Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

The First Statewide Implementation of a Regional Disaster Teleconsultation System to Expand Critical Care Surge Capacity: A Case Study in Vermont.

Background: In December 2021, the Region 1 Disaster Health Response System, the state of Vermont, and the National Emergency Tele-Critical Care Network partnered to provide statewide access to disaster teleconsultations during COVID-19 surge conditions. In this case report, we describe how a disaster teleconsultation system was implemented in Vermont to provide access to temporary tele-critical care consultations during the Omicron COVID-19 surge. Methods: We measured the time from request of service to implementation and calculated descriptive statistics. Results: Seven of Vermont's 14 hospitals requested the service. Despite a technology solution capable of providing services within hours, mean time to service implementation was 27 days (interquartile range 20-41 days). Conclusions: Integration of disaster teleconsultation systems into state and local emergency management plans are needed to bring administrative start-up times in line with technical readiness.

Assessment of antibody levels to SARS-CoV-2 in patients with idiopathic inflammatory myopathies receiving treatment with intravenous immunoglobulin.

Antibodies to Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) have been reported in pooled healthy donor plasma and intravenous immunoglobulin products (IVIG). It is not known whether administration of IVIG increases circulating anti-SARS-CoV-2 antibodies (COVID ab) in IVIG recipients. COVID ab against the receptor binding domain of the spike protein were analyzed using a chemiluminescent microparticle immunoassay in patients with idiopathic inflammatory myopathies (IIM) both receiving and not receiving IVIG (IVIG and non-IVIG group, respectively). No significant differences in COVID ab levels were noted between IVIG and non-IVIG groups (417 [67-1342] AU/mL in IVIG vs 5086 [43-40,442] AU/mL in non-IVIG, p = 0.11). In linear regression models including all post-vaccination patient samples, higher number of vaccine doses was strongly associated with higher COVID ab levels (2.85 [1.21, 4.48] log AU/mL, regression coefficient [Formula: see text] [95% CI], p = 0.001), while use of RTX was associated with lower ab levels (2.73 [- 4.53, - 0.93] log AU/mL, [Formula: see text][95%CI], p = 0.004). In the IVIG group, higher total monthly doses of IVIG were associated with slightly higher COVID ab levels (0.02 [0.002-0.05] log AU/mL, p = 0.04). While patients on IVIG did not have higher COVID ab levels compared to the non-IVIG group, higher monthly doses of IVIG were associated with higher circulating levels of COVID ab in patients receiving IVIG, particularly in patients concomitantly receiving RTX. Our findings suggest that IIM patients, especially those at increased risk of COVID infection and worse COVID outcomes due to RTX therapy may have protective benefits when on concurrent IVIG treatment.

Hospital-Level Implementation Barriers, Facilitators, and Willingness to Use a New Regional Disaster Teleconsultation System: Cross-Sectional Survey Study.

