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Urine Proteomics and Renal Single Cell Transcriptomics Implicate IL-16 in Lupus Nephritis

Fava, Andrea; Rao, Deepak A; Mohan, Chandra; Zhang, Ting; Rosenberg, Avi; Fenaroli, Paride; Belmont, H Michael; Izmirly, Peter; Clancy, Robert; Monroy Trujillo, Jose; Fine, Derek; Arazi, Arnon; Berthier, Celine C; Davidson, Anne; James, Judith A; Diamond, Betty; Hacohen, Nir; Wofsy, David; Raychaudhuri, Soumya; Apruzzese, William; Buyon, Jill; Petri, Michelle
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.
PMID: 34783463
ISSN: 2326-5205
CID: 5049062

High Systemic Type I Interferon Activity is Associated with Active Class III/IV Lupus Nephritis

Iwamoto, Taro; Dorschner, Jessica M; Selvaraj, Shanmugapriya; Mezzano, Valeria; Jensen, Mark A; Vsetecka, Danielle; Amin, Shreyasee; Makol, Ashima; Osborn, Thomas; Moder, Kevin; Chowdhary, Vaidehi R; Izmirly, Peter; Belmont, H Michael; Clancy, Robert M; Buyon, Jill P; Wu, Ming; Loomis, Cynthia A; Niewold, Timothy B
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.
PMID: 34782453
ISSN: 0315-162x
CID: 5049012

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19

Gomes, Claudia; Zuniga, Marisol; Crotty, Kelly A; Qian, Kun; Tovar, Nubia Catalina; Lin, Lawrence Hsu; Argyropoulos, Kimon V; Clancy, Robert; Izmirly, Peter; Buyon, Jill; Lee, David C; Yasnot-Acosta, Maria Fernanda; Li, Huilin; Cotzia, Paolo; Rodriguez, Ana
High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations.
PMCID:8441539
PMID: 34504035
ISSN: 2575-1077
CID: 5061302

Evaluation of Immune Response and Disease Status in SLE Patients Following SARS-CoV-2 Vaccination

Izmirly, Peter M; Kim, Mimi Y; Samanovic, Marie; Fernandez-Ruiz, Ruth; Ohana, Sharon; Deonaraine, Kristina K; Engel, Alexis J; Masson, Mala; Xie, Xianhong; Cornelius, Amber R; Herati, Ramin S; Haberman, Rebecca H; Scher, Jose U; Guttmann, Allison; Blank, Rebecca B; Plotz, Benjamin; Haj-Ali, Mayce; Banbury, Brittany; Stream, Sara; Hasan, Ghadeer; Ho, Gary; Rackoff, Paula; Blazer, Ashira D; Tseng, Chung-E; Belmont, H Michael; Saxena, Amit; Mulligan, Mark J; Clancy, Robert M; Buyon, Jill P
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.
PMCID:8426963
PMID: 34347939
ISSN: 2326-5205
CID: 5046532

Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus

Hartl, Johannes; Serpas, Lee; Wang, Yueyang; Rashidfarrokhi, Ali; Perez, Oriana A; Sally, Benjamin; Sisirak, Vanja; Soni, Chetna; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Caiello, Ivan; Bracaglia, Claudia; Volpi, Stefano; Ghiggeri, Gian Marco; Chida, Asiya Seema; Sanz, Ignacio; Kim, Mimi Y; Belmont, H Michael; Silverman, Gregg J; Clancy, Robert M; Izmirly, Peter M; Buyon, Jill P; Reizis, Boris
Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
PMID: 33783474
ISSN: 1540-9538
CID: 4830692

Hydroxychloroquine is associated with lower platelet activity and improved vascular health in systemic lupus erythematosus

Cornwell, MacIntosh Grant; Luttrell-Williams, Elliot S; Golpanian, Michael; El Bannoudi, Hanane; Myndzar, Khrystyna; Izmirly, Peter; Belmont, H Michael; Katz, Stuart; Smilowitz, Nathaniel R; Engel, Alexis; Clancy, Robert; Ruggles, Kelly; Buyon, Jill P; Berger, Jeffrey S
OBJECTIVE:Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS:Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS:Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION/CONCLUSIONS:HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.
PMID: 33737451
ISSN: 2053-8790
CID: 4818092

1037 Reducing the burden of fetal surveillance using the negative predictive value of anti-Ro antibody titer [Meeting Abstract]

