Faculty Bibliography

Background/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED:National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

OBJECTIVE:The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time. METHODS:-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis. RESULTS:= 0.002) the odds of an unstable aPL profile over time. CONCLUSION/CONCLUSIONS:Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.

OBJECTIVE:Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS:Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS:Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION/CONCLUSIONS:HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

Background/Purpose: Hydroxychloroquine (HCQ) is an antimalarial drug used in the treatment of systemic lupus erythematous (SLE). Cardiac toxicity is very rare in SLE, but has been reported in patients with ESRD. The normal corrected QT (QTc) interval is defined as 450 ms in males and 470 ms in females. Severe prolongation of QTc is defined as > 500 ms and is associated with higher risk of developing life threatening arrhythmias such as Torsades de pointes (Tdp). The purpose of this study was to compare QTc intervals in a cohort of SLE patients based on HCQ exposure and with and without chronic kidney disease (CKD).
Method(s): Retrospective Epic EMR review of 194 SLE patients fulfilling criteria in a faculty practice at NYU Langone Health between 3/12/12 - 5/1/20. Data was collected on EKG, QTc of first and last EKG (QTc prolongation defined as: > 450 ms in males or > 470 ms in females. Severe QTc prolongation defined as > 500 ms), creatinine and demographics. CKD defined as eGFR < 60 ml/min.
Result(s): 90 of the 194 patient had at least one EKG. Of these 90 patients, 91% were female, 32.2% African Americans, 6.6% Asian, 38.8% Caucasian, 20% Hispanic, 2.2% other and 75 on HCQ and 15 not on HCQ. QTC was prolonged in 8/75 HCQ and 1/15 without HCQ (table 1). There was no significant difference in mean QTc interval based on HCQ use (p= 0.586). In the 23 patients with CKD, QTC was prolonged in 4/19 on HCQ and 0/4 without. In patients with CKD there was no significant difference in mean QTc interval based on HCQ use (p= 0.784). No patients had documented tachyarrthymia or Tdp.
Conclusion(s): In a cohort of SLE patients, at least one EKG was available in 46%. There was no significant difference in mean QTc based on HCQ use. Patients with CKD were more likely to have prolonged QTc when compared to those without CKD, but there was no significant difference in mean QTc based on HCQ use as well in this subset. Severe prolongation of QTc was rare in all groups and no episodes of serious tachyarrhythmia or Tdp were observed. A role for more severe stages of CKD, underlying heart disease, or concurrent use of drugs that also affect QTc was not studied. The data supports current standard of care which does not require monitoring with baseline and serial EKGs in the routine management of SLE patients on HCQ. It remains uncertain if the effect of HCQ on the conducting system is limited to a physiological result yet is clinically inconsequential absent other risk factors

Background/Purpose: Lupus nephritis (LN) is a major complication of systemic lupus erythematous (SLE) and affects ~60% of patients during the course of their disease, leading to significant morbidity and mortality. Previous studies examining the safety of percutaneous kidney biopsy to diagnose LN have found variable complication rates depending on disease type studied, ranging from 4-11% in autoimmune/SLE patients to 15-17% in safety studies of any kidney disease. The purpose of our study was to define the safety of obtaining additional tissue for research during clinically indicated renal biopsies in a SLE cohort.
Method(s): Patients were enrolled across 15 clinical US sites in the SLE Accelerating Medicines Partnership (AMP). Kidney biopsies were clinically indicated to evaluate proteinuria (urine protein creatinine ratio [uPCR] > 0.5). Patients with a history of renal transplant, use of rituximab within 6 months of biopsy, and current pregnancy were excluded. Ultrasound/CT-guided kidney biopsies were performed by interventional radiologists/nephrologists generally using an 18-gauge needle although technique, number of routine passes and core lengths varied. An additional core taken solely for research purposes, or a piece of core with sufficient glomeruli remaining from the routine passes and not required for clinical diagnosis, was collected. All adverse events (AEs) occurring within 30 days of biopsy were reported, including duration, severity, type, and resolution.
Result(s): 482 patients underwent a renal biopsy between 2014 and 2020. All patients met criteria for SLE (ACR or SLICC) and the majority were female (85%). Pathologic assessment of clinical biopsies revealed ISN/RPS Class I-VI for most biopsies, although 45 biopsies (9%) yielded a non-LN diagnosis (Table 1). Overall, 37 patients (8%) experienced an AE with several more than one, with a total of 41 AEs reported. Of these AEs, 8 (20%) were considered by the site investigator to be unrelated or unlikely to be related (included pain, shortness of breath, cardiac arrest, fall, and hemoglobin decrease due to sepsis) and 33 (80%) were deemed possibly, probably, or definitely related to the study procedure. Of these events, 9/33 (28%) were mild, 10 (30%) were moderate, and 12 (36%) were deemed severe. In 18 patients (4%) the AEs were considered serious as defined by inpatient or prolonged hospitalization, significant incapacity, or requiring intervention to prevent permanent impairment. The most common related AEs were bleed-related complications, including hematoma, hemorrhage, and hemoglobin decrease (N= 29). Of these, 18 required hospitalization, with 4 of these patients receiving a blood transfusion. All 29 bleed-related complications resolved. The length of the research biopsy did not associate with an AE.
Conclusion(s): Procurement of an additional kidney biopsy core for research purposes in SLE patients undergoing a clinically-indicated kidney biopsy did not result in an increase in adverse events compared to the adverse event rate in prior studies of the safety of percutaneous kidney biopsy. Accordingly, inclusion of a research core should be considered feasible for future studies to advance discovery of new therapeutic targets and prognostic indicators in LN

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