Faculty Bibliography

Background/Purpose: Persistent proteinuria increases the risk of comorbidities in lupus nephritis, and rapid reductions in protein have shown to be predictive of improved long-term renal health. Patients with Class V lupus nephritis may take longer to respond to therapy, and treatments that efficiently reduce proteinuria in this population are needed. We report here on a post-hoc analysis of voclosporin in patients with Class V lupus nephritis using three years of pooled data from the Phase 3 AURORA 1 and AURORA 2 studies.
Method(s): AURORA 1 enrolled patients with biopsy-proven active lupus nephritis, urine protein creatinine ratio (UPCR) >=1.5 mg/mg (>=2.0 mg/mg for pure Class V), and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2. Patients completing AURORA 1 were eligible to enter AURORA 2 on the same blinded therapy (voclosporin or placebo) in combination with mycophenolate mofetil (MMF) and low-dose steroids for up to 3 years of treatment. Hazard ratios (HR) for the time to UPCR <=0.5 mg/mg and mean eGFR levels were assessed in patients with pure and mixed Class V lupus nephritis.
Result(s): A total of 80 patients with Class V lupus nephritis continued treatment in AURORA 2, 31 with pure Class V disease and 49 with mixed lesions. Mean baseline UPCR was 3.4 and 3.3 mg/mg in patients with pure Class V disease treated with voclosporin and control, respectively, and 3.4 and 3.9 mg/mg in voclosporin-and control-treated patients with mixed lesions. The differences between treatment arms in UPCR reductions were apparent within the first month and sustained at three years in both pure and mixed disease. For patients with pure Class V disease, the median times to UPCR <=0.5 mg/mg were 3.6 and 8.3 months in the voclosporin and control arms, respectively (HR 1.93; p=0.167, Figure 1). For patients with mixed lesions, the median times to this outcome were 3.7 and 18.0 months, respectively (HR 5.07; p< 0.0001). Mean corrected eGFR levels were similar in all treatment arms and stable throughout the study (Figure 2). Analysis of AURORA 2 patients with Class V disease includes pooled data from AURORA 1 and AURORA 2. Time to UPCR <=0.5 mg/mg was assessed with a Kaplan Meier analysis. UPCR, urine protein creatinine ratio. Analysis of AURORA 2 patients with Class V disease includes pooled data from AURORA 1 and AURORA 2. Renal function was assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL/min/1.73 m2. Analysis of LS mean corrected eGFR over time includes data from a follow up visit at four weeks after study drug discontinuation. CI, confidence interval; eGFR, estimated glomerular filtration rate; FUP, follow up; LS, least squares.
Conclusion(s): Voclosporin-treated patients with pure and mixed Class V lupus nephritis saw substantial reductions in UPCR that occurred faster than in those treated with MMF and low-dose steroids alone. Voclosporin may be beneficial in limiting the negative long-term impact of proteinuria in this population

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: 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

BACKGROUND:Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. PURPOSE/OBJECTIVE:To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. FIELD STRENGTH/SEQUENCE/UNASSIGNED:Stimulated echo acquisition mode (STEAM) sequence at 3 T. ASSESSMENT/RESULTS:MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. STATISTICAL TESTS/UNASSIGNED:Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. RESULTS:SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). DATA CONCLUSION/UNASSIGNED:SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. EVIDENCE LEVEL/UNASSIGNED:2 TECHNICAL EFFICACY: Stage 2.

Objective/UNASSIGNED:Previous studies have questioned the safety and efficacy of minor salivary gland biopsy in the diagnosis of Sjögren's syndrome, citing complications and difficulty of pathologic evaluation. This study aims to determine the rate of biopsy specimen adequacy and the risk of complications after minor salivary gland biopsy. Study Design/UNASSIGNED:Case series. Setting/UNASSIGNED:Single tertiary care center. Methods/UNASSIGNED:sample were considered positive. Results/UNASSIGNED:We identified 110 patients who underwent minor salivary gland biopsy. Ninety-three (85%) were female, and the median age was 49.1 years (range, 18.7-80.5). Seventy-seven procedures (70%) were performed in the office setting, and 33 (30%) were performed in the operating room. Nearly all biopsy samples (n = 108, 98%) were adequate, and 33 (31%) were interpreted as positive. Four patients (4%) experienced temporary lip numbness, which resolved with conservative management. No permanent complications were reported after lip biopsy. Nineteen (58%) patients with positive biopsy results had no Sjögren's-specific antibodies. Most patients with positive biopsy results (n = 20, 61%) subsequently started immunomodulatory therapy. Conclusion/UNASSIGNED:Minor salivary gland biopsy can be performed safely and effectively in both the office and the operating room. This procedure provides clinically meaningful information and can be reasonably recommended in patients suspected to have Sjögren's syndrome.

