Faculty Bibliography

OBJECTIVE:immunofluorescence test (CLIFT). To address the clinical impact of measuring these antibodies by two different assays, this study leveraged a well-phenotyped multiethnic/racial cohort. METHODS:All patients fulfilled the classification criteria for SLE by at least one of the validated schemes: American College of Rheumatology, Systemic Lupus Erythematosus International Collaborating Clinics and/or American College of Rheumatology/European League Against Rheumatism classification criteria. Patients with one or more simultaneously paired anti-dsDNA by multiplex EIA and CLIFT were identified. Analysis of concordance or discordance, titre comparability of assays and association with hybrid SLE Disease Activity Index score, prevalence of lupus nephritis (LN), ability to predict a flare and classification criteria was performed. RESULTS:207 patients were simultaneously tested by EIA and CLIFT at least once for anti-dsDNA, generating 586 paired results. 377 pairs were concordant and 209 were discordant. 41 of 207 patients always had discordant paired results and 39 patients always had results with titre discordance. In 100 patients with LN, 60 were positive by EIA and 72 by CLIFT. Sensitivities and specificities for patients with LN versus patients without LN were EIA 60% and 47%, and CLIFT 72% and 37%, respectively. 42 patients had flare assessment within 90 days of their paired result. Six of seven patients with mild flares and all four patients with severe flares had concordant positive results. CONCLUSION:Our data demonstrate that discordance of positivity between both assays for anti-dsDNA is relatively common, occurring in a fifth of patients overall and a third of visits. EIA positivity is associated with LN less often than CLIFT positivity. With the significant discordance of results between anti-dsDNA assays, obtaining both CLIFT and EIA assays may be beneficial for classification and routine monitoring of SLE.

SARS-CoV-2 has certainly been at the forefront of medical discussion and research for the past 3 years. While many are adjusting back to "normal," thanks to the rapid advancements in prevention and treatment, high-risk groups, such as adults with systemic autoimmune rheumatic diseases (SARDs), still require careful monitoring and care.

OBJECTIVES/OBJECTIVE:This integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase 2 and phase 3 clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations. METHODS:AURA-LV (phase 2) and AURORA 1 (phase 3) were randomized, placebo-controlled, double-blind trials with similar designs and endpoints comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately 1 year (Week 48 data from AURA-LV and Week 52 from AURORA 1). Safety was assessed throughout the trials. RESULTS:Overall, 534 patients (voclosporin 268, control 266) were included in the integrated analysis. Significantly more patients achieved a CRR at 1 year in the voclosporin than control group (43.7% vs. 23.3%, OR 2.76; 95% CI 1.88, 4.05 p<0.0001). The incidence of adverse events (AEs) was similar; 91.4% voclosporin and 87.2% control. Most AEs were mild to moderate in severity; the most commonly reported AEs were classified as infections and infestations (62.2% voclosporin, 54.9% control) and gastrointestinal disorders (45.3% voclosporin, 35.3% placebo). No new or unexpected safety signals were detected. CONCLUSIONS:This integrated analysis demonstrates the efficacy and safety of voclosporin in the treatment of LN across the diverse racial and ethnic groups studied. This article is protected by copyright. All rights reserved.

BACKGROUND/UNASSIGNED:Fibrosis and dystrophic calcification disrupting conduction tissue architecture are histopathological lesions characterizing cardiac manifestations of neonatal lupus (cardiac-NL) associated with maternal anti-SSA/Ro antibodies. OBJECTIVES/UNASSIGNED:Increased appreciation of heterogeneity in fibroblasts encourages re-examination of existing models with the consideration of multiple fibroblast subtypes (and their unique functional differences) in mind. This study addressed fibroblast heterogeneity by examining expression of α-Smooth Muscle Actin (myofibroblasts) and of S100 Calcium-Binding Protein A4 (S100A4). METHODS/UNASSIGNED:, supported by the evaluation of cord blood from cardiac-NL neonates and their healthy (anti-SSA/Ro-exposed) counterparts, and autopsy tissue from fetuses dying with cardiac-NL, the current study was initiated to more clearly define and distinguish the S100A4-positive fibroblast in the fetal cardiac environment. RESULTS/UNASSIGNED:fibroblasts expressed pro-angiogenic cytokines and proteases that degrade collagen. Cord blood levels of S100A4 in anti-SSA/Ro-exposed neonates tracked disease severity and, in discordant twins, distinguished affected from unaffected. CONCLUSIONS/UNASSIGNED:fibroblast alongside the canonical myofibroblast in the pathogenesis of cardiac-NL. Neonatal S100A4 levels support a novel biomarker of poor prognosis.

