Faculty Bibliography

Background/Purpose: The Manhattan Lupus Surveillance Program (MLSP) is a multi-racial/ ethnic population-based registry with the primary goal to determine the prevalence and incidence of Systemic Lupus Erythematosus (SLE). In this study, we compare the three most commonly used classification criteria for SLE (1997 revised ACR, Systemic Lupus International Collaborating Clinics (SLICC) and the recent EULAR/ACR classification criteria) to identify cases that fulfilled only one of the classification criteria and explore each criteria set's unique cases. In addition, we used the EULAR/ACR criteria to determine the incidence and prevalence of SLE in Manhattan.
Method(s): MLSP cases were identified from Manhattan-based hospitals and rheumatologists, and state population databases. For this analysis, SLE cases were defined as fulfilling 1) the 1997 ACR classification criteria, 2) the SLICC criteria or 3) EULAR/ACR classification criteria. We quantified the number of cases that uniquely associated with each classification criteria and the number that fulfilled all three classifications. Prevalence (2007) and incidence rates (2007-2009) using the EULAR/ACR classification criteria and associated 95% confidence intervals (CI) were calculated using denominators obtained from the US Census data (revised 2000-2009 intercensal population files) for Manhattan.
Result(s): Overall 1,568 cases fulfilled at least one of the three classification criteria. Of those, 1008 (64.3%) cases fulfilled all three classification criteria, 166 (10.5%) fulfilled only the SLICC criteria, 50 (3.2%) fulfilled only the 1997 ACR criteria and 36 (2.3%) fulfilled the EULAR/ACR criteria with the remaining cases fulfilling a combination of two classification criteria. Cases that only met one of the classification criteria, and the reasons why they did not meet the other two classification criteria with example cases, are detailed in Tables 1-3. Based on the EULAR/ACR classification criteria, the age-adjusted overall prevalence and incidence rates of SLE in Manhattan were 59.8 (n=1,029, 95%CI:56.1-63.6) and 4.9 (n=245, 95%CI 4.3-5.5) per 100,000 population. Prevalence was 9 times higher and incidence was 6.9 times higher among females compared to males. The age-adjusted prevalence per 100,000 was highest among non-Hispanic Black females (198.9), followed by Hispanic females (133.1), non-Hispanic Asian/Pacific Islander females (97.7) and non-Hispanic White females (59.8). Age-adjusted incidence rates per 100,000 were highest in non-Hispanic Black females (15.8), followed by Hispanic females (7.5), non-Hispanic Asian/Pacific Islander females (7.3) and non-Hispanic White females (6.3). Prevalence and incidence rates for males followed a similar pattern.
Conclusion(s): Applying the three commonly used classification systems to a multi-racial/ ethnic population-based registry allowed for identifying unique cases of SLE who only fulfilled one classification system. The EULAR/ACR classification criteria revealed similar prevalence and incidence estimates and gender and racial/ethnic disparities to the previously published results from the MLSP using the 1997 revised ACR and SLICC classification criteria

Background/Purpose: The Accelerating Medicines Partnership (AMP) Lupus Network was established with the goal of applying novel technologies to the interrogation of blood and tissue samples from patients with lupus nephritis (LN). In contrast to global LN clinical trials, the AMP LN cohort affords an opportunity to generate outcome data representative of a US multicenter multi-ethnic real-world experience. In this analysis, the AMP clinical dataset was investigated to determine the percentages of patients who attained prespecified definitions of partial or complete responses at 52 weeks. In addition, incorporation of response rates at weeks 12 and 26 to the analysis provided longitudinal patterns of response to standard of care.
Method(s): Patients with LN who were undergoing kidney biopsies as part of standard of care were eligible to enroll in the AMP LN study. Response definitions were only applied to cases whose baseline spot urine protein/creatinine (UPCR) ratios were > 1.0. Complete response (CR) required: 1) UPCR < 0.5; and 2) normal creatinine (< 1.3 mg/dL) or, if abnormal at baseline, < 125% of baseline; and 3) prednisone < 10 mg/day at the time of the study visit. Partial response required: 1) >50% reduction in UPCR without meeting UPCR criterion for CR; and 2) normal creatinine (< 1.3 mg/dL) or, if abnormal, < 125% of baseline; and 3) prednisone dose < 15 mg/day at the time of the study visit. Patients who did not achieve a CR or PR at the specific timepoints were considered non-responders (NR). Only patients with renal biopsies that demonstrated ISN/RPS classes III, IV, V or combined III or IV with V and data available at all four timepoints (baseline, weeks 12, 26 and 52) were included in this analysis. Cross-sectional and longitudinal analyses of responses were performed, and heat maps were generated to graphically display response patterns.
Result(s): Data on 121 patients with LN enrolled in AMP were included in this analysis. Cross-sectional response rates at 52 weeks were: CR: 28.1%; PR: 23.1%; NR: 48.8% (Table 1). Response rates at weeks 12 and 26 are additionally displayed in Table 1, and Figure 1 is a heat map demonstrating longitudinal responses of our patients. All patients were considered NR at baseline. Only 7.4% of patients had week 12 CR responses sustained through week 52, whereas 19% had attained PR or CR at all 3 visits. An additional 14.9% achieved a PR or CR at 26 weeks which was sustained at 52 weeks. Overall, 36.4% of patients were NR at all time points.
Conclusion(s): Clinical data from the AMP Lupus Network revealed rates of 52-week CR and PR that were consistent with placebo response data from recently conducted LN trials. Low sustained CR rates not only underscore the need for more efficacious therapies but highlight how critically important it is to understand the molecular pathways that are associated with response and non-response. (Figure Presented)

