Faculty Bibliography

The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. Although enhanced classical pathway activation by immune complexes was initially thought to be the main contributor to lupus nephritis (LN) pathogenesis, an increasing body of evidence has suggested the alternative and the lectin pathways are also involved. Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.

OBJECTIVE:Delayed detection of lupus nephritis associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. METHODS:275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 U.S. sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. RESULTS:At biopsy, 54 patients had UPCR <1 and 221 had UPCR >1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V, or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at one year. CONCLUSION/CONCLUSIONS:In this prospective study three quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.

OBJECTIVE:To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. METHODS:GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). RESULTS:GPI only. CONCLUSION:Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

BACKGROUND:The American College of Chest Physicians (ACCP) and National Institutes for health and care Excellence in the United Kingdom (NICE) recommend that patients who are high risk for thrombotic events but require cessation of oral anticoagulation with warfarin, due to bleeding risk of a planned procedure, undergo bridging therapy with heparin. However, those conditions which are considered high risk are not universal, nor do guidelines differentiate between low molecular weight heparin (LMWH) and unfractionated heparin. Triple positive antiphospholipid syndrome (APS) is a thrombophilic state with a very high risk for thrombotic events during periods of anticoagulation cessation. Patients with secondary antiphospholipid syndrome in the setting of SLE may be at an even greater risk of thrombotic events during the perioperative period. PURPOSE/OBJECTIVE:Along with a review of the literature for perioperative management in APS we present three cases of triple positive secondary APS in systemic lupus erythematosus (SLE) patients who had severe thrombotic complications after cessation of their oral anticoagulation despite being bridged with LWMH. CONCLUSION/CONCLUSIONS:Given the severity and rapidity of thrombotic complications with low molecular weight heparin bridging, we propose that all patients with triple positive APS, especially secondary APS with SLE should undergo bridging therapy with intravenous UFH to reduce time without anticoagulation and minimize risk of thrombotic complications. Furthermore, we propose that NICE include APS in the list of medical conditions which are high risk for thrombotic complications and require bridging therapy.

INTRODUCTION/BACKGROUND:Treatment failures for lupus nephritis (LN) are high with 10%-30% of patients progressing to end-stage renal disease (ESRD) within 10 years. Interstitial fibrosis/tubular atrophy (IFTA) is a predictor of progression to ESRD. Prior studies suggest that tubulointerstitial injury secondary to proteinuria in LN is mediated by complement activation in the tubules, specifically through the membrane attack complex (MAC). This study aimed to investigate the associations between tubular MAC deposition with IFTA and proteinuria. METHODS:In this cross-sectional study, LN kidney biopsies were assessed for MAC deposition by staining for Complement C9, a component of the MAC. Chromogenic immunohistochemistry was performed on paraffin-embedded human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197). Tubular C9 staining intensity was analysed as present versus absent. IFTA was defined as minimal (<10%), mild (10%-24%), moderate (25%-50%) and severe (>50%). RESULTS:Renal biopsies from 30 patients with LN were studied. There were 24 (80%) female sex, mean age (SD) was 33 (12) years old and 23 (77%) had pure/mixed proliferative LN. Tubular C9 staining was present in 7 (23%) biopsies. 27 patients had minimal-to-mild IFTA and 3 patients had moderate IFTA. Among the C9 + patients, 3 (43%) had moderate IFTA as compared with none in the C9- group, p=0.009. C9 + patients had higher median (IQR) proteinuria as compared with C9- patients: 6.2 g (3.3-13.1) vs 2.4 g (1.3-4.6), p=0.001 at the time of biopsy. There was no difference in estimated glomerular filtration rate (eGFR) between the C9 + and C9- groups. CONCLUSION/CONCLUSIONS:This study demonstrated that tubular MAC deposition is associated with higher degree of IFTA and proteinuria, which are predictors of progression to ESRD. These results suggest that tubular MAC deposition may be useful in classification of LN. Understanding the role of complement in tubulointerstitial injury will also identify new avenues for LN treatment.

BACKGROUND:Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. PURPOSE/OBJECTIVE:To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. FIELD STRENGTH/SEQUENCE/UNASSIGNED:Stimulated echo acquisition mode (STEAM) sequence at 3 T. ASSESSMENT/RESULTS:MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. STATISTICAL TESTS/UNASSIGNED:Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. RESULTS:SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). DATA CONCLUSION/UNASSIGNED:SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. EVIDENCE LEVEL/UNASSIGNED:2 TECHNICAL EFFICACY: Stage 2.

OBJECTIVE:Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN. METHODS:). Podocyte cell line gene expression was measured by real-time PCR. RESULTS:expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION/CONCLUSIONS:Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.

OBJECTIVES/OBJECTIVE:Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. METHODS:We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. RESULTS:Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. CONCLUSION/CONCLUSIONS:Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

OBJECTIVE:To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multi-ethnic/racial cohort of patients with systemic lupus erythematosus (SLE). METHODS:90 SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; IFN-γ production to assess T cell responses was measured by ELISpot. Disease activity was measured by the hybrid SLE disease activity index (SLEDAI) and flares were assigned by the SELENA/SLEDAI flare index. RESULTS:Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD than controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-dsDNA level prior to vaccination associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 Spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and antigen-specific IFN-γ production determined by ELISpot. In a subset of patients with poor antibody responses, IFN-γ production was likewise diminished. Pre-/post-vaccination SLEDAI scores were similar. Only 11.4% of patients had a post-vaccination flare; 1.3% were severe. CONCLUSION/CONCLUSIONS:In a multi-ethnic/racial study of SLE patients 29% had a low response to the COVID-19 vaccine which was associated with being on immunosuppression. Reassuringly, disease flares were rare. While minimal protective levels remain unknown, these data suggest protocol development is needed to assess efficacy of booster vaccination.