Background/Purpose: SLE is characterized by autoantibody production. The most common lupus-specific serology is the anti-dsDNA antibody (anti-DNA). Traditionally, anti-DNA is measured by an enzyme immunoassay or equivalent such as multiplex flow immunoassay (EIA), which is considered sensitive. In contrast, the crithidia luciliae immunofluorescence test (CLIFT) is considered more specific. Serial measurement of anti-DNA is often used to monitor lupus disease activity. With NYU's extensive multi-race/ethnic lupus registry, we studied the relationship between these two methods, their association with lupus nephritis (LN), and their ability to predict subsequent flares.
Method(s): Using the NYU Lupus Registry of patients who meet ACR, SLICC, or EULAR criteria, we identified patients who had one or more simultaneous anti-DNA results by multiplex EIA and CLIFT. We report on their concordance (e.g., always, never, or fluctuating), association with LN, and ability to predict flare within 90 days using the SELENA-SLEDAI Flare Index. To account for degree of positivity, we defined tertiles for EIA and CLIFT as low positive [11-50 and 1:10-1:40], mild positive [51-200 and 1:80-1:320], and high positive [> 200 and > 1:640]. Table 1. 586 total visits with paired EIA and CLIFT. H = high positive M = mild positive L = low positive defined in Methods section Table 2. Relationship between EIA, CLIFT and hypocomplementemia with lupus nephritis. Chi-square test comparing significance between 60/100 v 72/100 (EIA/CLIFT) p = 0.07 Table 3. Relationship between EIA, CLIFT, hypocomplementemia and flare within 90 days Results: 207 patients had one or more paired anti-DNA results generating 586 paired results (Table 1). Cohort demographics: 92% Female, 22% Hispanic ethnicity, 24% Black, 16% Asian, 49% White, 10% Other. Overall, 377 pairs were always concordant, and 209 were never concordant. 236 pairs demonstrated titer concordance and 350 with titer discordance. Of the 207 patients, 64 patients had only one and 143 patients had two or more paired tests. Of the 64 patients, 46 were always concordant: 18 had positive EIA/CLIFT and 28 had negative EIA/CLIFT. The remaining 18 patients were never concordant: 8 had +EIA/-CLIFT and 10 had-EIA/+CLIFT. The concordance of the 143 patients with multiple paired results: 73 always, 23 never, and 47 fluctuating. Whether by one or multiple paired tests, 41/207 patients were never concordant. 100 of the 207 patients had LN associated with +EIA in 60 and +CLIFT in 72 (Table 2). Hypocomplementemia was present in 88% of +EIA and 89% of +CLIFT patients with LN. 51 visits in 42 patients had paired anti-DNA results and a SELENA-SLEDAI Flare Index assessment within 90 days. 7 patients had mild flares with +EIA in 4 and +CLIFT in 3. 4 patients had severe flares with +EIA and +CLIFT in 3 (Table 3). Low C3 and or C4 occurred in 1 of 7 (14%) mild flares and in 4 of 4 (100%) severe flares.
Conclusion(s): Our data demonstrate that discordance of positivity between two assays for anti-DNA occurred in 41/207 (20%) patients, in 207/586 (36%) visits and in 350/586 (60%) visits magnitude of positivity nonconcordant. EIA positivity is associated with LN less often than CLIFT positivity. Flares were infrequent and associated with either EIA or CLIFT positivity, with severe flares more likely if accompanied by hypocomplementemia. We recommend the utility of more than one anti-DNA assay in routine monitoring for lupus disease activity

