Faculty Bibliography

Systemic lupus erythematosus (SLE) is a significant risk factor for cardiovascular disease. The relationship between SLE and perioperative cardiovascular risks following non-cardiac surgery is uncertain. We investigated associations between a diagnosis of SLE and outcomes following major non-cardiac surgery in a large national database from the United States. Patients age ≥ 18 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data from 2004 to 2014. Systemic lupus erythematosus and perioperative major adverse cardiovascular events (MACE; myocardial infarction, ischemic stroke or death) were defined by ICD-9 diagnosis codes. Perioperative MACE were reported for SLE patients stratified by age and sex. From 2004 to 2014, a total of 17,853,194 hospitalizations for major non-cardiac surgery met study inclusion criteria. SLE was identified in 70,578 (0.4%) hospitalizations. Overall, the frequency of perioperative MACE was higher in patients with vs. without SLE [2.4 vs. 2.0%, p < 0.001; adjusted OR (aOR) 1.25; 95% CI 1.18-1.31]. Perioperative MACE associated with SLE was largely driven by increased death (aOR 1.58 95% CI 1.40-1.77) and myocardial infarction (aOR 1.32; 95% CI 1.05-1.66) in younger patients with SLE. The increased risk of perioperative MACE associated with SLE in younger patients was attenuated with increasing age. A diagnosis of SLE is associated with increased risk of perioperative MACE, particularly among younger patients. Efforts to improve the perioperative management and outcomes of patients with SLE are needed.

Objectives/UNASSIGNED:The study aimed to determine if serum albumin at 12 months predicts long-term renal outcome at 48 months. Data from the NYU SAMPLE (Specimen and Matched Phenotype Linked Evaluation) Lupus Registry were used to compare the performance of albumin, anti-double-stranded DNA, C3/C4, proteinuria and haematuria. Methods/UNASSIGNED:82 patients with SLE with data at time of renal biopsy, at 12 months and at a second visit, and up to 48 months were included. The significance of each biomarker as a predictor of an adverse renal outcome (ARO), defined as doubling of serum creatinine, as creatinine >4 mg/dL if initial >2.5 mg/dL or ESRD, was evaluated in univariate and exploratory multivariable Cox proportional hazards models. Hazard ratios (HRs) for ARO with 95% CIs were generated. The receiver operating characteristic (ROC) curves at 48 months were used to identify the optimal cut-off point for albumin and proteinuria to predict ARO. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for albumin and proteinuria. Results/UNASSIGNED:Serum albumin and proteinuria had statistically significant HRs for ARO (0.140 and 1.459, respectively). The model with both albumin and proteinuria indicated no additional independent contribution of proteinuria to albumin alone. The ROC curves identified cut-offs of 3.7 g/dL for albumin and 0.964 urine protein to creatinine ratio for proteinuria. Albumin had a sensitivity of 94%, specificity of 87%, PPV of 64% and NPV of 98%. Conclusions/UNASSIGNED:This study demonstrates serum albumin >3.7 g/dL is a predictor of a favourable long-term renal outcome. These results support the inclusion of albumin as an outcome in lupus nephritis trials and treat-to-target guidelines.

Background/UNASSIGNED:We examined the usefulness of erythrocyte-bound C4d (EC4d) to monitor disease activity in SLE. Methods/UNASSIGNED:Data and blood samples were collected from three different studies, each of which included longitudinal evaluations using the Physicians Global Assessment (PGA) of disease activity and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE Disease Activity Index (SLEDAI), which was assessed without anti-double-stranded DNA (dsDNA) and low complement C3/C4 (clinical SELENA-SLEDAI). EC4d levels were determined using flow cytometry; other laboratory measures included antibodies to dsDNA, C3 and C4 proteins. Relationships between clinical SELENA-SLEDAI, PGA and the laboratory measures were analysed using linear mixed effect models. Results/UNASSIGNED:The three studies combined enrolled 124 patients with SLE (mean age 42 years, 97% women, 31% Caucasians and 34% African-Americans) followed for an average of 5 consecutive visits (range 2-13 visits). EC4d levels and low C3/C4 status were significantly associated the clinical SELENA-SLEDAI or PGA in each of the three study groups (p<0.05). Multivariate analysis revealed that EC4d levels (estimate=0.94±0.28) and low complement C3/C4 (estimate=1.24±0.43) were both independently and significantly associated with the clinical SELENA-SLEDAI (p<0.01) and PGA. EC4d levels were also associated with the clinical SELENA-SLEDAI (estimate: 1.20±0.29) and PGA (estimate=0.19±0.04) among patients with chronically low or normal C3/C4 (p<0.01). Anti-dsDNA titres were generally associated with disease activity. Conclusion/UNASSIGNED:These data support the association of EC4d with disease activity regardless of complement C3/C4 status and its usefulness in monitoring SLE disease. Additional studies will be required to support these validation data.

OBJECTIVE: Fetal exposure to maternal anti-SSA/Ro antibodies is necessary but not sufficient for the development of autoimmune congenital heart block (CHB), suggesting that other factors, such as fetal genetic predisposition, are important. Given the previously described association between major histocompatibility complex alleles and CHB risk, we undertook the present study to test the hypothesis that a variant form of HLA-C Asn80Lys, which binds with high affinity to an inhibitory killer cell immunoglobulin-like receptor (KIR) and thus renders natural killer (NK) cells incapable of restricting inflammation, contributes to the development of CHB. METHODS: Members of 192 pedigrees in the US and Europe (194 cases of CHB, 91 unaffected siblings, 152 fathers, 167 mothers) and 1,073 out-of-study controls were genotyped on the Immunochip single-nucleotide polymorphism microarray. Imputation was used to identify associations at HLA-C Asn80Lys (Asn, C1; Lys, C2) and KIR. Tests for association were performed using logistic regression. McNemar's test and the pedigree disequilibrium test (PDT) were used for matched analyses between affected and unaffected children. RESULTS: Compared with out-of-study controls of the same sex, the C2 allele was less frequent in the mothers (odds ratio [OR] 0.63, P = 0.0014) and more frequent in the fathers (OR 1.40, P = 0.0123), yielding a significant sex-by-C2 interaction (P = 0.0002). The C2 allele was more frequent in affected siblings than in unaffected siblings (OR 3.67, P = 0.0025), which was consistent with the PDT results (P = 0.016); these results were observed in both sexes and across the US and European cohorts. There was no difference in the frequency of the inhibitory KIR genotype (KIR AA) between affected and unaffected children (P = 0.55). CONCLUSION: These data establish C2 as a novel genetic risk factor associated with CHB. This observation supports a model in which fetuses with C2 ligand expression and maternal anti-SSA/Ro positivity may have impaired NK cell surveillance, resulting in unchecked cardiac inflammation and scarring.