Faculty Bibliography

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

Background Voclosporin (VCS) is a novel high potency calci-neurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. The recently completed Phase 3 AURORA study builds on the favorable efficacy seen in the Phase 2 AURA-LV study in patients with active LN. The AURORA study was conducted in active LN patients to evaluate the efficacy and safety of VCS vs placebo in combination with mycophenolate mofetil (MMF, 2 g/day) and rapidly tapered oral steroids. Methods AURORA is a global, randomized double-blind, placebo-controlled Phase 3 study with active LN. Key inclusion criteria include biopsy proven LN (Class III, IV, V) and proteinuria of >1.5 mg/mg or >2 mg/mg for Class V patients. The primary endpoint was renal response (RR) at 52 weeks defined as UPCR of < 0.5 mg/mg, eGFR > 60 mL/min or no confirmed decrease from baseline in eGFR of >20%, presence of sustained, low-dose steroids and no administration of rescue medication. Results AURORA enrolled 357 adult LN patients. The RR rate was 40.8% for voclosporin versus 22.5% for control (OR: 2.65; 95% CI: 1.64, 4.27; p<0.001). Also, a significantly higher proportion of LN patients achieved pre-specified hierarchical secondary endpoints for voclosporin including: RR at 24 weeks, partial renal response (PRR) at 24 and 52 weeks, time to achieve UPCR < 0.5 mg/mg, and time to 50% reduction in UPCR (table 1). The efficacy benefit of VCS on RR was seen across prespecified biopsy subgroups: for pure Class V LN (OR: 2.74; 95% CI: 0.78, 9.68), and for Class III/IV alone or in combination with Class V patients (OR: 2.63; 95% CI: 1.57, 4.41). Furthermore, all pre-specified subgroup analyses (age, sex, race, region, and prior MMF use) also favored VCS. The overall incidence of SAEs was similar in both groups (VCS 20.8% and control 21.3%), with infections most commonly reported (VCS 10.1% and control 11.2%). Overall mortality in the trial was low, with six deaths observed; one in the voclosporin arm and five in the control group. Additionally, at Week 52 the VCS arm showed no significant decrease in eGFR or increase in BP, lipids or glucose. Conclusion The addition of VCS to MMF and low-dose steroids demonstrated superior efficacy to standard of care in active LN patients. The 104-week double-blind AURORA continuation study will provide longer term safety and efficacy data

BACKGROUND:In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS:, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS:A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS:In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).

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:Although hydroxychloroquine (HCQ) is a mainstay of treatment for patients with systemic lupus erythematosus (SLE), ocular toxicity can result from accumulated exposure. As the longevity of patients with SLE improves, data are needed to balance the risk of ocular toxicity and the risk of disease flare, especially in older patients with quiescent disease. Accordingly, this study was initiated to examine the safety of HCQ withdrawal in older SLE patients. METHODS:Data were obtained by retrospective chart review at three major lupus centers in New York City. Twenty-six patients who discontinued HCQ and thirty-two patients on HCQ matched for gender, race/ethnicity, and age were included in this study. The primary outcome was the occurrence of a lupus flare classified by the revised version of the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare composite index, within 1 year of HCQ withdrawal or matched time of continuation. RESULTS:Five patients (19.2%) in the HCQ withdrawal group compared to five (15.6%) in the HCQ continuation group experienced a flare of any severity (odds ratio [OR] = 1.28; 95% CI 0.31, 5.30; p = 0.73). There were no severe flares in either group. The results were similar after adjusting for length of SLE, number of American College of Rheumatology criteria, low complement levels, and SELENA-SLEDAI score, and in a propensity score analysis (OR = 1.18; 95% CI 0.23, 6.16; p = 0.84). The analysis of time to any flare revealed a non-significant earlier time to flare in the HCQ withdrawal group (log-rank p = 0.67). Most flares were in the cutaneous and musculoskeletal systems, but one patient in the continuation group developed pericarditis. The most common reason for HCQ withdrawal was retinal toxicity (42.3%), followed by patient's preference (34.6%), other confirmed or suspected adverse effects (15.4%), ophthalmologist recommendation for macular degeneration (3.8%), and rheumatologist recommendation for quiescent SLE (3.8%). CONCLUSIONS:In this retrospective study of older stable patients with SLE on long-term HCQ, withdrawal did not significantly increase the risk of flares.

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:Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES/OBJECTIVE:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS:This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS:By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS:These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

OBJECTIVES/OBJECTIVE:To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS:All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS:=0.145). CONCLUSION/CONCLUSIONS:Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.

Autoimmune-mediated congenital heart block (CHB) is a severe manifestation of neonatal lupus in which conduction tissues of the fetal heart are damaged. This occurs due to passive transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies and subsequent inflammation and fibrosis of the atrioventricular (AV) node. Notably, the disease manifests after the fetal heart has structurally developed, ruling out other anatomical abnormalities that could otherwise contribute to the block of conduction. Complete AV block is irreversible and the most common manifestation of CHB, although other cardiac complications such as endocardial fibroelastosis (EFE), dilated cardiomyopathy, and valvular insufficiency have been observed. In this review, we detail the classification, prevalence, pathogenesis, and clinical management recommendations for autoimmune CHB.