BACKGROUND: The Region 1 Disaster Health Response System project is developing new telehealth capabilities to provide rapid, temporary access to clinical experts across US jurisdictions to support regional disaster health response. OBJECTIVE: To guide future implementation, we identified hospital-level barriers, facilitators, and willingness to use a novel regional peer-to-peer disaster teleconsultation system for disaster health response. METHODS: We used the National Emergency Department Inventory-USA database to identify all 189 hospital-based and freestanding emergency departments (EDs) in New England states. We digitally or telephonically surveyed emergency managers regarding notification systems used for large-scale no-notice emergency events, access to consultants in 6 disaster-relevant specialties, disaster credentialing requirements before system use, reliability and redundancy of internet or cellular service, and willingness to use a disaster teleconsultation system. We examined state-wise hospital and ED disaster response capability. RESULTS: Overall, 164 (87%) hospitals and EDs responded-126 (77%) completed telephone surveys. Most (n=148, 90%) receive emergency notifications from state-based systems. Forty (24%) hospitals and EDs lacked access to burn specialists; toxicologists, 30 (18%); radiation specialists, 25 (15%); and trauma specialists, 20 (12%). Among critical access hospitals (CAHs) or EDs with <10,000 annual visits (n=36), 92% received routine nondisaster telehealth services but lacked toxicologist (25%), burn (22%), and radiation (17%) specialist access. Most hospitals and EDs (n=115, 70%) require disaster credentialing of teleconsultants before system use. Among 113 hospitals and EDs with written disaster credentialing procedures, 28% expected completing disaster credentialing within 24 hours, and 55% within 25-72 hours, which varied by state. Most (n=154, 94%) reported adequate internet or cellular service for video-streaming; 81% maintained cellular service despite internet disruption. Fewer rural hospitals and EDs reported reliable internet or cellular service (19/22, 86% vs 135/142, 95%) and ability to maintain cellular service with internet disruption (11/19, 58% vs 113/135, 84%) than urban hospitals and EDs. Overall, 133 (81%) were somewhat or very likely to use a regional disaster teleconsultation system. Large-volume EDs (annual visits ≥40,000) were less likely to use the service than smaller ones; all CAHs and nearly all rural hospitals or freestanding EDs were likely to use disaster consultation services. Among hospitals and EDs somewhat or very unlikely to use the system (n=26), sufficient consultant access (69%) and reluctance to use new technology or systems (27%) were common barriers. Potential delays (19%), liability (19%), privacy (15%), and hospital information system security restrictions (15%) were infrequent concerns. CONCLUSIONS: Most New England hospitals and EDs have access to state emergency notification systems, telecommunication infrastructure, and willingness to use a new regional disaster teleconsultation system. System developers should focus on ways to improve telecommunication redundancy in rural areas and use low-bandwidth technology to maintain service availability to CAHs and rural hospitals and EDs. Policies and procedures to accelerate and standardize disaster credentialing are needed for implementation across jurisdictions.

Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination.

BACKGROUND: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. METHODS: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status. RESULTS: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. CONCLUSION: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Cardiovascular events and risk in patients with systemic lupus erythematosus: Systematic literature review and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that typically affects women aged 16-55 years. Cardiovascular disease (CVD) is a well-recognized complication of SLE. This systematic literature review and meta-analysis evaluated the relative risk (RR; compared with non-SLE controls), absolute risk (AR; as incidence proportion, n/N), and incidence rate (IR) of CVD events (including stroke, myocardial infarction [MI], and CVD [composite or undefined]) in adult patients with SLE. The RR of CV risk factors (including hypertension, diabetes, and metabolic syndrome [MetS]) was also examined. METHODS: PubMed and Embase were searched on September 10, 2020. Observational studies published between January 2010 and September 2020 that reported RR, AR, and/or IR of CVD events, or RR of CV risk factors, were eligible. Pooled risk estimates were calculated using a random-effects model. RESULTS: Forty-six studies (16 cross-sectional, 15 retrospective cohort, 14 prospective cohort, and 1 case-control) were included in meta-analyses. Most studies were considered high quality (Critical Appraisal Skills Programme checklists). Compared with adults without SLE, patients with SLE had statistically significantly higher RRs (95% CIs) of stroke (2.51 [2.03-3.10]; 12 studies), MI (2.92 [2.45-3.48]; 11 studies), CVD (2.24 [1.94-2.59]; 8 studies), and hypertension (2.70 [1.48-4.92]; 7 studies). RRs of diabetes (1.24 [0.78-1.96]; 3 studies) and MetS (1.49 [0.95-2.33]; 7 studies) were elevated but not significant. RRs of stroke and MI were generally higher in younger versus older patients with SLE. In patients with SLE, the pooled estimate of AR (95% CI) was 0.03 (0.02-0.05), 0.01 (0.00-0.02), and 0.06 (0.03-0.10) for stroke (7 studies), MI (6 studies), and CVD (8 studies), respectively. The pooled estimate of IR per 1000 person-years (95% CI) was 4.72 (3.35-6.32), 2.81 (1.61-4.32), and 11.21 (8.48-14.32) for stroke (10 studies), MI (6 studies), and CVD (8 studies), respectively. Although heterogeneity (based on I2 value) was high in most analyses, sensitivity analyses confirmed the robustness of the pooled estimates. CONCLUSIONS: This meta-analysis found an increased risk of stroke, MI, CVD, and hypertension in patients with SLE compared with the general population, despite substantial heterogeneity across the included studies.

