Faculty Bibliography

OBJECTIVE:AURORA 2 evaluated the long-term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one-year AURORA 1 study. METHODS:Enrolled patients continued their double-blinded treatment of voclosporin or placebo randomly assigned in AURORA 1, in combination with mycophenolate mofetil and low-dose glucocorticoids. The primary objective was safety assessed with adverse events (AEs), biochemical and hematological assessments. Efficacy was measured by renal response. RESULTS:(95% CI -8.4, -2.3) in the control group. Improved proteinuria persisted across three years of treatment leading to more frequent complete renal responses in voclosporin-treated patients (50.9% vs 39.0%; odds ratio 1.74; 95% CI 1.00, 3.03). CONCLUSION/CONCLUSIONS:Data demonstrate the safety and efficacy of long-term voclosporin treatment over 3 years of follow-up in patients with LN.

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: 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