EMBRACE: Phase 3/4, Randomized, 52-Week Study of Belimumab Efficacy and Safety in Patients of Black African Ancestry With Systemic Lupus Erythematosus
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.
Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus erythematosus: analysis of a multi-racial and multi-ethnic cohort
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.
Long-term safety and efficacy of anifrolumab in adults with systemic lupus erythematosus: results of a phase 2 open-label extension study
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 â‰¥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.
A Multianalyte Assay Panel With Cell-Bound Complement Activation Products Predicts Transition of Probable Lupus to American College of Rheumatology-Classified Lupus
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.
Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis
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/Î¼l in the RCB group versus 11 cells/Î¼l 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.
Leveraging the United States Epicenter to Provide Insights on COVID-19 in Patients with Systemic Lupus Erythematosus
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.
Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation
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.
Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation [Meeting Abstract]
Background/Purpose: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) was initially considered as a prophylaxis and treatment of COVID-19. Despite this optimism, more extensive reports have significantly dampened the promise of efficacy, however cardiac toxicity has surfaced raising attention to this complication. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, this initiative leveraged a unique opportunity to evaluate neonatal electrocardiograms (ECGs) in the context of HCQ levels to address any potential cardiotoxicity.
Method(s): Neonatal 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. The ECGs of affected newborns who met the primary outcome of advanced block were not included in this safety study so that the results only reflect those infants with no clinical cardiac disease. Using the Bazett formula to correct for heart rate, corrected QT (QTc) intervals were calculated and compared to age-matched normal values. For reference, the median (2nd percentile - 98th percentile) values for QTc were 413 (378-448) msec in males, and 420 (379-462) msec in females. QTc intervals were recorded in the absence of knowledge of the HCQ levels. Values exceeding 448 msec for males and 462 msec for females were considered abnormal. Levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure.
Result(s): There were 45 ECGs available for interpretation within the first 4 months of life in unaffected infants. Overall, there was no correlation between cord blood levels of HCQ and the QTc (R = 0.02, P = 0.86) or the average value of HCQ levels obtained during each individual pregnancy and cord blood and the QTc (R = 0.04, P = 0.80), as shown in Figure 1A and Figure 1B. Likewise there was no correlation between the average of the maternal HCQ levels obtained at each trimester and delivery plus cord levels and the QTc on the ECGs of the 31 infants evaluated on day of life 1-4 (R = 0.08, P = 0.63) or those of the 14 children older than 4 days (R = 0.01, P = 0.95). Maternal values of HCQ were sustained throughout pregnancy and delivery (Figure 2). Mean QTc values were nearly identical between those in the highest and lowest quartiles of cord blood HCQ levels (P = 0.57) and between the highest and lowest quartiles of average HCQ levels during pregnancy (P = 0.54) (Figure 3A and 3B). Among these 45 infants, only 5 had prolongation of the QTc (11%; 95% CI: 4% - 24%), 2 marked and 3 marginal. No arrhythmias occurred in any neonate that was not known to have heart block.
Conclusion(s): In aggregate, these data provide reassurances that the maternal use of HCQ is not associated with a high incidence of QTc prolongation in the neonate
Effects of Belimumab on Renal Outcomes, Overall SLE Control and Biomarkers: Findings from a Phase 3, Randomized, Placebo-controlled 104-week Study in Patients with Active Lupus Nephritis [Meeting Abstract]
Background/Purpose: Belimumab (BEL) has demonstrated efficacy in systemic lupus erythematosus (SLE) in 4 positive pivotal trials. This study assessed the efficacy and safety of intravenous (IV) BEL plus standard therapy (ST) in patients (pts) with active lupus nephritis (LN).
Method(s): This Phase 3, double-blind, placebo (PBO)-controlled study (GSK Study BEL114054; NCT01639339) randomized (1:1) adults with SLE and biopsy-proven LN (class III, IV, and/or V) to monthly BEL 10 mg/kg IV or PBO, plus ST. Randomization was stratified by race and treatment regimen (high-dose corticosteroids + either cyclophosphamide followed by azathioprine, or mycophenolate mofetil [MMF] followed by MMF). Primary endpoint: Primary Efficacy Renal Response (PERR; urine protein-creatinine ratio [uPCR] <=0.7; estimated glomerular filtration rate [eGFR] no worse than 20% below pre-flare value or >=60 ml/min/1.73m2; no rescue therapy) at Week (Wk) 104. Key secondary endpoints: Complete Renal Response (CRR; uPCR < 0.5; eGFR no worse than 10% below pre-flare value or >=90 ml/min/1.73m2; no rescue therapy) at Wk 104; Ordinal Renal Response (ORR; CRR, PRR or no response) at Wk 104; PERR at Wk 52; time to renal-related event (defined in Table 1) or death. Wk 104 PERR/CRR were analyzed in subgroups: treatment regimens, LN class, race. Additional evaluations included: time to first severe SFI flare (defined in Table 2); proportions of pts with SLEDAI-S2K (defined in Table 2) score < 4 and with prednisone dose <=7.5/5 mg/day, both at Wk 104; changes from baseline in biomarkers (anti-dsDNA, anti-C1q, C3, C4) at Wk 104; safety.
