Faculty Bibliography

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: 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: 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: Poor therapeutic response rates contribute to the increased morbidity and mortality associated with lupus nephritis. Early identification of patients likely to respond is crucial as delays in treatment associate with worse outcomes. This study evaluated response using prospectively collected data obtained from the multi-ethnic/racial, multi-center Accelerating Medicines Partnership (AMP) lupus nephritis cohort. This cohort represents a real-world clinical setting using provider chosen standard of care and uniform collection of data.
Method(s): This study included SLE patients based on ACR or SLICC classification enrolled in AMP who met the following criteria: urine protein-creatine ratio (UPCR) > 1 at entry, and histologic biopsy Class III, IV, V, or mixed. Patients were followed at 3, 12, 26 and 52 wks with demographics, history, laboratory results, disease activity, and medica-tions recorded at each visit. Follow up data were available for 136 patients at 26 wks and 118 at 52 wks. Complete response was defined as a reduction in UPCR to <.5, a normal serum creatinine or no greater than 125% of baseline, and < 10 mg prednisone at time of response assessment. Patients were partial responders if UPCR decreased > 50% but remained >.5 and nonresponders if < 50% reduction in UPCR and/or did not meet the other response criteria.
Result(s): Medications were reported at 12 wks (Table 1). The complete response rate was 26% at both 26 and 52 wks. For patients undergoing a first biopsy, the rates were 37% and 40% and for those with repeat biopsies, the rates were lower at 21% and 19% respectively (p=0.042 at 26 wks; p=0.015 at 52 wks). The complete response at 26 wks was generally sustained with only 4 of 27 patients experiencing a relapse at 52 wks. At 26 wks, patients with membranous histology were less likely to be complete responders than patients with proliferative histology. This trend was observed regardless of biopsy number and persisted for response status at 52 wks. Although baseline activity score did not predict responder status, complete responders had a significantly lower chronicity index than nonresponders (mean + SD, 2.26 + 2.22 vs 3.83 + 2.57, p=0.016) at 26 wks with similar results at 52 wks. Responder status at 26 and 52 wks whether first or repeat biopsy was independent of extrarenal disease at entry (Table 2). Complete responder status was associated with positive anti-dsDNA serology at baseline for repeat biopsy patients. Complete responders had a greater change in C3, hemoglobin, lymphocyte count, albumin, and UPCR at 12 wks compared to baseline values than nonresponders (Table 3). Similar trends were observed when considering response status at 52 wks.
Conclusion(s): The low complete response rates reported in the AMP cohort are consistent with findings in blinded controlled trials of standard-of-care therapies and support the critical need for new therapeutics particularly in patients undergoing repeat biopsies and those with increased chronicity

Background/Purpose: Lupus nephritis continues to be the complication with the highest standardized mortality ratio in Systemic Lupus Erythematosus (SLE), and a late diagnosis associates with worse outcomes. Clinicians traditionally rely on proteinuria to drive decisions regarding renal biopsy and subsequent management. Since threshold levels for such determinations are variable but critically important, this study leveraged the well-phenotyped multi-center multi- racial Accelerating Medicines Partnership (AMP) lupus nephritis cohort, to address whether urine protein to creatinine ratios (UPCR) between.5 and 1 differ from higher ratios with regard to clinical, serologic and histologic variables.
Method(s): 239 patients fulfilling ACR or SLICC criteria for SLE with a random or 24 hr uPCR > or =.5 and histologic biopsy Class III, IV, V, or mixed were consecutively enrolled in AMP at the time of renal biopsy and demographics, clinical history, medications, disease activity as assessed by the hybrid SELENA-SLEDAI were recorded. Patients with biopsy Classes I, II and VI were ineligible. Patients were followed at 3, 12, 26 and 52 weeks.
Result(s): At baseline, 38 patients had a UPCR < 1 (A), 113 had a UPCR 1-3 (B), and 88 had a UPCR > 3 (C). There were 14 additional patients with UPCR < 1, and 11 patients with UPCR > 1 who had biopsy class I or II. In group A, there were significantly more male patients (44% A; 23% B; 26% C, p=0.012) with no differences in age, race or ethnicity. Neither the SLEDAI nor serologic parameters (anti-dsDNA, C3, or C4) distinguished among the groups. Those in group C had a significantly increased creatinine and decreased hemoglobin and albumin compared to the other two groups (Table 1). Patients in group A trended toward having an increased frequency of proliferative histology (Table 2). This trend was not observed when considering patients for whom this was their first biopsy, but was significant for repeat biopsy patients (56% A; 41% B; 24% C, p=0.03). The activity index was independent of UPCR regardless of biopsy number. However, those in group C had a significantly higher chronicity index than those with lower UPCR. This correlation was shown for patients with a repeat biopsy (r=0.2299, p=0.003) but not first biopsy patients (r=0.0891, p=0.45). Although medications did not differ at baseline among the groups, at 12 weeks, for each group significantly more patients were taking Mycophenolate Mofetil than at the time of biopsy (Table 3).
Conclusion(s): A significant proportion of both first and recurrent biopsies in patients with a UPCR < 1 have proliferative histology and accompanying activity scores similar to that of patients with nephrotic range proteinuria. These results support renal biopsy at thresholds lower than a UPCR of 1 since histologic findings can inform therapeutic decisions

