Faculty Bibliography

Background Lupus nephritis can occur as an isolated component of disease activity or be accompanied by diverse extrarenal symptoms that can adversely affect a patient's quality of life (QOL). Whether renal disease absent other activity is sufficient to decrease QOL is unknown. A lack of reported QOL impairment may place patients at risk for delayed diagnosis of nephritis or medication noncompliance yet nephritis trials have largely neglected QOL. As such, this study leveraged the multi-center multi-racial Accelerating Medicines Partnership (AMP) lupus nephritis cohort to assess QOL measured by PROMIS-29. Methods Patients (n=182) fulfilling ACR or SLICC criteria for SLE with a uPCR >= .5 and biopsy Class III, IV, V, or mixed were consecutively enrolled in AMP at the time of renal biopsy and clinical history, PROMIS-29, and disease activity as assessed by the hybrid SELENA-SLEDAI were recorded. Patients were determined to have extrarenal clinical activity if, after excluding all laboratory parameters from the SLEDAI, the score remained >= 1. Raw PROMIS-29 scores were transformed to t-scores with the mean of 50 +/- 10 representing the US population and a difference of 5 points considered clinically meaningful. PROMIS-29 physical and mental health summary scores were calculated according to published formulas. Results Forty-three percent of patients (n=78) had extrarenal clinical manifestations including vasculitis (4%), arthritis (39%), rash (45%), alopecia (42%), mucosal ulcers (13%), pleurisy (12%), pericarditis (8%), and fever (4%). Patients with isolated renal disease (n=104, 57%) did not have PROMIS-29 scores that differed clinically from the US population whereas patients with extrarenal disease reported deficits in physical functioning, fatigue, social functioning, and pain (table 1). Patients with extrarenal disease had significantly lower physical health summary scores compared to patients with isolated disease (median [IQR]: 40.31 [35.79, 47.02] p<0.001 vs. 48.6 [40.14, 57.08]) and significantly lower mental health summary scores (44.12 [38.63, 51.39], p=0.024 vs. 48.67 [40.51, 55.07]). Female and African American patients and those with nephrotic range proteinuria or undergoing first biopsy had significantly lower physical health summary scores, but mental health summary scores did not differ by these variables. Patients on greater than 20 mg of prednisone had both significantly lower physical and mental health summary scores compared to those on lower doses. PROMIS-29 scores did not differ by low complements, anti-dsDNA, or anti-Ro antibodies. Stepwise multivariable linear regression analysis demonstrated that the association between extrarenal disease and lower PROMIS-29 summary scores was primarily driven by arthritis and independent of potential confounders (tables 2 and 3). Conclusion The majority of patients had isolated renal disease and report a QOL similar to that of the general population. In contrast, those with extrarenal manifestations report significantly worse QOL outcomes. These results reinforce the critical importance of routine laboratory surveillance and medication compliance for nephritis even in patients with seemingly quiescent clinical disease since lupus nephritis is often asymptomatic

Introduction Fetal cardiac disease is strongly associated with maternal anti-SSA/Ro antibodies, but gaps in our knowledge include the influence of antibody specificity and titer, maternal diagnosis, overall non-cardiac adverse pregnancy outcomes (APOs), optimal surveillance protocols, and efficacy of rapid treatment. Methods The multi-center Surveillance and Treatment To Prevent Fetal AV Block Likely to Occur Quickly (STOP BLOQ) study recruited pregnant women with commercially positive anti-Ro antibodies and stratified them into high and low titers of anti-Ro60 and Ro52 based on a research ELISA, using a cutoff defined by that obtained for 50 mothers with previous AVB offspring. Mothers with anti-Ro60 and/or 52 antibodies at or above 1,000 I.U. were trained to perform FHRM. From 17-25 weeks of gestation, FHRM was completed 3x/day in addition to weekly or biweekly fetal echocardiograms (echo). Mothers texted all audio sounds to the coordinating center. Texts deemed abnormal by mothers were immediately sent to an on call pediatric cardiologist who either reassured if FHRM was normal or referred for emergency fetal echo in < 6 hours if abnormal. Results 250 anti-Ro pregnant women (22% Hispanic, 50% white, 12% Black, 12% Asian, 4% other) have been consented, including 28 whose previous child had AVB. Of mothers tested to date, 153 were provided home monitors given high titer anti-Ro60 and/or 52 antibodies (26 high titer anti-Ro60 alone, 21 high titer anti-Ro52 alone,105 high titer antibodies to both antigens). The 83 patients with low titers were surveilled with echos per local standard of care. Regarding maternal diagnosis, of 161 assessed to date, 39% were asym/UAS, 11% RA, 31% SS, 19% SLE. Antibody titers did not significantly differ by ethnicity, race or diagnosis (table 1). Non-AVB APOs occurred in 18% and were not predicted by Ro60 or 52 titers but rather SLE diagnosis (table 2). In total, 24,759 FHRM audiotexts were received from 131 patients (90 of whom have delivered) during the monitoring period. Of these, 22 were evaluated by the on-call pediatric cardiologist, who prompted an emergency echo (all completed in < 6 hrs). In 11 cases, the emergency echo was normal. In 9, there were premature atrial contractions, confirming the mother's perception. In 2 with 2degree block on urgent echo (both treated per protocol with IVIG and dexamethasone), 1 reverted to normal sinus rhythm and the other progressed to 3degree block. In 2 others, the mother did not perceive abnormal FHRM for > 24 hrs, echo identified 3degree block, and retrospective cardiology review of FHRM audio captures identified an abnormality prior to obtaining the echo. All 4 AVB developed in fetuses of mothers with high titer antibodies to both Ro60 and 52 (mean 32,451 and 34,991 respectively). Of the 18 mothers with a previous AVB child who followed the 400mg hydroxychloroquine PATCH protocol, 1 developed AVB in accord with the results of Step 1 in that study. Conclusion These data support that APOs in this clinically diverse group of mothers are not influenced by anti-Ro titer or specificity, but rather SLE diagnosis. All conduction defects were initially identified by FHRM and in mothers with high titer anti-Ro60 and 52. Hydroxychloroquine continues to show efficacy in reducing the AVB recurrence rate with rapid intervention of emergent block being promising

