this classification system in the Ghanaian and Nigerian cohorts compared to the African American cohort. Clinical trials should consider offering wide ANA testing to cohorts in the developing world

Background/Purpose : In SLE Apolipoprotein L1 (APOL1) risk variants associate with cardiovascular and kidney damage. APOL1 is both a secreted and tissue intrinsic protein; the latter role mediates organ injury. Expression is driven by inflammatory stimuli which initially promotes survival through autophagy. At higher expression, APOL1 contributes to cell death partially by compromising mitochondria. The RV protein structure favors toxicity at lower thresholds. Macrophages express APOL1 and use metabolic plasticity to perform effector functions. We hypothesized that in activated macrophages, APOL1 expression impairs mitochondrial Methods : Healthy controls were genotyped for APOL1 reference allele (G0) risk variants (RV) (n=15; G0/G0=8, RV/ G0=4, RV/RV=3). Monocytes were isolated from PBMCs using a Miltenyi Biotec Pan Monocyte Isolation kit and differentiated into macrophages using GM-CSF. Cells were treated with SLE-relevant agonists ssRNA hY3 or IFNgamma; and APOL1 expression was observed by qPCR. As in-vivo correlates, APOL1 expression relative to IFN response gene, Siglec 1, in SLE patient monocytes (n=17); and expression in coronary artery tissue macrophages with (n=3) or without (n=3) atherosclerotic plaque were assessed through RNA seq data and immunohistochemistry respectively. To test mitochondrial respiration, cultured HC macrophages were left untreated or IFNgamma treated, and bioenergetics were measured by the Seahorse assay. Confirmatory fluorescent microscopy was done by staining cells with Mitoprobe (polarized mitochondria) and Mitotracker (all mitochondria) and the ratio of Mitoprobe to Mitotracker staining was quantified using ImageJ software. Results : Across the genotypes,hY3 and IFNgamma increased APOL1 mRNA expression 29.1+/-18.4 and 31.6+/-14.9 fold compared to untreated (p< 0.001 in each). In SLE monocytes, APOL1 significantly correlated with Siglec1 expression (R=0.64; P=0.005). APOL1 stained 4% of non-plaque containing and 18% of plaque-containing coronary arteries (p=0.05). APOL1 was apparent in multiple cell types including invading tissue macrophages (fig1). On the seahorse assay, there were genotype-dependent differences in Basal OCR (BO pmol/min), Spare Capacity (SC pmol/min), and total ATP production (ATP pmol/min) (G0/G0: BO: 99.4+/-11.3, SC:150.9+/-16.6, ATP: 88.1+/-9.5; RV/G0: BO: 46.1+/-4.5, SC: 52.1+/-8.8, ATP: 40.7+/-3.4; RV/RV: BO: 46+/-17.4, SC: 14.9+/-11.6, ATP: 36.7+/-9.5 each p< 0.001). Across genotype, these values fell with IFNgamma (G0/G0: BO: 73.9+/-6, SC: 129.4+/-17.3, ATP: 67.6+/-5.4; RV/G0: BO: 46+/-5.1, SC: 27.9+/-8.1, ATP: 39.5+/-3.9; RV/RV: BO: 42.1+/-8.6, SC: 9.5+/-8.3, ATP: 35.8+/-6.9) (fig2). Fluorescent microscopy confirmed findings with the mean respective MitoProbe/Mitotracker ratios in G0/G0, RV/G0, and RV/RV macrophages at rest 1.5+/-0.5, 0.86+/-0.3, and 0.89+/-0.3 and with IFNgamma 1.3+/-0.4, 0.74+/-0.3, and 0.6+/-0.2 (fig3). Conclusion : Inflammation both in vitro and in vivo due to hY3, IFNgamma, and ischemia increase macrophage APOL1 expression across genotypes. In RV carrying macrophages, this results in diminished mitochondrial energy production-a potential underpin of variant-mediated toxicity. (Figure Presented)