Background/Purpose: Hydroxychloroquine (HCQ) is an antimalarial drug used in the treatment of systemic lupus erythematous (SLE). There is limited data assessing cardiac toxicity as arrhythmias in association with HCQ exposure based on dose prescribed or pharmacy records and none relying on measured drug levels. Some of the risk factors associated with conduction abnormalities in the setting of hydroxychloroquine use include presence of chronic kidney disease, older age, underlying cardiomyopathy, and the use of concomitant prolonging QTc agents. In a retrospective study of 194 SLE patients on HCQ, the authors found that there was no significant difference in mean QTc based on HCQ use. Additionally, 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 Torsade de Pointes were observed. The purpose of this study is to determine the relationship between whole blood HCQ levels and QTc intervals on simultaneous EKG performed during a routine visit.
Method(s): This prospective study was IRB approved and all patients provided consent. At the time of data lock, 84 patients fulfilled ACR/SLICC criteria for SLE. These patients were on HCQ for at least 3 months at doses used for standard of care treatment. Whole blood levels were drawn and EKGs were obtained during a routine outpatient faculty practice visit for patients consecutively seen between February 5 and May 10, 2021 with senior author. Statistical analyses was performed using one way ANOVA, Pearson's correlation coefficient and t-test.
Result(s): 84 patients, 93% female, 47% European, 35% African, 15% Asian, and 25% Hispanic were included (Table 1). HCQ levels were higher in patients on 400 mg, lower after 10 years of exposure, and unrelated to eGFR (Table 2). There was no correlation between blood HCQ levels and QTc intervals in the 84 patients (r=-0.017; p=0.87) (Fig 1a). Additionally, there was no correlation between blood HCQ levels and QTc intervals in patients on 200 mg or 400 mg of HCQ (r=0.113, p=0.61; r=-0.06, p=0.65) (Fig 1b-c). There was no correlation between blood HCQ levels and QTc intervals in patients who had chronic kidney disease (defined as eGFR < 60), (r=-0.482, p=0.09) or those with underlying cardiac abnormalities noted on transthoracic echocardiogram (r=-0.430, p=0.16) (Fig 1d-e). However, there was a positive correlation between blood HCQ levels and QTc intervals in patients who were on concomitant QTc prolonging agents, (r=0.795, p=0.005). but none in excess of 456 msec (Fig 1f).
Conclusion(s): Our study provides reassurance that hydroxychloroquine is not associated with QTc prolongation in patients with SLE and across different subsets of patients irrespective of blood level, dose prescribed, CKD or underlying cardiac abnormalities. There was a positive correlation between blood HCQ levels and QTc intervals in patients on concomitant QTc prolonging agents, but none were severely prolonged (eg > 500 msec). This is the first study relying on measured blood levels demonstrating the absence of consequential increase in QTc levels in HCQ treated SLE patients