Baseline Elevations of Leukotriene Metabolites and Altered Plasmalogens Are Prognostic Biomarkers of Plaque Progression in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is associated with an increased incidence of acute and chronic cardiovascular disease as compared to the general population. This study uses a comprehensive metabolomic screen of baseline sera from lupus patients to identify metabolites that predict future carotid plaque progression, following 8-9 years of follow-up. Nine patients had SLE without plaque progression, 8 had SLE and went on to develop atherosclerotic plaques (SLEPP), and 8 patients were controls who did not have SLE. The arachidonic acid pathway metabolites, leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE), and the oxidized lipids 9/13-hydroxyoctodecadienoic acid (HODE) were found to be significantly altered (p < 0.05 and fold-change >2) in SLEPP patients compared to SLE patients without plaque progression. SLEPP patients also exhibited significantly altered levels of branched chain amino acid (BCAA) metabolites and plasmalogens compared to the non-SLE controls. Taken together with the rich literature on these metabolites, these findings suggest that the identified metabolites may not only be prognostic of cardiovascular disease development in SLE patients, but they may also be active drivers of atheroma formation. Early identification of these high risk SLE patients may help institute preventive measures early in the disease course.

Assessing the validity of QRISK3 in predicting cardiovascular events in systemic lupus erythematosus.

OBJECTIVES: Traditional cardiovascular risk calculators such as the Framingham Risk Score (FRS) have been shown to underestimate risk in patients with SLE. The QRISK3 calculator is unique in including SLE and corticosteroid use as risk factors. This study aims to assess the validity of QRISK3 compared with other cardiovascular risk models in a cohort of patients with SLE in the USA. METHODS: We studied a prospective cohort of 366 adult patients with SLE without history of any cardiovascular event and followed them for 10 years. We compared the diagnostic performance of QRISK3 with FRS, modified FRS, Atherosclerotic Cardiovascular Disease (ASCVD), and Predictors of Risk for Elevated Flares, Damage Progression and Increased Cardiovascular Disease in Patients with SLE (PREDICTS). RESULTS: Sixty-four of the 366 patients (17.4%) experienced at least one cardiovascular event during the 10-year follow-up period. Of these patients 45% had a QRISK3 score >10%, whereas 20.5% of patients who did not have an event had a QRISK3 score >10% (p<0.001). The corresponding numbers for FRS, modified FRS, ASCVD and PREDICTS were 11.0% vs 7.2% (p=ns), 40.6% vs 28.0% (p=0.05), 12.2% vs 5.9% (p=ns), and 77% vs 32.1% (p<0.001), respectively. The areas under the receiver operating characteristic curve using QRISK3 >10% and high-risk PREDICTS were both larger than those using ASCVD >10%, FRS >10% and modified FRS >10%. CONCLUSIONS: Both QRISK3 and PREDICTS demonstrated better performance in predicting risk of cardiovascular disease in this cohort of patients with SLE compared with FRS, modified FRS and ASCVD.

A Panel of Biomarkers Associates With Increased Risk for Cardiovascular Events in Women With Systemic Lupus Erythematosus.

OBJECTIVE: The increase in cardiovascular events (CVEs) in systemic lupus erythematosus (SLE) is not fully explained by traditional risk factors. We previously identified four biomarkers (proinflammatory high-density lipoprotein, leptin, soluble TNF-like weak inducer of apoptosis (sTWEAK), and homocysteine) that we combined with age and diabetes to create the predictors of risk for elevated flares, damage progression, and increased cardiovascular diseasein patients with SLE (PREDICTS) risk profile. PREDICTS more accurately identified patients with SLE at risk for progression of subclinical atherosclerosis than any individual variable. We examined whether PREDICTS can also identify patients with SLE at risk for future CVEs. METHODS: A total of 342 patients with SLE and 155 matched control subjects participated in this longitudinal prospective study. A high PREDICTS score was defined as three or more predictors or diabetes + one or more predictor. The biomarkers were measured at baseline using published methods. All major adverse CVEs (MACEs) were confirmed by medical record review. RESULTS: During 116 months of follow-up, 5% of patients with SLE died, 12% had a cerebrovascular event, and 5% had a cardiac event. Overall, 20% of patients with lupus experienced any new MACE compared with 5% of control subjects (P < 0.0001). More patients with SLE with a new MACE had high PREDICTS score at baseline (77%) versus patients with no new events (34%) (P < 0.0001). High baseline PREDICTS score also associated with cerebrovascular (P < 0.0001) and cardiac events (P < 0.0001) in SLE. Using Cox regression, a baseline high PREDICTS score associated with a 3.7-fold increased hazard ratio (HR) for a new MACE (P < 0.0001) in SLE. Hypertension (HR = 2.1; P = 0.006) was also a risk. CONCLUSION: A high PREDICTS score and hypertension confer increased risk for new MACEs in patients with SLE.

