Faculty Bibliography

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.

Introduction Fetal cardiac disease is strongly associated with maternal anti-SSA/Ro antibodies, but gaps in our knowledge include the influence of antibody specificity and titer, maternal diagnosis, overall non-cardiac adverse pregnancy outcomes (APOs), optimal surveillance protocols, and efficacy of rapid treatment. Methods The multi-center Surveillance and Treatment To Prevent Fetal AV Block Likely to Occur Quickly (STOP BLOQ) study recruited pregnant women with commercially positive anti-Ro antibodies and stratified them into high and low titers of anti-Ro60 and Ro52 based on a research ELISA, using a cutoff defined by that obtained for 50 mothers with previous AVB offspring. Mothers with anti-Ro60 and/or 52 antibodies at or above 1,000 I.U. were trained to perform FHRM. From 17-25 weeks of gestation, FHRM was completed 3x/day in addition to weekly or biweekly fetal echocardiograms (echo). Mothers texted all audio sounds to the coordinating center. Texts deemed abnormal by mothers were immediately sent to an on call pediatric cardiologist who either reassured if FHRM was normal or referred for emergency fetal echo in < 6 hours if abnormal. Results 250 anti-Ro pregnant women (22% Hispanic, 50% white, 12% Black, 12% Asian, 4% other) have been consented, including 28 whose previous child had AVB. Of mothers tested to date, 153 were provided home monitors given high titer anti-Ro60 and/or 52 antibodies (26 high titer anti-Ro60 alone, 21 high titer anti-Ro52 alone,105 high titer antibodies to both antigens). The 83 patients with low titers were surveilled with echos per local standard of care. Regarding maternal diagnosis, of 161 assessed to date, 39% were asym/UAS, 11% RA, 31% SS, 19% SLE. Antibody titers did not significantly differ by ethnicity, race or diagnosis (table 1). Non-AVB APOs occurred in 18% and were not predicted by Ro60 or 52 titers but rather SLE diagnosis (table 2). In total, 24,759 FHRM audiotexts were received from 131 patients (90 of whom have delivered) during the monitoring period. Of these, 22 were evaluated by the on-call pediatric cardiologist, who prompted an emergency echo (all completed in < 6 hrs). In 11 cases, the emergency echo was normal. In 9, there were premature atrial contractions, confirming the mother's perception. In 2 with 2degree block on urgent echo (both treated per protocol with IVIG and dexamethasone), 1 reverted to normal sinus rhythm and the other progressed to 3degree block. In 2 others, the mother did not perceive abnormal FHRM for > 24 hrs, echo identified 3degree block, and retrospective cardiology review of FHRM audio captures identified an abnormality prior to obtaining the echo. All 4 AVB developed in fetuses of mothers with high titer antibodies to both Ro60 and 52 (mean 32,451 and 34,991 respectively). Of the 18 mothers with a previous AVB child who followed the 400mg hydroxychloroquine PATCH protocol, 1 developed AVB in accord with the results of Step 1 in that study. Conclusion These data support that APOs in this clinically diverse group of mothers are not influenced by anti-Ro titer or specificity, but rather SLE diagnosis. All conduction defects were initially identified by FHRM and in mothers with high titer anti-Ro60 and 52. Hydroxychloroquine continues to show efficacy in reducing the AVB recurrence rate with rapid intervention of emergent block being promising

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

Therapeutics for patients hospitalized with coronavirus disease 2019 (COVID-19) are urgently needed during the pandemic. Bamlanivimab is a potent neutralizing monoclonal antibody that blocks severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) attachment and entry into human cells, which could potentially lead to therapeutic benefit. J2W-MC-PYAA was a randomized, double-blind, sponsor unblinded, placebo-controlled, single ascending dose first-in-human trial (NCT04411628) in hospitalized patients with COVID-19. A total of 24 patients received either placebo or a single dose of bamlanivimab (700 mg, 2,800 mg, or 7,000 mg). The primary objective was assessment of safety and tolerability, including adverse events and serious adverse events, with secondary objectives of pharmacokinetic (PK) and pharmacodynamic analyses. Treatment-emergent adverse event (TEAE) rates were identical in the placebo and pooled bamlanivimab groups (66.7%). There were no apparent dose-related increases in the number or severity of TEAEs. There were no serious adverse events or deaths during the study, and no discontinuations due to adverse events. PKs of bamlanivimab is linear and exposure increased proportionally with dose following single i.v. administration. The half-life was ~ 17 days. These results demonstrate the favorable safety profile of bamlanivimab, and provided the initial critical evaluation of safety, tolerability, and PKs in support of the development of bamlanivimab in several ongoing clinical trials.

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

Background/UNASSIGNED:Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. Methods/UNASSIGNED:For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. Findings/UNASSIGNED:67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. Interpretation/UNASSIGNED:Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. Funding/UNASSIGNED:National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

OBJECTIVE:To investigate long-term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS:This 3-year, multinational, open-label extension (OLE) enrolled adult patients who completed treatment (48 weeks anifrolumab or placebo; 12-week follow-up) in the MUSE phase 2b randomized controlled trial (RCT). Patients initially received intravenous anifrolumab 1000 mg every 4 weeks, reduced to 300 mg every 4 weeks based on the benefit/risk profile established in MUSE. Adverse events (AEs) were assessed monthly. Exploratory endpoints included SLE Disease Activity Index 2000 (SLEDAI-2K), SLICC Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS:Of 246 patients who completed the RCT, 218 (88.6%) enrolled in the OLE; 139/218 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of OLE treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment because of AEs. No new safety signals were identified. Improvement in SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 Health Survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. CONCLUSION/CONCLUSIONS:Long-term anifrolumab treatment demonstrated an acceptable safety profile with sustained improvement in disease activity, HRQoL, and serologies.

OBJECTIVE:To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. METHODS:Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1-3 years to evaluate transition into ACR-classifiable SLE. Individual cell-bound complement activation products (CB-CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme-linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. RESULTS:Of the 92 patients with pSLE enrolled, 74 had one or two follow-up visits 9-35 months after enrollment for a total of 128 follow-up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR-classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow-up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. CONCLUSION/CONCLUSIONS:Approximately one-third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.