Faculty Bibliography

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.

Background/Purpose : We reported (R amsey-Goldman et al., Arthritis Rheumatol 2018: 70 [suppl 10]) that cellbound complement activation products (CB-CAPs) and a multi-analyte assay panel with algorithm (MAP) are positive more frequently than standard immunological markers in patients with probable systemic lupus erythematosus (pSLE) who fulfilled 3 ACR criteria. We followed pSLE prospectively to evaluate whether CB-CAPs and MAP positivity at enrollment predict transition to classifiable SLE by fulfillment of a fourth ACR criterion. Methods : pSLE were followed prospectively at academic lupus centers and clinical and laboratory data were collected. Biomarkers were measured at every visit. CB-CAPs -C4d bound to erythrocytes (EC4d) and B-cells (BC4d) -were measured by quantitative flow cytometry and expressed as mean fluorescent intensity (MFI). Serum C3 and C4 and autoantibodies were measured by turbidimetry and ELISA, respectively. Anti-dsDNA positivity was confirmed by immunofluorescence (IFA) with Crithidia Luciliae . MAP was evaluated as previously described (Dervieux T, et al. J Immunol Methods 2017) and consists of an algorithm which utilizes CB-CAPs and autoantibodies. A MAP score >0.1 is considered positive, the higher the number (to 3.5) the greater the likelihood of SLE. For this study, decision analysis with Youden index showed that MAP >0.8 and EC4d >20 MFI reflected the optimal cutoff. Data were analyzed by Fisher's exact test and Kaplan-Meier with log-rank test and Cox proportional hazards model for time to fulfillment of a fourth ACR criterion, expressed as hazard ratios. Results : Of the 92 pSLE enrolled, 69 had 1 follow up visit 9-18 months after enrollment (average+/-SD = 12.4+/-1.7 months; median = 12 months). The time to acquire the 4th ACR criterion was estimated by the investigators at the follow up visit. Twenty pSLE (29%) fulfilled a fourth ACR criterion during this time. SLICC fulfillment at enrollment did not predict fulfillment of ACR criteria (p =0.27). Eight of the 20 (40%) pSLE who transitioned to classifiable SLE by ACR criteria had MAP >0.8 at enrollment while 8/48 (17%) non-transitioned patients had MAP > 0.8 at enrollment (p =0.06). Patients with MAP >0.8 at enrollment fulfilled ACR criteria with a hazard ratio (HR) =3.11 within 18 months (p < 0.01 by log-rank test). HR of MAP was higher than other individual biomarkers, although anti-dsDNA and EC4d >20 MFI were of borderline significance (Table). Conclusion : Complement activation as detected by MAP >0.8 at enrollment may predict disease evolution of pSLE into classifiable SLE by ACR criteria better than anti-dsDNA and low serum complement. (Table Presented)