Kaizer, A; Buyon, J; Chang, M; Clancy, R; Tebo, A; Cuneo, B
Objective: The risk of fetal atrioventricular block (AVB) in anti-Ro exposed pregnancies approximates 2% with no prior affected pregnancies. Antibody titer may be contributory to AVB, but there are no data on the negative predictive value (NPV) of antibody titer identifying fetuses unlikely to develop AVB, thus averting costly serial echocardiographs currently recommended for all anti-Ro pregnancies. Using a commercial core laboratory specifying anti-Ro52 and anti-Ro60 antibodies, we sought to develop a threshold level identifying fetuses unlikely to develop AVB, thus averting costly echo surveillance currently recommend for all anti Ro pregnancies.
Study Design: We performed a retrospective multicenter (Children's Hospital Colorado fetal database and NYU Research Registry for Neonatal Lupus) review of women screened for anti-Ro antibodies by several local commercial laboratories because of rheumatic disease or a previous child with AVB. Serum from anti-Ro positive women was sent to a 2nd commercial core laboratory at Associated Regional and University Pathologists laboratories (Salt Lake City, UT) to determine anti-Ro52 and anti-Ro60 antibody (TheraDiag, France) levels. We calculated the NPV individually of anti-Ro52 and anti-Ro60 and the two combined (anti-Ro) using a logistic regression model and a parallel testing strategy.
Result(s): Of 332 women, 142 had a child with AVB and 190 never had a child with AVB. An anti-Ro60 threshold of <101 AU/mL achieved 90% NPV for AVB with 79 titers falling below the threshold (Figure). The logistic regression model with both anti-Ro52 and anti-Ro60 using a threshold of a predicted probability <22% achieved a 91% NPV with a larger sample size below the cutoff (n=87) than any other method (Table).
Conclusion(s): While we could not determine a cutoff for no AVB, the likelihood of AVB developing if the maternal anti-Ro60 titer <101 AU/mL is 10%. Our logistic regression model gives a likelihood of 9% to develop fetal AVB below the threshold. These data may help to guide surveillance of future anti-Ro positive pregnancies. [Formula presented] [Formula presented]
Copyright
EMBASE:2010867559
ISSN: 0002-9378
CID: 4783622

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation

Friedman, Deborah M; Kim, Mimi; Costedoat-Chalumeau, Nathalie; Clancy, Robert; Copel, Joshua; Phoon, Colin K; Cuneo, Bettina; Cohen, Rebecca; Masson, Mala; Wainwright, Benjamin J; Zahr, Noel; Saxena, Amit; Izmirly, Peter; Buyon, Jill P
Background - Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) is being considered as prophylaxis and treatment of COVID-19. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. Methods - To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal electrocardiograms (ECGs) and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. Results - Forty-five ECGs were available for QTc measurement, and levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of HCQ and the neonatal QTc (R = 0.02, P = 0.86) or the mean of HCQ values obtained throughout each individual pregnancy and the QTc (R = 0.04, P = 0.80). In total 5 (11%; 95% CI: 4% - 24%) neonates had prolongation of the QTc > 2SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. Conclusions - In aggregate, these data provide reassurances that the maternal use of HCQ is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered.
PMID: 32907357
ISSN: 1941-3084
CID: 4589322

Urine Proteomic Classifiers Predict Renal Histological Activity and Chronicity Indices and May Predict Treatment Response in Lupus Nephritis [Meeting Abstract]

