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Longitudinal analysis of ANA in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort

Choi, May Yee; Clarke, Ann Elaine; Urowitz, Murray; Hanly, John; St-Pierre, Yvan; Gordon, Caroline; Bae, Sang-Cheol; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Bernatsky, Sasha; Wallace, Daniel J; Isenberg, David; Rahman, Anisur; Merrill, Joan T; Fortin, Paul R; Gladman, Dafna D; Bruce, Ian N; Petri, Michelle; Ginzler, Ellen M; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Manzi, Susan; Jönsen, Andreas; Alarcón, Graciela S; van Vollenhoven, Ronald F; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Lim, Sam; Inanc, Murat; Kalunian, Ken; Jacobsen, Søren; Peschken, Christine; Kamen, Diane L; Askanase, Anca; Buyon, Jill P; Costenbader, Karen H; Fritzler, Marvin J
OBJECTIVES/OBJECTIVE:A perception derived from cross-sectional studies of small systemic lupus erythematosus (SLE) cohorts is that there is a marked discrepancy between antinuclear antibody (ANA) assays, which impacts on clinicians' approach to diagnosis and follow-up. We compared three ANA assays in a longitudinal analysis of a large international incident SLE cohort retested regularly and followed for 5 years. METHODS:Demographic, clinical and serological data was from 805 SLE patients at enrolment, year 3 and 5. Two HEp-2 indirect immunofluorescence assays (IFA1, IFA2), an ANA ELISA, and SLE-related autoantibodies were performed in one laboratory. Frequencies of positivity, titres or absorbance units (AU), and IFA patterns were compared using McNemar, Wilcoxon and kappa statistics, respectively. RESULTS:At enrolment, ANA positivity (≥1:80) was 96.1% by IFA1 (median titre 1:1280 (IQR 1:640-1:5120)), 98.3% by IFA2 (1:2560 (IQR 1:640-1:5120)) and 96.6% by ELISA (176.3 AU (IQR 106.4 AU-203.5 AU)). At least one ANA assay was positive for 99.6% of patients at enrolment. At year 5, ANA positivity by IFAs (IFA1 95.2%; IFA2 98.9%) remained high, while there was a decrease in ELISA positivity (91.3%, p<0.001). Overall, there was >91% agreement in ANA positivity at all time points and ≥71% agreement in IFA patterns between IFA1 and IFA2. CONCLUSION/CONCLUSIONS:In recent-onset SLE, three ANA assays demonstrated commutability with a high proportion of positivity and titres or AU. However, over 5 years follow-up, there was modest variation in ANA assay performance. In clinical situations where the SLE diagnosis is being considered, a negative test by either the ELISA or HEp-2 IFA may require reflex testing.
PMID: 35338033
ISSN: 1468-2060
CID: 5205902

Short- and Long-Term Progression of Kidney Involvement in Systemic Lupus Erythematosus Patients with Low-Grade Proteinuria

Wang, Shudan; Spielman, Allan; Ginsberg, Mindy; Petri, Michelle; Rovin, Brad; Buyon, Jill; Broder, Anna
PMID: 35882508
ISSN: 1555-905x
CID: 5276442

Breakthrough SARS-CoV-2 infections, morbidity, and seroreactivity following initial COVID-19 vaccination series and additional dose in patients with SLE in New York City

Saxena, Amit; Engel, Alexis J; Banbury, Brittany; Hasan, Ghadeer; Fraser, Nicola; Zaminski, Devyn; Masson, Mala; Haberman, Rebecca H; Scher, Jose U; Ho, Gary; Law, Jammie; Rackoff, Paula; Tseng, Chung-E; Belmont, H Michael; Clancy, Robert M; Buyon, Jill P; Izmirly, Peter M
PMID: 35856060
ISSN: 2665-9913
CID: 5279052

To Be or Not to Be Treated: That Is the Question in Managing a Fetus With Cardiac Injury Exposed to Anti-SSA/Ro [Letter]

Buyon, Jill; Saxena, Amit; Friedman, Deborah; Izmirly, Peter
PMID: 35730612
ISSN: 2047-9980
CID: 5275942

Reducing the burden of surveillance in pregnant women with no history of fetal atrioventricular block using the negative predictive value of anti-Ro/SSA antibody titers