OBJECTIVE:To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multi-ethnic/racial cohort of patients with systemic lupus erythematosus (SLE). METHODS:90 SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; IFN-γ production to assess T cell responses was measured by ELISpot. Disease activity was measured by the hybrid SLE disease activity index (SLEDAI) and flares were assigned by the SELENA/SLEDAI flare index. RESULTS:Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD than controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-dsDNA level prior to vaccination associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 Spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and antigen-specific IFN-γ production determined by ELISpot. In a subset of patients with poor antibody responses, IFN-γ production was likewise diminished. Pre-/post-vaccination SLEDAI scores were similar. Only 11.4% of patients had a post-vaccination flare; 1.3% were severe. CONCLUSION/CONCLUSIONS:In a multi-ethnic/racial study of SLE patients 29% had a low response to the COVID-19 vaccine which was associated with being on immunosuppression. Reassuringly, disease flares were rare. While minimal protective levels remain unknown, these data suggest protocol development is needed to assess efficacy of booster vaccination.

OBJECTIVE:Enrollment of patients of Black African ancestry with systemic lupus erythematosus (SLE) in Phase 2 and 3 belimumab trials was not reflective of the racial distribution observed in the lupus population. This study assessed efficacy and safety of intravenous (IV) belimumab plus standard therapy in patients of self-identified black race. METHODS:EMBRACE (GSK Study BEL115471; NCT01632241): 52-week multicenter, double-blind (DB), placebo-controlled trial in adults of self-identified black race with active SLE, receiving monthly belimumab 10 mg/kg IV, or placebo, plus standard therapy. The optional 26-week open-label extension phase included patients who completed the DB phase. The primary endpoint was SLE Responder Index response rate at Week 52 with modified proteinuria scoring adapted from the SLEDAI-2K (SRI-S2K). Key secondary endpoints included: Week 52 SRI response rate, time to first severe flare, and reductions in prednisone dose. RESULTS:The modified intention-to-treat population comprised 448 patients (96.9% female; mean [standard deviation] age: 38.8 [11.42] years). The primary endpoint (SRI-S2K response rate at Week 52) was not achieved (belimumab 48.7%, placebo 41.6%; p=0.1068); however, numerical improvements favoring belimumab were observed, especially in patients with high baseline disease activity or renal manifestations. The safety profile of belimumab was generally consistent with previous SLE trials. Adverse events were the primary reason for DB phase withdrawals (belimumab 5.4%; placebo 6.7%). CONCLUSIONS:The primary endpoint of this study was not achieved, but improvement with belimumab versus placebo was observed, suggesting that belimumab remains a suitable treatment option for SLE management in patients of Black African ancestry.

Background Voclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN significantly increased rates of complete renal response at 52 weeks. Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 study. Methods Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, IV, or V +/- III/IV), proteinuria >=1.5 mg/mg (>=2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m². Patients who completed AURORA 1 were eligible to enter AURORA 2 to continue on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed. Results In total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%]; table 1). Eight patients in each arm experienced serious adverse events of infection; serious coronavirus infections were observed in two patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2; four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m² at 4 weeks following study drug discontinuation (figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation. Conclusion Voclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period and the significant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a long-term treatment benefit of VCS in patients with LN. Disclosures AS reports payments for Aurinia Pharmaceuticals Inc. speaker bureaus; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; advisory fees from Eli Lilly, Astra-Zeneca, GlaxoSmithKline and Kezar Life Sciences. YKOT reports research grants from commercial organizations including an unrestricted research grant from GlaxoSmithKline and Aurinia Pharmaceuticals Inc.; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; consultancy fees paid to institution from Aurinia Pharmaceuticals Inc., Novartis, GlaxoSmithKline, KezarBio, Vifor Pharma and Otsuka Pharmaceuticals. CC, NE, and HL are employees and shareholders of Aurinia Pharmaceuticals, Inc. HL is an employee and shareholder of Aurinia Pharmaceuticals, Inc. Data first presented by Saxena A et al. at the EULAR Congress June 1-4, 2022. Editorial support provided by MediComm Partners Ltd. Aurinia Pharmaceuticals Inc. provided funding for the study and presentation