Faculty Bibliography

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.

OBJECTIVE:To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). METHODS:In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group) or with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. RESULTS:Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. CONCLUSION/CONCLUSIONS:The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

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

OBJECTIVE:To characterize patients with Systemic Lupus Erythematosus (SLE) affected by COVID-19 and to analyze associations of comorbidities and medications on infection outcomes. METHODS:Patients with SLE and RT-PCR-confirmed COVID-19 were identified through an established New York University lupus cohort, query of two hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected from asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. RESULTS:A total of 226 SLE patients were included: 41 patients with confirmed COVID-19; 19 patients who tested negative for COVID-19; 42 patients with COVID-19-like symptoms who did not get tested; and 124 patients who remained asymptomatic without testing. Of those SLE patients with COVID-19, 24 (59%) required hospitalization, four required intensive care unit-level of care, and four died. Hospitalized patients tended to be older, non-white, Hispanic, have higher BMI, history of nephritis, and at least one comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least one comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION/CONCLUSIONS:In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.

Background - Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) is being considered as prophylaxis and treatment of COVID-19. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. Methods - To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal electrocardiograms (ECGs) and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. Results - Forty-five ECGs were available for QTc measurement, and levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of HCQ and the neonatal QTc (R = 0.02, P = 0.86) or the mean of HCQ values obtained throughout each individual pregnancy and the QTc (R = 0.04, P = 0.80). In total 5 (11%; 95% CI: 4% - 24%) neonates had prolongation of the QTc > 2SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. Conclusions - In aggregate, these data provide reassurances that the maternal use of HCQ is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered.

Background/Purpose: Neonatal Lupus (NL) is a model of passively acquired autoimmunity conferred by exposure to maternal anti-Ro antibodies with major manifestations being congenital heart block (CHB) and/or cutaneous disease. This study was initiated to address the development of de novo autoimmunity in these children and identify associated clinical and genetic risk factors.
Method(s): In a retrospective cohort study of enrollees in the Research Registry for Neonatal Lupus (RRNL), 511 children exposed to anti-Ro in utero responded to a follow up questionnaire focused on symptoms of autoimmunity. Self-reported diseases were confirmed via medical record review. Bivariate analyses were performed with potential risk factors for the development of autoimmune disease (AD) and included the NL status per se, a disease severity score based on mortality risk factors, and maternal AD (inclusive of lupus, Sjogren's syndrome, psoriasis, rheumatoid arthritis, or thyroid disease). A subset of 99 CHB, 9 cutaneous, and 55 unaffected anti-Ro exposed RRNL individuals were genotyped at Class II HLA DRB1 and DQB1 four-digit alleles, which were assigned by imputation (HIBAG) or sequencing. Generalized estimating equations (logit link, exchangeable correlation) were used to test for associations between HLA alleles and the development of AD.
Result(s): Of the respondents, 182 offspring had CHB, 95 had cutaneous only NL and 234 were siblings without NL. Females comprised 53% and 80% were Caucasian. The mean age was 14.2+/-9.7; 4% age 0-2 years, 48% 2-13 years, and 47% > 13 years. An AD developed in 38 offspring (20 CHB, 7 cutaneous NL, 11 non-NL siblings; Table 1). The most prevalent AD was thyroid disease. The development of an AD was significantly associated with presence of CHB vs. cutaneous only or non-NL siblings (11% vs. 5%, p=0.033). The maternal health status did not influence the development of an AD in the child (7% mothers with AD vs. 6% asymptomatic mothers, p=0.67). Mean NL severity score was higher in offspring with AD (3.8+/-4.8 vs. 2.2+/-4.0, p= 0.031). Other markers of fetal CHB disease severity were associated with subsequent AD development, including in-utero exposure to fluorinated steroids (15% vs. 6%, p=0.088) and beta agonists such as terbutaline (23% vs. 9%, p=0.043). In the study of 163 RRNL cases with HLA data (20 with AD, 143 without), HLA DRB1*03:01 (OR 3.4, CI 1.46-7.90, p=0.0045), DQA1*05:01 (OR 3.39, CI 1.16-9.92, p=0.0262), and DQB1*02:01 (OR 4.28, CI 1.73-10.62, p=0.0017) were associated with increased risk of AD (of note, these loci are in high linkage disequilibrium). In contrast, these alleles were not significantly associated with development of CHB (99 CHB vs. 64 without).
Conclusion(s): The development of an autoimmune disease was more common in anti-Ro exposed children with CHB, greater NL severity, and MHC Class II haplotypes. These factors may relate to an inherent susceptibility to inflammation and fibrosis, occuring in utero and later in life