Background/Purpose: Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease (CKD) and end stage renal disease (ESRD). While prior studies showed complement activation mediates glomerular injury, the role of complement in renal tubular damage has not been evaluated. The objective of this study is to investigate the association between complement activation as measured by tubular complement 9 (C9) deposition with interstitial fibrosis and tubular atrophy (IFTA) in LN.
Method(s): LN biopsies from July 2014 to July 2016 were evaluated. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-mum human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the membrane attack complex (MAC) activation. C3 glomerulopathy was used as a positive control and normal kidney served as a negative control. Tubular basement membrane C9 staining intensity was analyzed as absent (0) versus present (1 to 3) scored on a semi-quantitative scale by a renal pathologist. IFTA was categorized as 0-10%, 11-20%, and >20%. Clinical parameters were assessed at the time of biopsy and 6 months post biopsy.
Result(s): Renal biopsies from 30 LN patients were studied, of which 23 (77%) were proliferative LN. There were 24 (80%) women, mean age 33 (standard deviation) (12) years. Positive tubular C9 staining (C9+) was observed in 7 (23%) biopsies. At the time of renal biopsy, C9+ patients had significantly higher proteinuria, compared to C9- patients: median (interquartile range) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p< 0.01. The differences persisted at 6 months after induction therapy: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p=0.06. Tubular C9 deposition was associated with the finding of interstitial fibrosis on biopsy: 3 out of 7 (42.9%) had >20% interstitial fibrosis as compared to none in the C9- group, p=< 0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 3 out of 7 (42.9%) vs 2 out of 23 (8.7%) in the C9- group, p=0.07. There was no significant difference in eGFR at renal biopsy between the two groups.
Conclusion(s): Tubular C9 deposition is associated with proteinuria, interstitial fibrosis and increased chronicity which are predictors of progression to ESRD. Complement activation may play an important role in tubulointerstitial damage in LN

BACKGROUND Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. CASE REPORT Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. CONCLUSIONS We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.

BACKGROUND:Although hydroxychloroquine (HCQ) is a mainstay of treatment for patients with systemic lupus erythematosus (SLE), ocular toxicity can result from accumulated exposure. As the longevity of patients with SLE improves, data are needed to balance the risk of ocular toxicity and the risk of disease flare, especially in older patients with quiescent disease. Accordingly, this study was initiated to examine the safety of HCQ withdrawal in older SLE patients. METHODS:Data were obtained by retrospective chart review at three major lupus centers in New York City. Twenty-six patients who discontinued HCQ and thirty-two patients on HCQ matched for gender, race/ethnicity, and age were included in this study. The primary outcome was the occurrence of a lupus flare classified by the revised version of the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare composite index, within 1 year of HCQ withdrawal or matched time of continuation. RESULTS:Five patients (19.2%) in the HCQ withdrawal group compared to five (15.6%) in the HCQ continuation group experienced a flare of any severity (odds ratio [OR] = 1.28; 95% CI 0.31, 5.30; p = 0.73). There were no severe flares in either group. The results were similar after adjusting for length of SLE, number of American College of Rheumatology criteria, low complement levels, and SELENA-SLEDAI score, and in a propensity score analysis (OR = 1.18; 95% CI 0.23, 6.16; p = 0.84). The analysis of time to any flare revealed a non-significant earlier time to flare in the HCQ withdrawal group (log-rank p = 0.67). Most flares were in the cutaneous and musculoskeletal systems, but one patient in the continuation group developed pericarditis. The most common reason for HCQ withdrawal was retinal toxicity (42.3%), followed by patient's preference (34.6%), other confirmed or suspected adverse effects (15.4%), ophthalmologist recommendation for macular degeneration (3.8%), and rheumatologist recommendation for quiescent SLE (3.8%). CONCLUSIONS:In this retrospective study of older stable patients with SLE on long-term HCQ, withdrawal did not significantly increase the risk of flares.

Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has both a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by interferon-gamma. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, it was observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8 T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8 cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways may be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

The Accelerating Medicines Partnership (AMP) Lupus Network was established as a partnership between the NIH, pharmaceutical companies, non-profit stakeholders and lupus investigators across multiple academic centers to apply high throughput technologies to the analysis of renal tissue, urine and blood from patients with lupus nephritis (LN). The AMP network provides publicly accessible data to the community with the goal of generating new scientific hypotheses and improving diagnostic and therapeutic tools so as to improve disease outcomes. We present here a description of the structure of the AMP Lupus Network and a summary of the preliminary results from the Phase 1 studies. The successful completion of Phase 1 sets the stage for analysis of a large cohort of LN samples in Phase 2 and provides a model for establishing similar discovery cohorts.