Result(s): Randomized pts: 448 (efficacy: 223/group; safety: 224/group). The study met its primary and key secondary endpoints (Table 1). Risk of a renal-related event or death was lower over the study with BEL vs PBO (HR [95% CI] 0.5 [0.3, 0.8]; p=0.001). Table 2 displays additional endpoints. The odds of PERR/CRR responses at Wk 104 on BEL vs PBO were numerically greater for listed subgroups, except pure class V LN (Figure); however, in class V, a numerically greater proportion of BEL vs PBO pts achieved PERR/CRR response at Wk 52 (PERR: 44.4% vs 33.3%; CRR: 36.1% vs 27.8%, respectively). At Wk 104, in pts with baseline autoantibodies, median (IQR) percent change from baseline (BEL vs PBO) in anti-dsDNA was -74.2 (-85.1, -49.5) vs -36.6 (-69.7, 28.6); and anti-C1q was -73.2 (-84.1, -59.0) vs -57.9 (-76.1, -33.2). *p-value was from a rank ANCOVA model comparing belimumab and placebo with covariates for treatment group, induction regimen (CYC vs MMF), race (black vs non-black), baseline uPCR, and baseline eGFR. Study WD, TF, and IPD were imputed as non-responders; +defined as eGFR no worse than 10% below baseline value or within normal range, >=50% decrease in uPCR (either uPCR <1.0 if baseline ratio <=3.0, or uPCR <3.0 if baseline ratio >3.0), no rescue therapy, and not a CRR; ++defined as the first event experienced among the following: endstage renal disease/doubling of serum creatinine/renal worsening/renal disease-related treatment failure or death; Pnumber/proportion of pts reporting the event ANCOVA, analysis of covariance; BEL, belimumab; CI, confidence interval; CRR, Complete Renal Response; CyC, cyclophosphamide; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IPD, investigational product discontinuation; IV, intravenous; MMF, mycophenolate mofetil; NR, non-responder; OR, odds ratio; ORR, Ordinal Renal Response; PBO, placebo; PERR, Primary Efficacy Renal Response; PRR, Partial Renal Response; TF, treatment failure; uPCR, urine protein-creatinine ratio; WD, withdrawal; Wk, Week In pts with low baseline complement levels, median (IQR) percent change from baseline (BEL vs PBO) in C3 was 43.8 (17.1, 88.9) vs 30.0 (13.5, 59.8) and in C4 was 115.5 (60.0, 177.8) vs 66.7 (22.2, 166.7). Adverse events (AEs; >=1) were reported for 95.5% of BEL and 94.2% of PBO pts; 12.9% of pts in each group had >=1 AE resulting in study treatment discontinuation. Serious AEs (>=1) were reported for 25.9% of BEL and 29.9% of PBO pts, most commonly infections and infestations (13.8% of BEL vs 17.0% of PBO pts); 1.8% of BEL and 1.3% of PBO pts developed on-treatment fatal AEs (mainly due to infections).
Conclusion(s): In this large 2-year LN study, compared with ST alone, BEL plus ST improved renal outcomes, overall SLE disease activity, and biomarker levels, while reducing steroid use, with a favorable safety profile
COVID-19 in Patients with Systemic Lupus Erythematosus [Meeting Abstract]
Background/Purpose: Patients with systemic lupus erythematosus (SLE) represent a unique population in considering risk for coronavirus disease 2019 (COVID-19) with biologic, genetic, demographic, clinical and treatment issues all at play. By the nature of their chronic inflammatory autoimmune condition and regular use of immunosuppressive medications, these individuals would traditionally be considered at high risk of contracting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and having a worse prognosis. Accordingly, we aimed to characterize patients with SLE affected by COVID-19 in New York City (NYC) and analyze associations of comorbidities and medications on outcomes.
Method(s): Patients with SLE and COVID-19 (confirmed by RT-PCR testing), were identified through a longitudinal survey of an established NYU lupus cohort, query of New York University Langone Health and Bellevue Hospitals systems and referrals from rheumatologists at those institutions. All patients were age 18 or older and met SLE classification criteria or carried a rheumatologist's diagnosis of SLE. Only English-, Spanish- or Mandarin-speaking patients were included in the study. Data were prospectively collected via a web-based questionnaire and review of electronic medical records. Baseline characteristics and medications were compared between the hospitalized and ambulatory patients with COVID-19. A logistic regression analysis was performed to identify independent predictors of hospital admission.
Result(s): A total of 41 SLE patients were confirmed COVID-19 positive by RT-PCR. The patients were predominantly female and encompassed the major racial/ethnic demographics seen in NYC. The most common symptoms of COVID-19+ patients were cough (78.4%), fever (64.9%), and shortness of breath (64.9%). Of those SLE patients with COVID-19, 24 (59%) were hospitalized, 4 required ICU level of care, and 4 died, all of hypoxic respiratory failure, Table 1. Hospitalized patients tended to be older, non-white, Hispanic, and have higher BMI, antiphospholipid syndrome, a history of lupus nephritis and at least one medical comorbidity, Table 2. There was no difference between the groups in use of hydroxychloroquine, systemic steroids or immunosuppressants. Logistic regression analysis identified the following independent predictors of being hospitalized with COVID-19: race (OR = 7.78 for non-white vs. white; 95% CI: 1.13 to 53.58; p=0.037), the presence of at least one comorbidity (OR=4.66; 95% CI: 1.02 to 21.20; p=0.047), and BMI (OR = 1.08 per increase in kg/m2; 95% CI: 0.99 to 1.18; p=0.096).
Conclusion(s): Patients with SLE and COVID-19 have a high rate of hospitalization but similar mortality rate to the general population in NYC. Risk factors such as non-white race, higher BMI, and the presence of one or more comorbidities were identified as independent predictors of hospitalization in SLE patients who develop COVID-19. The use of hydroxychloroquine and immunosuppressants did not appear to influence the outcomes of patients with SLE in the setting of COVID-19. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE