Faculty Bibliography

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

OBJECTIVES/OBJECTIVE:The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS:Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS:The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%). CONCLUSIONS:The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.

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: 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 - Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) is being considered as prophylaxis and treatment of COVID-19. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. Methods - To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal electrocardiograms (ECGs) and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. Results - Forty-five ECGs were available for QTc measurement, and levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of HCQ and the neonatal QTc (R = 0.02, P = 0.86) or the mean of HCQ values obtained throughout each individual pregnancy and the QTc (R = 0.04, P = 0.80). In total 5 (11%; 95% CI: 4% - 24%) neonates had prolongation of the QTc > 2SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. Conclusions - In aggregate, these data provide reassurances that the maternal use of HCQ is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered.

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.

BACKGROUND:Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES/OBJECTIVE:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS:This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS:By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS:These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

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.

OBJECTIVE:Autoimmune disease is an emerging condition among persons exposed to the September 11, 2001, attack on the World Trade Center (WTC). Components of the dust cloud resulting from the collapse of the WTC have been associated with systemic autoimmune diseases (SAID), as has posttraumatic stress disorder (PTSD). We sought to determine whether dust exposure and PTSD were associated with an increased risk of SAID in a 9/11-exposed cohort. METHODS:Among 43,133 WTC Health Registry enrollees, 2,786 self-reported a post-9/11 SAID. We obtained consent to review medical records to validate SAID diagnoses for 1,041. SAIDs were confirmed by classification criteria, rheumatologist diagnosis, or having been prescribed SAID medication. Controls were enrollees who denied an autoimmune disease diagnosis (n=37,017). We used multivariable log-binomial regression to examine the association between multiple 9/11 exposures and risk of post-9/11 SAID, stratifying by responders and community members. RESULTS:We identified 118 persons with SAID. Rheumatoid arthritis was most frequent (n=71), followed by SjÓ§gren's syndrome (n=22), systemic lupus erythematosus (n=20), myositis (n=9), mixed connective tissue disease (n=7), and scleroderma (n=4). Among 9/11 responders, those with intense dust cloud exposure had almost twice the risk of SAID (adjusted risk ratio =1.86, 95% CI=1.02-3.40). Community members with PTSD had a nearly three-fold increased risk of SAID. CONCLUSION/CONCLUSIONS:Intense dust cloud exposure among responders and PTSD among community members were associated with a statistically significant increased risk of new-onset SAID. Clinicians treating 9/11 survivors should be aware of the potential increased risk of SAID in this population.