Background/Purpose: Data on fluctuation of antibodies against domain 1 (anti-D1) of beta2-glycoprotein I (beta2GPI) are scarce. Patients with antiphospholipid syndrome (APS) and all three criteria tests for antiphospholipid antibodies (aPL) display higher titers of anti-D1, which correlate with abeta2GPI levels. This project aims at evaluating anti-D1 titers over time in a large international cohort of persistently aPL positive patients.
Method(s): AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Registry was created to study the course of persistently aPL-positive patients with or without autoimmune disorders over at least 10 years. Inclusion criteria are positive aPL by Updated Sapporo Criteria tested within one year prior to enrolment. Patients are followed up every 12+/-3 months with clinical data and blood collection. Patients with available blood samples from at least three time points were included in this analysis. Anti-beta2 GPI and anti-D1 IgG were tested by chemiluminescence (BioFlash, INOVA Diagnostics) at APS ACTION core laboratories. Positive results were defined as >20 CU. Clinical data were retrieved from APS ACTION online database. Anti-D1 titers within the same subject were compared by Friedman's test. The association between categorical and continuous variables was assessed by chi-squared and Spearman's tests.
Result(s): In this longitudinal study, 1942 samples from 515 patients were tested for anti-D1 and abeta2GPI IgG; 230 patients with anti-D1 tested at >=3 time points were included (Table). Patients with thrombotic APS had anti-D1 titers significantly higher than those without thrombosis (p=0.022). Among 135 patients with at least one anti-D1 positive result, anti-D1 titers varied significantly over time (Friedman statistics: 508.5, p< 0.0001; anti-D1 geometric mean [95%CI] at baseline 189.0 [115.9-308.3]; T1 132.3 [81.1-215.8]; T2 113.8 [69.8-185.5]; T3 109.2 [66.9-178.1]. Anti-D1 titers were significantly higher at baseline compared to T3 (p=0.029). Over time, anti-D1 titers significantly decreased in 107 patients, and increased in 28 (p< 0.0001). In 11.3% of patients, anti-D1 results changed from positive to neg-ative (n: 20), or negative to positive (n: 6). (Mc Nemar's chi2=6.5; p=0.011). Anti-beta2GPI titers correlated with anti-D1 titers and significantly reduced at T3 compared to baseline (abeta2GPI at baseline 187.1 [14.5-1586.5]; T1 150.8 [11.1-1379.2]; T2 124.9 [12.2-1304]; T3 117.6 [8.7-1136.6]; Friedman statistics=11.32, p=0.010).
Conclusion(s): Anti-D1 antibodies vary significantly overtime and approximately 10% may become negative during follow up. Our future analysis of the registry will demonstrate the clinical relevance of this variation, and the impact of treatment. (Figure Presented)

Background/Purpose: Damage Index in APS (DIAPS) is a scoring system developed to assess long-term damage in thrombotic primary antiphospholipid syndrome (PAPS), which also correlates with impaired quality of life (EuroQoL) in Latin Americans. DIAPS is not validated in aPL-positive patients without thrombosis. Our primary objective was to quantify damage accrual measured by DIAPS in aPL-positive patients with or without a history of thrombosis in an international cohort. Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients.
Method(s): In this cross-sectional study, we analyzed the baseline damage, measured by DIAPS, in APS ACTION Registry patients. The inclusion criteria were positive aPL according to Updated Sapporo Classification Criteria tested within one year prior to enrollment. We excluded patients with other autoimmune diseases. We analyzed the demographic, clinical, and laboratory characteristics of patients based on two subgroups: (1) thrombotic APS patients with high (DIAPS >=3) versus low damage (DIAPS < 3); and (2) non-thrombotic aPL-positive patients with damage (DIAPS >0) versus without damage (DIAPS=0). Chi-square, Fisher's exact test, Mann-Whitney U and Student t test were used when applicable. In the multivariate analysis, our model included age, gender, race and variables with p< 0.10 in the univariate analysis.
Result(s): Of the 826 aPL-positive patients included in the registry as of April 2020, 576 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 164 non-thrombotic [108 aPL only and 56 obstetric]). Baseline demographic, clinical and laboratory characteristics are summarized in Table 1. For the thrombotic group, the most frequent domains contributing to damage were peripheral vascular (n=260, 63% -mainly deep vein thrombosis), neuropsychiatric (n=107, 30% -mainly ischemic stroke with sequelae) and cardiovascular (n=57, 14% -mainly heart valve disease). Older age, male gender, hypertension, hyperlipidemia and obesity were associated with high damage (Table 1). In the multivariate analysis, male gender (OR 1.73, 95%CI 1.10-2.71, p=.018) and hypertension (OR 1.90, 95%CI 1.21-2.99, p=.006) were independently correlated with high damage. For the non-thrombotic group, the most frequent domains contributing to damage were neuropsychiatric (n=25, 15% -mainly cognitive impairment) and cardiovascular (n=13, 8% -mainly heart valve disease). Hypertension and hyperlipidemia were independently associated with damage in the multivariate analysis (OR 2.72, 95%CI 1.09-6.80, p=.032 and OR 4.48, 95%CI 1.62-12.29, p=.004, respectively). There was no correlation between aPL profile (triple vs double vs single aPL) and damage in either group.
Conclusion(s): DIAPS was able to discriminate damage in a large multicenter cohort of aPL-positive patients. Traditional cardiovascular risk factors, namely older age, male gender, hypertension, hyperlipidemia and obesity, correlate with higher damage in thrombotic primary APS patients. Hypertension and hyperlipidemia also correlate with damage in aPL-positive patients without a history of thrombosis. (Figure Presented)

OBJECTIVES:In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis. METHODS:475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines. RESULTS:34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved. CONCLUSIONS:Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

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.

INTRODUCTION/BACKGROUND:Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. METHODS:We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010-March 2021 on the clinical features and management of C3GN in the setting of SLE. RESULTS:In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. CONCLUSIONS:C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

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.