OBJECTIVE:In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. METHODS:We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded. RESULTS:We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. CONCLUSIONS:We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.

High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations.

Background/Purpose: The Accelerating Medicines Project (AMP) has enabled significant increases in understanding of SLE nephritis pathology, providing a profile of dozens of leukocyte subsets within affected kidneys by single-cell RNA sequencing of nephritis biopsies. While these results suggest a complex network of interactions between cell populations during nephritis, the spatial positioning of these cells is lost during the sequencing process. Inferred interactions between the diverse identified cell types would be greatly strengthened by detailed spatial information, placing these cells in context with each other and with the surrounding structures of the kidney.
Method(s): In consultation with AMP, we have used CODEX, a multicycle imaging technology allowing for staining of up to 40 targets on a single tissue sample without tissue degradation, to capture preliminary images of the AMP tissue biopsies available at New York University. Extensive antibody screening, sample preparation, optimization of antigen retrieval, and imaging steps are required, which remain under active optimization to allow for imaging the entirety of the AMP biopsy cohort available at the Grossman School of Medicine, which has been fully processed for future staining.
Result(s): At present we are able to image sixteen targets capturing dense interstitial T and B cell infiltrates, intratubular and interstitial myeloid populations, and sparser glomerular infiltrating cells in our demonstration cohort, with clear imaging of the glomeruli, tubules, and interstitial spaces. Further targets will be added as they are optimized, further allowing subsetting of T, B, and myeloid populations, with the goal of capturing the populations identified previously in single-cell sequencing.
Conclusion(s): CODEX imaging of renal biopsy samples provides spatial context for prior observations across a range of SLE nephritis samples, with complex interstitial populations found around glomeruli and tubules in active disease. Deeper profiling with expanded antigen targets to enable further sub-population phenotyping and activation states and imaging of the full cohort of biopsies available at NYU will provide a spatial atlas to SLE nephritis and further reveal underlying mechanisms of disease

