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Background/Purpose: We reported previously (Ramsey-Goldman et al., Arthritis Rheumatol 2020) that score > 0.8 of a multianalyte assay panel (MAP) with algorithm predicts fulfillment of a 4th ACR criterion 9-18 months (median 12) after enrollment in patients with probable systemic lupus erythematosus (pSLE). We continued to follow pSLE to better evaluate transition to classifiable SLE.
Method(s): pSLE, defined as fulfilling 3 ACR criteria, were followed at academic lupus centers. At enrollment, 35 (38%) of the 92 pSLE fulfilled SLICC criteria. CB-CAPs - C4d bound to erythrocytes (EC4d) and B-cells (BC4d) - were measured by quantitative flow cytometry, serum C3 and C4 by turbidimetry, and autoantibodies by ELISA. Anti-dsDNA positivity was confirmed by immunofluorescence (IFA). MAP index consists of an algorithm with CB-CAPs and autoantibodies (Dervieux et al., J Immunol Methods 2017). Initial decision analysis with Youden index showed that MAP > 0.8 and EC4d > 20 mean fluorescence intensity units (MFI) reflected the optimal cutoffs for transition to ACR classifiable SLE; the same cutoffs were used for analysis of all follow-up visits. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis; associations were analyzed by log-rank test and Cox proportional hazards model and are expressed as hazards ratio (HR).
Result(s): Of the 92 pSLE, 74 had 1 or 2 follow-up visits 9-35 months after enrollment for a total of 128 visits. Overall, 28 pSLE (30.4%) transitioned to ACR classifiable SLE: 16 (57%) in the 1st year and 12 (43%) in the 2nd. The clinical or laboratory features that defined fulfillment of ACR criteria are in Table 1. Use of hydroxychloroquine and immunosuppressants was similar in those who did and did not transition to SLE. Of the 17 subjects who accrued hematological criteria during the study (11 as the sole criterion and 6 as one of the new criteria), a minority were on immunosuppressants: 6 at enrollment, 5 at the 1st visit, and 3 at the 2nd. Neither SLICC criteria nor individual biomarkers were significantly associated with transition to SLE (Table 2). Only MAP > 0.8 had significantly high HR for transition to SLE; EC4d > 20 MFI, low complement, and anti-dsDNA were not significant (Table 2).
Conclusion(s): The majority of pSLE transitioned within a year. MAP > 0.8 predicted disease evolution into classifiable SLE better than other biomarkers or fulfillment of SLICC criteria

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

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: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.

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).

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.

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.

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

OBJECTIVES/OBJECTIVE:Cardiac manifestations of neonatal lupus (NL) have been associated with significant morbidity and mortality; however, there is minimal information on long-term outcomes of affected individuals. This study was initiated to evaluate the presence of and the risk factors associated with cardiac dysfunction in NL after birth in multiple age groups to improve counselling, to further understand pathogenesis and to provide potential preventative strategies. METHODS:Echocardiogram reports were evaluated in 239 individuals with cardiac NL: 143 from age 0-1 year, 176 from age >1-17 years and 64 from age >17 years. Logistic regression analyses evaluated associations of cardiac dysfunction at each age group with demographic, fetal and postnatal factors, using imputation to address missing data. RESULTS:Cardiac dysfunction was identified in 22.4% at age 0-1 year, 14.8% at age >1-17 years and 28.1% at age >17 years. Dysfunction in various age groups was significantly associated with male sex, black race, lower fetal heart rates, fetal extranodal cardiac disease and length of time paced. In 106 children with echocardiograms at ages 0-1 year and >1-17 years, 43.8% with dysfunction at age 0-1 year were also affected at age >1-17 years, while the others reverted to normal. Of children without dysfunction at age 0-1 year, 8.9% developed new dysfunction between ages >1 and 17 years. Among 34 with echocardiograms at ages >1-17 years and >17 years, 6.5% with normal function at age >1-17 years developed dysfunction in adulthood. CONCLUSIONS:Risk factors in fetal life can influence cardiac morbidity into adulthood.Although limited by a small number of cases, cardiac dysfunction in the first year often normalises by later childhood. New-onset dysfunction, although rare, can occur de novo after the first year.

OBJECTIVE:To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients suspected of systemic lupus erythematosus (probable SLE [pSLE]) and the usefulness of this biomarker as predictor of the evolution of pSLE into classified SLE by the American College of Rheumatology (ACR) criteria. METHODS:Patients suspected of SLE by lupus experts and fulfilling 3 ACR classification criteria for SLE (pSLE) were enrolled, along with patients with established SLE by both ACR and Systemic Lupus International Collaborating Clinics (SLICC) criteria, primary Sjogren's syndrome (SjS), and other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry and positivity rate was compared to that of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. pSLE were followed prospectively. RESULTS:The 92 pSLE were diagnosed more recently than the 53 established SLE and the use of antirheumatic medications was lower. More pSLE were positive for CB-CAPs (28%) or MAP (40%) than for low complement (9%) at the enrollment visit (p = 0.0001, for each). In pSLE, MAP score > 0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio = 3.11, p<0.01). CONCLUSION/CONCLUSIONS:Complement activation occurs in some patients with pSLE and can be detected with higher frequency by CB-CAPs and MAP than traditional serum complement protein levels. MAP positivity above 0.8 predicts transition to classifiable SLE according to ACR criteria. This article is protected by copyright. All rights reserved.