Kaizer, Alexander M; Lindblade, Christopher; Clancy, Robert; Tebo, Anne E; Drewes, Bailey; Masson, Mala; Chang, Miao; Fraser, Nicola; Buyon, Jill P; Cuneo, Bettina F
BACKGROUND:The risk of fetal atrioventricular block in anti-Ro/SSA antibody-exposed pregnancies with no previous affected offspring is approximately 2%. A high antibody titer is necessary but not sufficient for atrioventricular block, and specific antibody titers do not predict risk. However, there are no data on the negative predictive value of antibody titer to identify pregnancies at low risk of fetal atrioventricular block, and may not require surveillance. OBJECTIVE:This study aimed to define anti-Ro52 and anti-Ro60 antibody thresholds for the identification of fetuses unlikely to develop atrioventricular block using clinically validated and research laboratory tests. STUDY DESIGN/METHODS:This study performed a multicenter review of pregnant subjects who tested positive in their local commercial laboratories for anti-Ro/SSA antibodies at the University of Colorado Children's Hospital (2014-2021) and Phoenix Children's Hospital (2014-2021) and enrolled in the Research Registry for Neonatal Lupus (RRNL) at New York University Langone Medical Center (2002-2021). The subjects were referred on the basis of rheumatologic symptoms or history of atrioventricular block in a previous pregnancy and were retrospectively grouped on the basis of pregnancy outcome. Group 1 indicated no fetal atrioventricular block in current or past pregnancies; group 2 indicated fetal atrioventricular block in the current pregnancy; and group 3 indicated normal current pregnancy but with fetal atrioventricular block in a previous pregnancy. Maternal sera were analyzed for anti-Ro52 and anti-Ro60 antibodies using a clinically validated multiplex bead assay (Associated Regional and University Pathologists Laboratories, Salt Lake City, UT) and a research enzyme-linked immunosorbent immunoassay (New York University). This study calculated the negative predictive value separately for anti-Ro52 and anti-Ro60 antibodies and for the 2 combined using a logistic regression model and a parallel testing strategy. RESULTS:This study recruited 270 subjects (141 in group 1, 66 in group 2, and 63 in group 3). Of note, 89 subjects in group 1 had data on hydroxychloroquine treatment: anti-Ro/SSA antibody titers were no different between those treated (n=46) and untreated (n=43). Mean anti-Ro52 and anti-Ro60 titers were the lowest in group 1 and not different between groups 2 and 3. No case of fetal atrioventricular block developed among subjects with anti-Ro52 and anti-Ro60 titers of <110 arbitrary units per milliliter using the multiplex bead assay of the Associated Regional and University Pathologists Laboratories (n=141). No case of fetal atrioventricular block developed among subjects with research laboratory anti-Ro52 titers of <650 and anti-Ro60 of <4060 enzyme-linked immunosorbent immunoassay units (n=94). Using these 100% negative predictive value thresholds, more than 50% of the anti-Ro/SSA antibody pregnancies that ultimately had no fetal atrioventricular block could be excluded from surveillance based on clinical and research titers, respectively. CONCLUSION/CONCLUSIONS:Study data suggested that there is a clinical immunoassay level of maternal anti-Ro/SSA antibodies below which the pregnancy is at low risk of fetal atrioventricular block. This study speculated that prospectively applying these data may avert the costly serial echocardiograms currently recommended for all anti-Ro/SSA-antibody positive pregnancies and guide future management.
PMID: 35690080
ISSN: 1097-6868
CID: 5283322

Evaluation of the European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus in a Population Based Registry

Guttmann, Allison; Denvir, Brendan; Aringer, Martin; Buyon, Jill P; Belmont, H Michael; Sahl, Sara; Salmon, Jane E; Askanase, Anca; Bathon, Joan M; Geraldino-Pardilla, Laura; Ali, Yousaf; Ginzler, Ellen M; Putterman, Chaim; Gordon, Caroline; Helmick, Charles G; Parton, Hilary; Izmirly, Peter M
OBJECTIVE:Using the Manhattan Lupus Surveillance Program (MLSP), a multi-racial/ethnic population-based registry, we compared three commonly used classification criteria for Systemic Lupus Erythematosus (SLE) to identify unique cases and determine the incidence and prevalence of SLE using the EULAR/ACR criteria. METHODS:SLE cases were defined as fulfilling 1997 ACR, SLICC, or EULAR/ACR classification criteria. We quantified the number of cases uniquely associated with each and the number fulfilling all three. Prevalence and incidence using the EULAR/ACR classification criteria and associated 95% confidence intervals (CI) were calculated. RESULTS:1,497 cases fulfilled at least one of the three classification criteria, with 1,008 (67.3%) meeting all three classifications, 138 (9.2%) fulfilling only SLICC criteria, 35 (2.3%) fulfilling only ACR criteria and 34 (2.3%) uniquely fulfilling EULAR/ACR criteria. Patients solely satisfying EULAR/ACR criteria had fewer than four manifestations. The majority classified only by the ACR criteria did not meet any of the defined immunologic criteria. Patients fulfilling only SLICC criteria did so based on the presence of features unique to this system. Using the EULAR/ACR classification criteria, age-adjusted overall prevalence and incidence rates of SLE in Manhattan were 59.6 (95%CI:55.9-63.4) and 4.9 (95%CI 4.3-5.5) per 100,000 population, with age-adjusted prevalence and incidence rates highest among non-Hispanic Black females. CONCLUSION/CONCLUSIONS:Applying the three commonly used classification criteria to a population-based registry identified patients with SLE fulfilling only one validated definition. The most recently developed EULAR/ACR classification criteria revealed similar prevalence and incidence estimates to those previously established for the ACR and SLICC classification schemes.
PMID: 35638708
ISSN: 2151-4658
CID: 5235872

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

High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the Accelerating Medicines Partnership

Carlucci, Philip M; Li, Jessica; Fava, Andrea; Deonaraine, Kristina K; Wofsy, David; James, Judith A; Putterman, Chaim; Diamond, Betty; Davidson, Anne; Fine, Derek M; Monroy-Trujillo, Jose; Atta, Mohamed G; DeJager, Wade; Guthridge, Joel M; Haag, Kristin; Rao, Deepak A; Brenner, Michael B; Lederer, James A; Apruzzese, William; Belmont, H Michael; Izmirly, Peter M; Zaminski, Devyn; Wu, Ming; Connery, Sean; Payan-Schober, Fernanda; Furie, Richard; Dall'Era, Maria; Cho, Kerry; Kamen, Diane; Kalunian, Kenneth; Anolik, Jennifer; Barnas, Jennifer; Ishimori, Mariko; Weisman, Michael H; Buyon, Jill P; Petri, Michelle
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.
PMID: 35212719
ISSN: 1462-0332
CID: 5172492

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.
PMID: 34347939
ISSN: 2326-5205
CID: 5046532