Background/Purpose: Anti-Ro autoantibody production often precedes the development of Systemic Lupus Erythematosus (SLE) or Sjogren's syndrome (SS) by years. For anti-Ro+ mothers enrolled in the Research Registry for Neonatal Lupus (RRNL), progression to SS or SLE occurs in about a quarter, while most remain asymptomatic or develop only minor rheumatic symptoms (Asym/UAS). Thus, RRNL mothers uniquely offer a promise to identify genotype-phenotype relationships that are important to preclinical autoimmunity. Since multiple SLE risk alleles from Class II HLA genes are present in anti-Ro+ mothers, we examined interactions of specific microbiome taxa with Class II HLA by independent analytic paths with the goal to identify HLA-related microbiome associations in Anti-Ro+ Mothers of Children with Neonatal Lupus.
Method(s): Subjects included 125 RRNL mothers and 23 healthy controls. Stool microbiomes of anti-Ro+ women in RRNL (Asym/UAS, SS/SLE), and healthy controls (HC) were processed using 16S ribosomal RNA sequencing. Sera/ plasma were evaluated for cytokines and autoantibody levels. Alleles from HLA Class II genes were genotyped using NextGen sequencing of HLA region or imputed (HIBAG) from GWAS data. Independent analytic paths sought to explore associations of specific taxa and class II HLA included: 1) use of a cumulative logit model to test interactions between FDR significant genera and HLA alleles and 2) assignment of SLE, SS, UAS patients and HC to molecular phenotype clusters by Random Forest (RF), an unsupervised machine learning tool using Z-score transformed cytokine soluble mediators and autoantibody values with settings and the gap statistic that were used to estimate the optimal number of patients and HC within clusters. The overlapping distribution of SS/SLE, HLA alleles and taxa at clusters were then examined.
Result(s): Findings related to DRB1*15:01 and an interaction with genera of the Ruminococcaceae family were tested. Oscillibacter, with FDR-adjusted significance was shown to exhibit evidence of an interaction (P=0.033 (OR=0.60 (0.37-0.96)). In order to authenticate that SLE HLA risk alleles modify the strength of the association, we examined the molecular phenotype clusters from RF clustering. Radar plots were used to visualize the distribution HLA alleles and the enrichment of microbiome taxa within these clinically relevant phenotypic clusters (Figure 1). DRB1*1501 shows enrichment at cluster 4. Interestingly, the distribution of Oscillibacter, but not Coprococcus 3 was nearly superimposable with the Class II HLA allele with enrichment at cluster 4. However, the distribution of DRB1*1501 was not enriched at cluster profiles representing evaluations of DRB1*0301 and SS/SLE disease classification (Figure 2) demonstrating a limitation of DRB1*1501 to predict risk for transition from benign to pathologic autoimmunity in anti-Ro+ mothers of children with neonatal lupus.
Conclusion(s): These data support the use of molecular phenotypes that are linked to genetic-environmental interactions to identify HLA-related microbiome associations

Background/Purpose: Congenital Heart Block (CHB) complicates 2% of anti-Ro/ SSA antibody positive pregnancies and carries substantial perinatal morbidity and mortality. Almost all survivors require lifelong pacing. Data suggests the potential of anti-inflammatory treatment of 1degree and 2degree CHB in preventing progression to immutable complete block. However, the optimal surveillance strategy to detect rapidly transitioning and potentially reversible conduction disease is unknown. This study addresses the feasibility, acceptance and accuracy of the fetal heart rate and rhythm technique (FHRM) in high risk mothers.
Method(s): Prospective data from the Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ) study were leveraged. Mothers referred to the study all had commercially positive anti-Ro/ SSA antibodies and were stratified into high and low titers of anti-Ro60 and Ro52 based on a research ELISA which used a threshold cutoff defined as the titer above or below that obtained for 50 mothers with a previous CHB offspring. Mothers with anti-Ro60 or 52 antibodies at or above 1,000 I.U or with a previous CHB offspring, were trained to perform FHRM with an educational video and personal instruction from a pediatric cardiologist. From 17-25 weeks of gestation, FHRM was completed 3x/day in addition to weekly or biweekly fetal echocardiograms (echo). Mothers texted all FHRM sounds to the study's data coordinating center. For those FHRM deemed abnormal by the mothers, texts were immediately sent to an on call pediatric cardiologist who either reassured if FHRM was normal or referred for emergency fetal echo in < 6 hours if abnormal. Postnatal electrocardiograms were evaluated for CHB.
Result(s): Fifty-six mothers with commercial anti-Ro/ SSA positivity were consented to the study. Of these, 37 (inclusive of 6 with previous CHB) performed FRHM since they had high titer anti-Ro60 (n=8) or 52 antibodies (n=7) or both (n=21), albeit one mother had unexpectedly low titer antibodies to both Ro60 and 52 and a child with incomplete CHB 4 yrs prior to enrollment. In total 3,360 FHRM audiotexts were received during the monitoring period. Of these, 39 recordings from 5 concerned mothers prompted an immediate call with the cardiologist. All but 2 recordings were deemed to be normal based on review of the audiotext alone; the cardiologist requested that the patient send repeat recordings after review as part of re-training and to provide additional reassurance. In the 2 cases an emergency echo was completed in < 6 hrs. In both there were premature atrial contractions which confirmed the mother's perception of the FHRM abnormality. However, there was no evidence of conduction disease. All surveillance echoes were normal. Thus, the overall rate of false positive recordings for the concern of a conduction defect perceived by the mothers was 1.1% (38/3360). There were no cases of CHB at birth.
Conclusion(s): These data support that FHRM is feasible and accurate. Mothers can be empowered to detect rhythm abnormalities with very few false perceptions thus supporting this technique to substantially enhance the management of anti-Ro/ SSA pregnancies

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)