Background/Purpose : Osteoporosis and bone fractures are a frequent cause of morbidity in systemic lupus erythematosus (SLE), and are felt to be related both to disease activity and glucocorticoid (GC) exposure. Dual energy X-ray absorptiometry (DEXA) is the standard tool to assess bone density, but it does not measure bone quality or strength and is not a robust predictor of fractures in SLE. Clinical 3T MRI scans have been shown to assess information about bone not captured by DEXA. This study aims to evaluate factors associated with bone structure measured by DEXA and MRI in an SLE cohort. Methods : DEXAs were performed on 31 women with SLE and 3T MRI of the non-dominant hip were performed on 29 of these cases. Results were associated with multiple demographic, clinical and laboratory measures. MRI parameters measured included trabecular plate width (PW), trabecular plate to rod ratio (PRR), plate volume fraction (PVF), rod volume fraction (RVF), trabecular bone thickness (Tb.Th), trabecular spacing (Tb.Sp) and trabecular network area (TNA). DEXA BMD was measured, and osteoporosis (OP) was defined as hip, spine or femoral neck Z score < -2.0 in premenopausal women, and T score < -2.5 in others, and low bone density (LBD) as Z score < -2.0 in premenopausal women and T score < -1.0 in others. Results : By DEXA, 8/31 (25.8%) had OP and 12 (38.7%) had LBD. History of lymphopenia (75.0% vs. 31.8%, p=0.049) and lower concurrent HCQ dose (340 vs. 400 mg, p=0.006) associated with DEXA OP, while older age (48.3 vs. 36.3 y, p=0.024) associated with LBD. Higher ESR was inversely correlated with favorable bone structure (PW r(22) = -.49, p=0.025, PRR rs = -.51, p=0.018, PVF rs = -.51, p=0.018, RVF rs = .51, p=0.018, Tb.Th rs = -.58, p=0.005, Tb.Sp rs = .44, p=0.046, TNA rs = -.50, p=0.022). Higher CRP was likewise inversely correlated with favorable bone structure (PW r(20) = -.61, p=0.004, PRR rs = -.57, p=0.009, PVF rs = -.57, p=0.009, RVF rs =.57, p=0.009, Tb.Th rs = -.56, p=.011, Tb.Sp rs =.67, p=0.001, TNA rs = -.64, p=0.002). A history of lupus nephritis was associated with unfavorable bone structure (PW 705.3 vs. 833.3 mum, p=0.048, PRR 6.6 vs. 8.1, p=0.024, PVF 0.83 vs. 0.89, p=0.024, RVF 0.17 vs. 0.11, p=0.024, Tb.Th 178.1 vs. 193.4 mm, p=0.012, Tb.Sp 358.6 vs. 296.5 mm, p=0.056, TNA 0.41 vs. 0.54 (1/mm), p=0.009). ESR, CRP and history of lupus nephritis were not significantly associated with DEXA hip BMD, OP or LBD. MRI parameters for favorable bone structure were inversely correlated with DEXA hip BMD (PW r(28) = -.47, p=0.011, Tb.Th rs = -.53, p=0.003) and BMI (PW r(28) = -.54, p=0.003, TbTh rs = -.72, p< 0.001, TNA rs = -.44, p=0.017). Conclusion : Higher ESR and CRP and a history of lupus nephritis associated with MRI parameters of unfavorable bone structure, but did not associate with DEXA abnormalities in SLE patients. MRI may be a more sensitive tool than DEXA to measure inflammatory effects on bone and potentially cumulative dose of steroid exposure. There were inverse correlations of MRI parameters with traditional osteoporosis risk factors and BMD measures on DEXA, and it is possible that each tool evaluates different aspects of bone health. Further evaluation of MRI screening for fracture risk in SLE and GC exposed individuals is warranted to better quantify risk and guide treatment

