Faculty Bibliography

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: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 Patients with Systemic Lupus Erythematosus (SLE) represent a unique population at risk for COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. This study was initiated to evaluate for the presence of SARS-CoV-2 IgG antibodies in SLE patients with and without prior COVID-19-related symptoms or COVID-19 RT PCR testing. Methods A total of 329 patients with SLE from two cohorts, one serially monitored for COVID-19 in Spring 2020 (the Web-based Assesment of Autoimmune, Immune-Mediated and Rheumatic Patients (WARCOV) and one undergoing routine surveillance (NYU Lupus Cohort) were tested for SARS-CoV-2 IgG via commercially available immunoassays processed through hospital or outpatient laboratories between April 29, 2020 and February 9, 2021. Results Overall, 16% of 329 patients had a reactive SARSCoV- 2 IgG antibody test. Seropositive patients were more likely to be Hispanic. Other demographic variables, lupus-specific factors and immunosuppressant use were not associated with reactivity. Of the 29 patients with prior RT-PCR confirmed COVID-19, 83% developed an antibody response despite 62% being on immunosuppressants. Six percent of patients who had symptoms suspicious for COVID-19 but negative concurrent RT-PCR testing developed an antibody response. Twenty-three percent of patients who had COVID- 19-related symptoms but no RT-PCR testing and 5% of patients who had no symptoms of COVID-19 developed an antibody response. Among patients initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially. In COVID- 19-confirmed patients high percentages had antibody positivity beyond 30 weeks from disease onset, 88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks. Conclusions Most patients with SLE and confirmed COVID- 19 were able to produce a serologic response despite use of a variety of immunosuppressants. These findings provide reassurances regarding the efficacy of humoral immunity and possible reinfection protection in patients with SLE

Background Voclosporin, a novel calcineurin inhibitor, has been tested successfully in two pivotal trials in adult patients with lupus nephritis. The Phase 3 AURORA 1 study and the Phase 2 AURA-LV study showed that compared with mycophenolate mofetil (MMF) and low-dose steroids alone, the addition of voclosporin significantly increased the complete renal response rate at approximately one year of treatment. Patients that completed the AURORA 1 study were eligible to enroll in the AURORA 2 extension study. Here we report the first interim analysis of AURORA 2. Methods AURORA 2 is a two-year, blinded, controlled extension study. Patients completing AURORA 1 continued the same randomized treatment in AURORA 2 of voclosporin (23.7 mg twice daily) or placebo, in combination with MMF (1 g twice daily) and low-dose steroids. The interim analysis evaluated urine protein creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) in patients with up to two years of total treatment. In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in the extension study, of which 73 patients in the voclosporin arm and 51 patients in the control arm received two years of treatment at the time of this interim analysis. Results Mean UPCR at pre-treatment AURORA 1 baseline was 3.9 mg/mg in the voclosporin arm (n=116) and 3.9 mg/mg in the control arm (n=100). The least square (LS) mean change in UPCR from pre-treatment AURORA 1 baseline to year two was -3.1 mg/mg for the voclosporin arm (n=73) and -2.1 mg/ mg for control arm (n=51; figure 1). Mean corrected eGFR at pre-treatment AURORA 1 baseline was 79.6 mL/min/1.73 m² for the voclosporin arm (n=116) and 78.9 mL/min/1.73 m² for the control arm (n=100) and at year two, was 79.0 mL/min/1.73 m² for the voclosporin arm (n=73) and 82.9 mL/min/1.73 m² for the control arm (n=51). There was a small, expected, and early decrease in mean eGFR in the voclosporin arm in the first four weeks of treatment (in AURORA 1) after which eGFR remained stable throughout year one and year two. Additionally, there were no unexpected new adverse events observed in patients who continued with voclosporin treatment compared to control-treated patients. Mixed effects model for repeated measures (MMRM) analysis of least squares mean change from pre-treatment AURORA 1 baseline for UPCR included terms for baseline covariate, treatment, visit and treatment by visit interaction. Interim analysis of AURORA 2 patients includes data from pre-treatment baseline of AURORA 1, the one-year treatment period in AURORA 1 and up to one-year treatment period in AURORA 2. Conclusions Patients in the voclosporin treatment arm maintained meaningful reductions in proteinuria with no change in mean eGFR at two years of treatment. Additional AURORA 2 efficacy and safety data will be provided at the conclusion of the study

Background/Purpose: Voclosporin, a novel calcineurin inhibitor (CNI), has been tested successfully in 2 pivotal trials in adult patients with lupus nephritis (LN). Previously reported results from the Phase 3 AURORA 1 and Phase 2 AURA-LV studies showed that compared with mycophenolate mofetil (MMF) and low-dose steroids alone, the addition of voclosporin significantly increased the renal response rate and reduced proteinuria, as measured by urine protein creatinine ratio (UPCR), in patients with LN at 48 weeks in AURA-LV and 52 weeks in AURORA 1.
Method(s): Here we report on the second interim analysis of the ongoing 2-year, blinded, controlled extension study, AURORA 2, with exposure up to 30 months (12 months from AURORA 1 and up to an additional 18 months in AURORA 2). All patients enrolled in AURORA 1 had a diagnosis of systemic lupus erythematosus according to the ACR criteria and biopsy-proven LN; patients completing AURORA 1 were eligible to continue in AURORA 2 with the same randomized treatment of voclosporin (23.7 mg BID) or placebo, in combination with MMF (1 g BID) and low-dose oral steroids. UPCR and estimated glomerular filtration rate (eGFR) were evaluated. In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in the extension study; 90 and 78 patients, respectively, had received 30 months of total treatment as of this interim analysis.
Result(s): Mean UPCR at pre-treatment (AURORA 1) baseline was 3.94 mg/mg in the voclosporin arm (n=116) and 3.87 mg/mg in the control arm (n=100). The LS mean change in UPCR from pre-treatment baseline to month 30 was -3.32 mg/mg for the voclosporin arm (n=90) and -2.55 mg/mg for the control arm (n=78; Figure 1). There was a small, expected and early decrease in mean eGFR in the voclosporin arm in the first 4 weeks of treatment in AURORA 1, after which eGFR remained stable through month 30 (Figure 2). There were no unexpected new adverse events reported in patients who continued voclosporin treatment compared to control-treated patients. A total of 6 and 10 patients in the voclosporin and control arms reported events of coronavirus (COVID-19) infection, with 2 and 6 patients, respectively, reporting serious coronavirus infections.
Conclusion(s): Patients in the voclosporin treatment arm maintained meaningful reductions in proteinuria with no change in mean eGFR at 30 months of treatment. Additional AURORA 2 efficacy and safety data will be provided at the conclusion of the study