Weeding, E; Fava, A; Buyon, J; Belmont, H M; Izmirly, P; Clancy, R; Monroy-Trujillo, J; Fine, D; Apruzzese, W; Mischak, H; Petri, M
Background/Purpose: Current management of lupus nephritis (LN) is guided by histopathological features on kidney biopsy and measurement of proteinuria. Urine proteomics is a non-invasive source of novel biomarkers which may better reflect the complex dynamic immunobiology of LN in real time. Two composite measures include CKD273, which can predict the risk of progression of chronic kidney disease in the general population, and LN120, which was designed to diagnose LN. Both are multidimensional urine proteomic classifiers consisting of 273 or 120 peptides, respectively, with major components including collagen fragments, abundant blood-derived proteins, and proteins involved in inflammation. We investigated the ability of these classifiers to predict traditional biopsy features and disease response in LN.
Method(s): A total of 31 adults with biopsy-proven LN were included in this study. All participants met the SLICC and 2019 EULAR/ACR Classification Criteria for SLE based on a spot urine protein-to-creatinine ratio of >0.5 and class III, IV, and/or V LN on renal biopsy. Urine samples were collected at week 0 (at the time of renal biopsy) and week 12 and then subjected to peptidome analysis using a capillary electrophoresis-mass spectrometry (CE-MS) platform. This peptidome data was used to calculate CKD273 and LN120 classifiers at each time point. LN response status was determined at week 52 based on proteinuria, creatinine, and prednisone dosage (no more than 10 mg daily). Spearman's rank correlation and t-tests were used to compare proteomic classifiers with renal biopsy characteristics and response.
Result(s): At week 0, both CKD273 and LN120, but not proteinuria, exhibited a moderate to strong correlation with histological activity index on renal biopsy (Figure 1; rho = 0.65 with p = 0.00024 for CKD273; rho = 0.47 with p = 0.013 for LN120). CKD273 also correlated with chronicity index (rho = 0.54, p = 0.0037). Neither classifier significantly correlated with lupus nephritis ISN class. With respect to response, CKD273 and LN120 were not significantly different between groups at week 0. However, a reduction in LN120 was observed in 100% of complete responders, 60% of partial responders, and 50% of non-responders at week 12 (Figure 2). The magnitude of this change in LN120 in complete responders versus non-responders did not reach statistical significance (p = 0.13), though this is potentially because of the small number of responders with CE-MS data available at both time points (n = 4). CKD273 did not significantly change with time in any response group (Figure 3).
Conclusion(s): This work provides proof of concept that urine proteomic classifiers can noninvasively predict histological activity and chronicity in LN. Complete responders, but not partial responders or non-responders, exhibited an impressive numerical decrease in LN120 by week 12, suggesting that proteomic scores may track with and predict a durable treatment response. Larger studies are needed to validate these findings
EMBASE:634235215
ISSN: 2326-5205
CID: 4804772

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation [Meeting Abstract]

Friedman, D; Kim, M; Costedoat-Chalumeau, N; Clancy, R; Copel, J; Phoon, C; Cuneo, B; Cohen, R; Masson, M; Wainwright, B; Zahr, N; Saxena, A; Izmirly, P; Buyon, J
Background/Purpose: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) was initially considered as a prophylaxis and treatment of COVID-19. Despite this optimism, more extensive reports have significantly dampened the promise of efficacy, however cardiac toxicity has surfaced raising attention to this complication. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, this initiative leveraged a unique opportunity to evaluate neonatal electrocardiograms (ECGs) in the context of HCQ levels to address any potential cardiotoxicity.
Method(s): Neonatal ECGs and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies. The ECGs of affected newborns who met the primary outcome of advanced block were not included in this safety study so that the results only reflect those infants with no clinical cardiac disease. Using the Bazett formula to correct for heart rate, corrected QT (QTc) intervals were calculated and compared to age-matched normal values. For reference, the median (2nd percentile - 98th percentile) values for QTc were 413 (378-448) msec in males, and 420 (379-462) msec in females. QTc intervals were recorded in the absence of knowledge of the HCQ levels. Values exceeding 448 msec for males and 462 msec for females were considered abnormal. Levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure.
Result(s): There were 45 ECGs available for interpretation within the first 4 months of life in unaffected infants. Overall, there was no correlation between cord blood levels of HCQ and the QTc (R = 0.02, P = 0.86) or the average value of HCQ levels obtained during each individual pregnancy and cord blood and the QTc (R = 0.04, P = 0.80), as shown in Figure 1A and Figure 1B. Likewise there was no correlation between the average of the maternal HCQ levels obtained at each trimester and delivery plus cord levels and the QTc on the ECGs of the 31 infants evaluated on day of life 1-4 (R = 0.08, P = 0.63) or those of the 14 children older than 4 days (R = 0.01, P = 0.95). Maternal values of HCQ were sustained throughout pregnancy and delivery (Figure 2). Mean QTc values were nearly identical between those in the highest and lowest quartiles of cord blood HCQ levels (P = 0.57) and between the highest and lowest quartiles of average HCQ levels during pregnancy (P = 0.54) (Figure 3A and 3B). Among these 45 infants, only 5 had prolongation of the QTc (11%; 95% CI: 4% - 24%), 2 marked and 3 marginal. No arrhythmias occurred in any neonate that was not known to have heart block.
Conclusion(s): In aggregate, these data provide reassurances that the maternal use of HCQ is not associated with a high incidence of QTc prolongation in the neonate
EMBASE:634233135
ISSN: 2326-5205
CID: 4804852