OBJECTIVE:To assess the prevalence of atherosclerotic cardiovascular disease (ASCVD) and its individual phenotypes of coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease by age and sex in a large US cohort of hospitalized patients with systemic lupus erythematosus (SLE). METHODS:A nested case-control study of adults with and without SLE was conducted from the January 1, 2008, through December 31, 2014, National Inpatient Sample. Hospitalized patients with SLE were matched (1:3) by age, sex, race, and calendar year to hospitalized patients without SLE. The prevalences of CAD, PAD, and cerebrovascular disease were evaluated, and associations with SLE were determined after adjustment for common cardiovascular risk factors. RESULTS:Among the 252,676 patients with SLE and 758,034 matched patients without SLE, the mean age was 51 years, 89% were women, and 49% were white. Patients with SLE had a higher prevalence of ASCVD vs those without SLE (25.6% vs 19.2%; OR, 1.45; 95% CI, 1.44-1.47; P<.001). After multivariable adjustment, SLE was associated with a greater odds of ASCVD (adjusted odds ratio [aOR], 1.46; 95% CI, 1.41-1.51). The association between SLE and ASCVD was observed in women and men and was attenuated with increasing age. Also, SLE was associated with increased odds of CAD (aOR, 1.42; 95% CI, 1.40-1.44), PAD (aOR, 1.25; 95% CI, 1.22-1.28), and cerebrovascular disease (aOR, 1.68; 95% CI, 1.65-1.71). CONCLUSION/CONCLUSIONS:In hospitalized US patients, SLE was associated with increased ASCVD prevalence, which was observed in both sexes and was greatest in younger patients.

Background/Purpose: Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, are enriched in ancestrally African populations due to a conferred superior resistance to Trypanosoma brucei. This improved infectious evolutionary fitness comes at the cost of propensity toward progressive renal disease by multiple causes including SLE. In Ghana's Ashanti people, Allelic frequencies for G0, G1, and G2 have been reported at 0.46, 0.49, and 0.13 respectively. Despite their high frequencies, and the established role in SLE nephritis, no study has examined outcomes in a Ghanaian SLE cohort. Accordingly, this prospective study evaluated APOL1 risk traits including renal, damage accrual, and mortality in 101 Ghanaian patients followed at Korle bu Teaching Hospital in Accra, Ghana.
Method(s): From 05/2015-04/2018, 101 Ghanaian patients meeting at least 4 ACR criteria for SLE were followed prospectively with data evaluated every six months. DNA was extracted from saliva and patients were stratified by APOL1 genotype as follows: reference allele (G0/G0), RV heterozygote (RV/G0), and RV homozygotes (RV/RV). Sera were shipped to the NYU clinical lab for confirmation of anti-dsDNA. Clinical endpoints included demographics, ACR criteria, SLEDAI score, SLICC damage index, mortality, vital signs, and laboratory values as available.
Result(s): The frequencies of the G1, and G2 alleles were 0.24, and 0.12 respectively- lower than would be expected given the reported regional frequencies. Subjects were 100% female, with an average age of 32.1 years and disease duration of 2.9 years. There were no differences in demographics across the genotypes. The RV associated with higher BP: 108/71, 108/ 73, and 120/82 in the G0/G0, RV/G0, and RV/RV groups respectively (p=0.04 systolic; 0.009 diastolic). Among those with nephritis, RV/RV carriers presented with higher dipstick proteinuria than G0/G0 and RV/G0 carriers (2.6 vs 1.2 and 1.3 respectively; p=0.05; F=3.1). While proteinuria responded most robustly to therapy in RV/RVs, it remained higher at each time point compared to the other genotypes (p=0.002; F=5.4). SLEDAI scores were comparable across the genotypes, however RV/RV carriers had lower dsDNA titers (10.7 IU/mL) than G0/G0 (57.1 IU/mL) and RV/G0 (95.6 IU/mL) carriers (p: 0.03). RV homozygosity associated with elevated SLICC damage index: G0/G0 or RV/G0: 0.95 vs RV/RV: 1.7; driven by renal, CVD, and neurologic manifestations G0/G0: 0.46, RV/G0: 0.39, RV/RV: 1.25; (p=0.03). There were 5 deaths during the study period: 1 death in the G0/G0 group (ESRD), 1 in the RV/G0 group (post-partum sepsis plus renal), and 3 in the RV/RV group (myocarditis/heart failure; ESRD; unknown). RV carrier status associated with mortality with 25% of the RV/RV group succumbing to disease vs 2% in the G0/G0 and RV/G0 groups (p=0.003; F=6.3).
Conclusion(s): Taken together, APOL1 RV associates with renal progression, organ damage accrual, and mortality in this Ghanaian SLE cohort. Despite having poorer outcomes, RV homozygotes exhibited lower dsDNA titers and similar SLEDAI scores compared to G0/G0 or RV/G0 patients suggesting a genetic effect independent of SLE activity. APOL1 genotyping could have important prognostic implications in ancestrally African SLE patients