Faculty Bibliography

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/Purpose: We reported previously (Ramsey-Goldman et al., Arthritis Rheumatol 2020) that score > 0.8 of a multianalyte assay panel (MAP) with algorithm predicts fulfillment of a 4th ACR criterion 9-18 months (median 12) after enrollment in patients with probable systemic lupus erythematosus (pSLE). We continued to follow pSLE to better evaluate transition to classifiable SLE.
Method(s): pSLE, defined as fulfilling 3 ACR criteria, were followed at academic lupus centers. At enrollment, 35 (38%) of the 92 pSLE fulfilled SLICC criteria. CB-CAPs - C4d bound to erythrocytes (EC4d) and B-cells (BC4d) - were measured by quantitative flow cytometry, serum C3 and C4 by turbidimetry, and autoantibodies by ELISA. Anti-dsDNA positivity was confirmed by immunofluorescence (IFA). MAP index consists of an algorithm with CB-CAPs and autoantibodies (Dervieux et al., J Immunol Methods 2017). Initial decision analysis with Youden index showed that MAP > 0.8 and EC4d > 20 mean fluorescence intensity units (MFI) reflected the optimal cutoffs for transition to ACR classifiable SLE; the same cutoffs were used for analysis of all follow-up visits. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis; associations were analyzed by log-rank test and Cox proportional hazards model and are expressed as hazards ratio (HR).
Result(s): Of the 92 pSLE, 74 had 1 or 2 follow-up visits 9-35 months after enrollment for a total of 128 visits. Overall, 28 pSLE (30.4%) transitioned to ACR classifiable SLE: 16 (57%) in the 1st year and 12 (43%) in the 2nd. The clinical or laboratory features that defined fulfillment of ACR criteria are in Table 1. Use of hydroxychloroquine and immunosuppressants was similar in those who did and did not transition to SLE. Of the 17 subjects who accrued hematological criteria during the study (11 as the sole criterion and 6 as one of the new criteria), a minority were on immunosuppressants: 6 at enrollment, 5 at the 1st visit, and 3 at the 2nd. Neither SLICC criteria nor individual biomarkers were significantly associated with transition to SLE (Table 2). Only MAP > 0.8 had significantly high HR for transition to SLE; EC4d > 20 MFI, low complement, and anti-dsDNA were not significant (Table 2).
Conclusion(s): The majority of pSLE transitioned within a year. MAP > 0.8 predicted disease evolution into classifiable SLE better than other biomarkers or fulfillment of SLICC criteria

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/Purpose: Belimumab (BEL) has demonstrated efficacy in systemic lupus erythematosus (SLE) in 4 positive pivotal trials. This study assessed the efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in patients (pts) with active lupus nephritis (LN).
Method(s): This Phase 3, double-blind, placebo (PBO)-controlled study (GSK Study BEL114054; NCT01639339) randomized (1:1) adults with SLE and biopsy-proven LN (class III, IV, and/or V) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomization was stratified by race and treatment regimen (high-dose corticosteroids + either cyclophosphamide followed by azathioprine, or mycophenolate mofetil [MMF] followed by MMF). Primary endpoint: Primary Efficacy Renal Response (PERR; urine protein-creatinine ratio [uPCR] <=0.7; estimated glomerular filtration rate [eGFR] no worse than 20% below pre-flare value or >=60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: Complete Renal Response (CRR; uPCR < 0.5; eGFR no worse than 10% below pre-flare value or >=90 ml/min/1.73m2; no rescue therapy) at Wk 104; Ordinal Renal Response (ORR; CRR, PRR or no response) at Wk 104; PERR at Wk 52; time to renal-related event (defined in Table 1) or death. Wk 104 PERR/CRR were analyzed in subgroups: treatment regimens, LN class, race. Additional evaluations included: time to first severe SFI flare (defined in Table 2); proportions of pts with SLEDAI-S2K (defined in Table 2) score < 4 and with prednisone dose <=7.5/5 mg/day, both at Wk 104; changes from baseline in biomarkers (anti-dsDNA, anti-C1q, C3, C4) at Wk 104; safety.
Result(s): Randomized pts: 448 (efficacy: 223/group; safety: 224/group). The study met its primary and key secondary endpoints (Table 1). Risk of a renal-related event or death was lower over the study with BEL vs PBO (HR [95% CI] 0.5 [0.3, 0.8]; p=0.001). Table 2 displays additional endpoints. The odds of PERR/CRR responses at Wk 104 on BEL vs PBO were numerically greater for listed subgroups, except pure class V LN (Figure); however, in class V, a numerically greater proportion of BEL vs PBO pts achieved PERR/CRR response at Wk 52 (PERR: 44.4% vs 33.3%; CRR: 36.1% vs 27.8%, respectively). At Wk 104, in pts with baseline autoantibodies, median (IQR) percent change from baseline (BEL vs PBO) in anti-dsDNA was -74.2 (-85.1, -49.5) vs -36.6 (-69.7, 28.6); and anti-C1q was -73.2 (-84.1, -59.0) vs -57.9 (-76.1, -33.2). *p-value was from a rank ANCOVA model comparing belimumab and placebo with covariates for treatment group, induction regimen (CYC vs MMF), race (black vs non-black), baseline uPCR, and baseline eGFR. Study WD, TF, and IPD were imputed as non-responders; +defined as eGFR no worse than 10% below baseline value or within normal range, >=50% decrease in uPCR (either uPCR <1.0 if baseline ratio <=3.0, or uPCR <3.0 if baseline ratio >3.0), no rescue therapy, and not a CRR; ++defined as the first event experienced among the following: endstage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure or death; Pnumber/proportion of pts reporting the event ANCOVA, analysis of covariance; BEL, belimumab; CI, confidence interval; CRR, Complete Renal Response; CyC, cyclophosphamide; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IPD, investigational product discontinuation; IV, intravenous; MMF, mycophenolate mofetil; NR, non-responder; OR, odds ratio; ORR, Ordinal Renal Response; PBO, placebo; PERR, Primary Efficacy Renal Response; PRR, Partial Renal Response; TF, treatment failure; uPCR, urine protein-creatinine ratio; WD, withdrawal; Wk, Week In pts with low baseline complement levels, median (IQR) percent change from baseline (BEL vs PBO) in C3 was 43.8 (17.1, 88.9) vs 30.0 (13.5, 59.8) and in C4 was 115.5 (60.0, 177.8) vs 66.7 (22.2, 166.7). Adverse events (AEs; >=1) were reported for 95.5% of BEL and 94.2% of PBO pts; 12.9% of pts in each group had >=1 AE resulting in study treatment discontinuation. Serious AEs (>=1) were reported for 25.9% of BEL and 29.9% of PBO pts, most commonly infections and infestations (13.8% of BEL vs 17.0% of PBO pts); 1.8% of BEL and 1.3% of PBO pts developed on-treatment fatal AEs (mainly due to infections).
Conclusion(s): In this large 2-year LN study, compared with ST alone, BEL plus ST improved renal outcomes, overall SLE disease activity, and biomarker levels, while reducing steroid use, with a favorable safety profile

BACKGROUND:In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS:, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS:A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS:In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).

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).

Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.

OBJECTIVES/OBJECTIVE:To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS:All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS:=0.145). CONCLUSION/CONCLUSIONS:Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.