Background/Purpose: Zetomipzomib is a first-in-class selective inhibitor of the immunoproteasome that is active in multiple autoimmune disease models, including murine models of SLE and LN. The MISSION study (NCT03393013) is a Phase 1b/2, open-label study to evaluate safety, tolerability, and preliminary efficacy of zetomipzomib in patients with SLE with +/- LN. In the previously reported Phase 1b portion, zetomipzomib demonstrated a favorable safety and tolerability profile in patients with active SLE +/- LN and resulted in improvement across multiple exploratory disease activity measures as well as biomarkers. Phase 2 fully enrolled in Nov 2021, and interim results from this signal-seeking study are reported here.
Method(s): The MISSION Phase 2 study evaluated zetomipzomib 60 mg subcutaneously once weekly for 24 weeks (1st dose: 30 mg) in patients with active LN (Class III or IV +/- Class V) with urine protein to creatinine ratio (UPCR) >=1 despite stable background therapy with corticosteroids and at least one immunosuppressive. The primary endpoint was the number of patients with a 50% reduction in UPCR from baseline after 24 weeks of treatment. Safety, tolerability, UPCR, renal response parameters (e.g., complete renal response [CRR] and partial renal response [PRR])*, renal function, SLE disease activity and biomarkers were measured, and an interim analysis was performed. *CRR was defined as UPCR <=0.5, eGFR >=60 mL/min/1.73m2 or no worsening of eGFR from baseline of >=25%, prednisone (or equivalent) <=10 mg and no use of prohibited medication. PRR was defined as 50% reduction in UPCR and/or UPCR < 1 (if baseline UPCR < 3) and/or UPCR< 3 (if baseline UPCR >=3), eGFR >=60 mL/min/1.73m2 or no worsening of eGFR from baseline of >=25% and no use of prohibited medication. CRR and PRR were calculated using absolute UPCR values.
Result(s): As of October 1, 2021, 10 patients had reached study week (W) 13; 80% were female with mean age 39.4 years, median LN duration 7.6 years, mean 24-hour UPCR 2.2 and mean eGFR 78.5 mL/min/1.73m2 at baseline. All 10 patients were on prednisone (or equivalent), 8 patients were also taking mycophenolate mofetil or mycophenolic acid, and 5 patients were also taking hydroxychloroquine. Five patients had reached the end of treatment visit (W25). Following 24 weeks of zetomipzomib therapy, 3 of 5 patients achieved a >=50% reduction in UPCR; 4 of the 5 patients had renal responses (2 CRR and 2 PRR). Zetomipzomib administration improved UPCR and anti-dsDNA as early as W13 and was associated with a favorable safety and tolerability profile. The most common adverse event (AE) was injection site reaction. Most reported AEs were mild to moderate (<=Grade 2). Two Serious AEs were reported in 2 patients (1 related and 1 unrelated to treatment). There were no study discontinuations due to drug-related AEs. No opportunistic infections were reported.
Conclusion(s): An interim analysis of MISSION Phase 2 demonstrated that zetomipzomib added to stable background medications led to an overall renal response in 4 of the first 5 patients to complete treatment. Zetomipzomib maintained a favorable safety and tolerability profile over the six-month treatment period. The MISSION Phase 2 is fully enrolled, and an updated analysis of the completed study will be shared

Background/Purpose: Patients with systemic lupus erythematosus (SLE) are at high risk for severe disease from COVID-19 and decreased vaccine efficacy, due to inherent immune perturbations and frequent immunosuppressant use. The impact of vaccine responses was "pressure" tested in New York City (NYC) from December 2021-February 2022, due to the highly infectious omicron BA.1 variant which resulted in a significant increase in COVID-19 cases and hospitalizations. This study was performed to assess clinical efficacy and seroreactivity in SLE patients with and without an additional vaccination dose after initial vaccine series, particularly during the omicron BA.1 surge in NYC.
Method(s): COVID-19 infections after vaccination were evaluated during patient encounters and chart review in subjects from the NYU Lupus Cohort who received an initial SARS-CoV-2 vaccine series with follow-up for at least 6 months or until breakthrough infection. Clinical follow-up was required after February 4, 2022 (when NYC COVID-19 cases returned to their preomicron BA.1 baseline), with last patient follow-up recorded April 24, 2022. Positive PCR or antigen-based testing was required, performed at the clinical site or self-reported. Fifty-seven patients receiving additional vaccine doses were evaluated longitudinally for recombinant SARS-CoV-2 spike receptor binding domain antibodies (#BT10500; R&D Systems). Low post-vaccine antibody response was defined as <=100 units/ml.
Result(s): Among the 163 subjects evaluated, 125 (76.7%) received an additional COVID-19 vaccination after the initial series. Demographics and medication usage were similar in patients who did and did not receive the additional vaccination dose, with 50% on at least one immunosuppressant and 16% on more than one at the time of the initial vaccine. Twentyeight (63.6%) of the 44 patients with a breakthrough infection had received an additional vaccination compared to 97 (81.5%) of the 119 without breakthrough infection (p=0.022) (Table 1). Of the 44 COVID-19 cases, only 2 occurred prior to the omicron wave, both in patients who did not receive the additional dose. There were no COVID-19 related deaths and two patients were hospitalized. Among the 57 patients with serologic evaluation, the median antibody level after initial vaccination series was 397 u/mL (IQR 57-753), and 1036 (IQR 517-1338.5) after the additional dose. After initial vaccination, 21 (37%) had low ELISA responses, but only 4 (7%) continued to have low responses after the additional dose. There was no association between the level of antibody after the additional dose and COVID-19 breakthrough.
Conclusion(s): SLE patients from a cohort of patients in NYC who received an additional SARS-CoV-2 vaccine dose were significantly less likely to have a subsequent COVID-19 infection compared to those who only completed their initial vaccine series. SLE patients demonstrated an improvement in serologic response after an additional dose of SARS-CoV-2 vaccine. The mild disease in all vaccinated patients is reassuring given the risks inherent and frequent immunosuppressant use in this patient population