Background/Purpose : Black patients have more severe SLE and more frequent lupus nephritis vs other racial groups. Efficacy and safety of intravenous (IV) belimumab was demonstrated in three Phase 3 SLE studies; few black patients were included, limiting subgroup analyses. The EMBRACE study assessed efficacy and safety of IV belimumab plus standard of care (SoC) in black patients with SLE. Primary and key secondary endpoints have been presented; 1 here we focus on efficacy in patients with high disease activity (HDA) and renal manifestations. Methods : EMBRACE (NCT01632241; GSK study 115471) is a multicenter, double-blind, placebo-controlled trial in patients of self-identified black race, >=18 years, with active SLE by ACR criteria at screening. Patients were randomized (2:1) to receive monthly belimumab 10 mg/kg IV or placebo, plus SoC. The primary endpoint was the difference in modified SLE Responder Index (SRI-S2K) response rates between belimumab and placebo. SRI-S2K incorporates the SLEDAI-2K (S2K) proteinuria definition ( >0.5 mg/24 h) rather than the SELENA-SLEDAI (SS) version ( >0.5 mg/24-h increase). A response is defined as >=4-point reduction in S2K, no worsening [increase < 0.3] in Physician's Global Assessment, and no new BILAG A/2 B domain scores. SRI response (SS proteinuria scoring) at Week 52 was a key secondary endpoint. Subgroup analyses of SRI-S2K and SRI in patients with HDA (anti-dsDNA antibody positive, hypocomplementemia, or high SS-S2K scores [SS with S2K proteinuria scoring]) at baseline were performed. Other endpoints included time to renal flare, change from baseline in SS-S2K renal domain, and in proteinuria, over 52 weeks. Results : No significant differences were seen in the mITT population (N=448) for SRI-S2K ( Table ). Among patients meeting HDA definitions at baseline, greater proportions were SRI-S2K responders at Week 52 with belimumab vs placebo; in the high anti-dsDNA group, the difference numerically favored belimumab. Similar results were observed with the SRI. Belimumab patients (mITT) had a 46% lower risk of a renal flare vs placebo (hazard ratio [95% CI]: 0.54 [0.21, 1.36]; p=0.1880). Among those with baseline renal involvement measured by SS-S2K, numerically more belimumab patients experienced improvements in this domain at Week 52 vs placebo (23/55 [41.8%] vs 7/34 [20.6%]). Among those without baseline renal involvement measured by SS-S2K, the percentage worsening at Week 52 was low for both groups (placebo: 9/115 [7.8%], belimumab: 15/244 [6.1%]). In patients with baseline proteinuria >0.5 g/24 h, median (interquartile range) percentage reduction at Week 52 was numerically greater with belimumab (-65.3% [-81.1, -38.8%], n=38) vs placebo (-32.9% [-76.6, 36.3%], n=23; p=0.0558); more of these patients experienced proteinuria normalization (values <=0.5 g/24 h) with belimumab (16/38 [42.1%]) vs placebo (6/23 [26.1%]) at Week 52. No new safety concerns were identified. Conclusion : Black patients with SLE and HDA demonstrate benefits with belimumab vs placebo, with reductions in disease activity and SLEDAI renal domain scores

Background/Purpose : Measuring improvement or worsening is problematic in lupus trials. The British Isles Lupus Assessment Group (BILAG) index often fails to capture sustained decrease in disease activity when the change levels off. The SLE Disease Activity Index (SLEDAI) is inflexible if improvement does not meet a low threshold definition. False positive or negative flares create additional problems. Mild/moderate worsening on the SLEDAI Flare Index (SFI) can be due to insignificant changes. According to an older BILAG flare definition ( >/= 2 new B or 1 new A), which is still commonly used, a false flare occurs if previously improving disease stabilizes, while true worsening is frequently missed when organ scores remain unchanged. A newer BILAG flare definition addresses most of these issues, but fails to account for > 1 feature flaring in a single organ or to allow a moderately severe flare in only 1 organ to rate more than mild. Given the pitfalls of glossary-based measures, we sought the advice of the clinician in determining changes in disease severity. Methods : A simple algorithm for clinician ' s global impression of change (CGIC) was tested during a phase 2 trial of the B Cell modulator, Xmab5871. investigators were asked to rate disease progress at each visit as no change or insignificant change (NC) significant partial improvement (PI), major or complete improvement (MI), significant moderate worsening (MW), or severe worsening (SW). Discrepancies between the CGIC and other instruments were brought to the investigators' attention, but it was emphasized that the clinician ' s opinion could conflict with the technical scoring. Results were collected in an online database along with the BILAG, SLEDAI, PGA and SFI results. Results : Of 104 randomized patients, data from 102 were available from 2-11 visits. The results of the trial have been reported elsewhere; briefly, the primary endpoint, maintenance of improvement, was met by 42% of XmAb5871-treated patients vs 28.6% of the placebo (PBO) group (p=0.18) and time to flare was longer in the XmAb5871 group (p=0.025). Using the CGIC, clinicians rated 445 visits as NC, 148 PI, 64 MI, 84 MW and 8 SW. CGIC was tested as a gold standard for the comparison of other measures of change that are used in SLE trials. Results of this study are summarized in Tables 1 and 2. Conclusion : Clinician ' s opinion, recorded using CGIC, is better reflected by changes of BILAG and PGA than it is by the SLEDAI, which offers fewer gradations of scoring. More patients were free of flare using the CGIC compared to other instruments. In the double-blind trial of Xmab5871 the increased CGIC threshold for defining worsening disease impacted results for patients receiving active treatment more than PBO, suggesting the utility of CGIC as a gold standard for clinical significance