Cardiovascular disease in systemic lupus erythematosus.

There is a well-known increased risk for cardiovascular disease that contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Major adverse cardiovascular events and subclinical atherosclerosis are both increased in this patient population. While traditional cardiac risk factors do contribute to the increased risk that is seen, lupus disease-related factors, medications, and genetic factors also impact the overall risk. SLE-specific inflammation, including oxidized lipids, cytokines, and altered immune cell subtypes all are likely to play a role in the pathogenesis of atherosclerotic plaques. Research is ongoing to identify biomarkers that can help clinicians to predict which SLE patients are at the greatest risk for cardiovascular disease (CVD). While SLE-specific treatment regimens for the prevention of cardiovascular events have not been identified, current strategies include minimization of traditional cardiac risk factors and lowering of overall lupus disease activity.

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis.

OBJECTIVE: To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). METHODS: In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. RESULTS: Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/µl in the RCB group versus 11 cells/µl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. CONCLUSION: The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

Utility of the AVISE Connective Tissue Disease test in predicting lupus diagnosis and progression.

Background: The AVISE Connective Tissue Disease (CTD) test uses autoantibody, erythrocyte-bound C4d (EC4d) and B-cell-bound C4d (BC4d) levels to aid in diagnoses of SLE, other CTDs and fibromyalgia. We evaluated the utility of the AVISE CTD test in predicting SLE disease development and damage progression. Methods: Patients who had undergone AVISE CTD testing were assessed for SLE diagnosis by the Systemic Lupus International Collaborating Clinics (SLICC) and American College of Rheumatology criteria and for SLE damage by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at the time of AVISE testing (t=0) and 2 years later (t=2). Results: Among 117 patients without a previous diagnosis of SLE, 65% of patients who tested positive developed SLE at t=2, compared with 10.3% of patients who tested non-positive (p<0.0001). AVISE-positive patients fulfilled significantly more SLICC diagnostic criteria than AVISE-non-positive patients at both t=0 (3.8±2.1 vs 1.9±1.1, p=0.001) and t=2 (4.5±2.2 vs 2.1±1.2, p<0.0001). AVISE-positive patients also had had significantly higher SDI at t=2 (1.9±1.3 vs 1.03±1.3, p=0.01). BC4d levels correlated with the number of SLICC criteria at t=0 (r=0.33, p<0.0001) and t=2 (r=0.34, p<0.0001), as well as SDI at t=0 (r=0.25, p=0.003) and t=2 (r=0.26, p=0.002). Conclusions: The AVISE CTD test can aid in SLE evaluation by predicting SLE disease development and future damage progression.

Comparison of PREDICTS atherosclerosis biomarker changes after initiation of new treatments in patients with SLE.

OBJECTIVE: Patients with SLE have an increased risk of atherosclerosis (ATH) that is not adequately explained by traditional risk factors. We previously described the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular disease in PaTients with SLE (PREDICTS) atherosclerosis-risk panel, which includes proinflammatory HDL (piHDL), leptin, soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) and homocysteine, as well as age and diabetes. A high PREDICTS score confers 28-fold increased odds for future atherosclerosis in SLE. The aim of this study is to determine whether PREDICTS biomarkers are modifiable by common lupus therapies. METHODS: This prospective observational study included SLE subjects started on new lupus treatments. Leptin, sTWEAK, homocysteine and antioxidant function of HDL were measured at baseline (prior to drug initiation), 6 weeks and 12 weeks. RESULTS: 16 subjects started mycophenolate (MMF), 18 azathioprine (AZA) and 25 hydroxychloroquine (HCQ). In MMF-treated subjects, HDL function progressively improved from 2.23 ± 1.32 at baseline to 1.37±0.81 at 6 weeks (p=0.02) and 0.93±0.54 at 12 weeks (p=0.009). sTWEAK levels also improved in MMF-treated subjects from 477.5±447.1 to 290.3±204.6 pg/mL after 12 weeks (p=0.04), but leptin and homocysteine levels were not significantly changed. In HCQ-treated subjects, only HDL function improved from 1.80±1.29 at baseline to 1.03±0.74 after 12 weeks (p=0.05). There were no changes in the AZA group. MMF treatment was still associated with significant improvements in HDL function after accounting for potential confounders such as total prednisone dose and changes in disease activity. Overall, the mean number of high-risk PREDICTS biomarkers at week 12 significantly decreased in the entire group of patients started on a new lupus therapy (2.1±0.9 to 1.8±0.9, p=0.02) and in the MMF-treated group (2.4±0.8 vs 1.8±0.9, p=0.003), but not in the AZA or HCQ groups. In multivariate analysis, the odds of having a high PREDICTS atherosclerosis risk score at 12 weeks were lower with MMF treatment (OR 0.002, 95% CI 0.000 to 0.55, p=0.03). CONCLUSIONS: 12 weeks of MMF therapy improves the overall PREDICTS atherosclerosis biomarker profile. Further studies will determine whether biomarker changes reflect decreases in future cardiovascular events.

Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3-4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. METHODS: Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. RESULTS: The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. CONCLUSION: This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.

BACKGROUND: A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS: Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS: We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS: In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).

Effects of Repository Corticotropin Injection on Medication Use in Patients With Rheumatologic Conditions: A Claims Data Study.

Background: Currently, specific studies identifying how repository corticotropin injection (RCI) is used in rheumatologic conditions are lacking. This is a first step to familiarize the trends of demographics using RCI as well as other medication use. Objective: RCI may produce anti-inflammatory as well as immune-modulatory effects. The purpose of this study is to examine the demographics of those who use RCI and the change in medication use, specifically prednisone, after RCI initiation. Method: This study used the Symphony Health Solutions (SHA) Claims database from 2008 to 2015. International Classification of Disease, Ninth Revision, codes were used to identify rheumatologic conditions including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and polymyositis. Information including RCI dose and concomitant medication uses was also obtained. Results: A total of 2749 patients with rheumatologic conditions receiving RCI were investigated for demographic information, and a total of 1048 patients with rheumatologic conditions on RCI were examined for medication use. The use of nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and biologics overall decreased significantly in all 3 rheumatologic conditions except biologics in dermatomyositis/polymyositis. In addition, mean prednisone dose before and after RCI use significantly decreased one quarter (12 weeks) after RCI initiation. Conclusion: Claims-based study on RCI use indicates that RCI use might reduce use of prednisone, disease-modifying anti-rheumatic drugs, and other biologics. Further prospective study is needed.

Paraoxonase-3 is depleted from the high-density lipoproteins of autoimmune disease patients with subclinical atherosclerosis.

Patients with autoimmune diseases have a significantly increased risk of developing cardiovascular disease. In disease, high-density lipoprotein (HDL) particles lose their anti-inflammatory and antioxidant properties and become dysfunctional. The purpose of this study was to test the hypothesis that alterations in the HDL proteomic profile are associated with subclinical atherosclerosis and HDL dysfunction in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes. Targeted proteomics was used to quantify the relative abundance of 18 proteins in HDL from SLE patients with and without atherosclerotic plaque detectable by carotid ultrasound. Changes in the proteomic profile were compared against the in vitro ability of HDL to protect against lipid oxidation. The same proteins were quantified in HDL from patients with type 1 diabetes with or without coronary artery calcification as determined by computed tomography. In each population, paraoxonase-3 (PON3), a potent antioxidant protein, was depleted from the HDL of patients with subclinical atherosclerosis. PON3 expression in HDL was positively correlated with HDL antioxidant function. These results suggest that PON3 may be an important protein in preventing atherosclerosis and highlight the importance of antioxidant proteins in the prevention of atherosclerosis in vivo.

Pathogenesis and treatment of atherosclerosis in lupus.

The prevalence of atherosclerosis (ATH) is higher in patients with systemic lupus erythematosus (SLE) and occurs at an earlier age. The lupus-related factors that account for this increased risk are likely numerous and related to the factors described in this article. Identifying of at-risk subjects and increasing the understanding of pathogenesis of ATH in SLE is critical for improving the quality of care and improving mortality in this vulnerable population.