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The modifying influence of HLA class II DQB1∗06:02 on the Streptococcus and clinical phenotype correlation among anti-Ro+ mothers of children with neonatal lupus

Clancy, Robert M; Guthridge, Carla J; Marion, Miranda C; Guthridge, Joel; Howard, Timothy D; Izmirly, Peter M; Masson, Mala; Buyon, Jill P; James, Judith A; Langefeld, Carl D
PMCID:10311177
PMID: 37397545
ISSN: 2352-3042
CID: 5539022

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

Platelet LGALS3BP Induces Myeloid Inflammation In Systemic Lupus Erythematosus

El Bannoudi, Hanane; Cornwell, MacIntosh; Luttrell-Williams, Elliot; Engel, Alexis; Rolling, Christina; Barrett, Tessa J; Izmirly, Peter; Belmont, H Michael; Ruggles, Kelly; Clancy, Robert; Buyon, Jill; Berger, Jeffrey S
OBJECTIVE:Platelets are mediators of inflammation with immune effector cell properties, and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet associated lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE, and a potential biomarker associated with clinical phenotypes. METHODS:We performed RNA sequencing on platelets of patients with SLE (n=54) and age, sex, and race-matched controls (n=18) and measured LGALS3BP in platelet releasate and in circulating serum. We investigated the association between levels of LGALS3BP with the prevalence, disease severity, and clinical phenotpyes of SLE, and studied platelet-mediated effects on myeloid inflammation. RESULTS:). Platelet-released LGALS3BP was highly correlated with circulating LGALS3BP (R = 0.69, p < 0.0001). Circulating LGALS3BP correlated with the SLE disease activity index (R = 0.32, p = 0.0006). Specifically, circulating LGALS3BP was higher in SLE patients with lupus nephritis than those with inactive disease (4.0 μg/mL vs 2.3 μg/mL, P < 0.001). IFN-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) cells in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced pro-inflammatory cytokine production by macrophages. CONCLUSIONS:These data support that platelets act as potent effector cells contributing to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.
PMID: 36245285
ISSN: 2326-5205
CID: 5360062

Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype

Cornwell, MacIntosh G; Bannoudi, Hanane El; Luttrell-Williams, Elliot; Engel, Alexis; Barrett, Tessa J; Myndzar, Khrystyna; Izmirly, Peter; Belmont, H Michael; Clancy, Robert; Ruggles, Kelly V; Buyon, Jill P; Berger, Jeffrey S
BACKGROUND:The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. METHODS:Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. RESULTS:There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. CONCLUSIONS:In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.
PMCID:10082503
PMID: 37029410
ISSN: 1479-5876
CID: 5459472

Autoimmune Congenital Complete Heart Block: How Late Can It Occur?

Makadia, Luv; Izmirly, Peter; Buyon, Jill P; Phoon, Colin K L
PMCID:10166639
PMID: 37168107
ISSN: 2157-6998
CID: 5544602

Prospective Evaluation of High Titer Autoantibodies and Fetal Home Monitoring in the Detection of Atrioventricular Block Among Anti-SSA/Ro Pregnancies

Buyon, Jill P.; Masson, Mala; Izmirly, Caroline G.; Phoon, Colin; Acherman, Ruben; Sinkovskaya, Elena; Abuhamad, Alfred; Makhoul, Majd; Satou, Gary; Hogan, Whitnee; Pinto, Nelangi; Moon-Grady, Anita; Howley, Lisa; Donofrio, Mary; Krishnan, Anita; Ahmadzia, Homa; Levasseur, Stephanie; Paul, Erin; Owens, Sonal; Cumbermack, Kristopher; Matta, Jyothi; Joffe, Gary; Lindblade, Christopher; Haxel, Caitlin; Kohari, Katherine; Copel, Joshua; Strainic, James; Doan, Tam; Bermudez-Wagner, Karla; Holloman, Conisha; Sheth, Shreya S.; Killen, Stacy; Tacy, Theresa; Kaplinski, Michelle; Hornberger, Lisa; Carlucci, Philip M.; Izmirly, Peter; Fraser, Nicola; Clancy, Robert M.; Cuneo, Bettina F.
Objective: This prospective study of pregnant patients, Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), addresses the impact of anti-SSA/Ro titers and utility of ambulatory monitoring in the detection of fetal second-degree atrioventricular block (AVB). Methods: Women with anti-SSA/Ro autoantibodies by commercial testing were stratified into high and low anti"“52-kD and/or 60-kD SSA/Ro titers applying at-risk thresholds defined by previous evaluation of AVB pregnancies. The high-titer group performed fetal heart rate and rhythm monitoring (FHRM) thrice daily and weekly/biweekly echocardiography from 17"“26 weeks. Abnormal FHRM prompted urgent echocardiography to identify AVB. Results: Anti"“52-kD and/or 60-kD SSA/Ro met thresholds for monitoring in 261 of 413 participants (63%); for those, AVB frequency was 3.8%. No cases occurred with low titers. The incidence of AVB increased with higher levels, reaching 7.7% for those in the top quartile for anti"“60-kD SSA/Ro, which increased to 27.3% in those with a previous child who had AVB. Based on levels from 15 participants with paired samples from both an AVB and a non-AVB pregnancy, healthy pregnancies were not explained by decreased titers. FHRM was considered abnormal in 45 of 30,920 recordings, 10 confirmed AVB by urgent echocardiogram, 7 being second-degree AVB, all <12 hours from normal FHRM and within another 0.75 to 4 hours to echocardiogram. The one participant with second/third-degree and two participants with third-degree AVB were diagnosed by urgent echocardiogram >17 to 72 hours from an FHRM. Surveillance echocardiograms detected no AVB when the preceding interval FHRM recordings were normal. Conclusion: High-titer antibodies are associated with an increased incidence of AVB. Anti-SSA/Ro titers remain stable over time and do not explain the discordant recurrence rates, suggesting that other factors are required. Fetal heart rate and rhythm (FHRM) with results confirmed by a pediatric cardiologist reliably detects conduction abnormalities, which may reduce the need for serial echocardiograms. (Figure presented.).
SCOPUS:85176589398
ISSN: 2326-5191
CID: 5615912

Low incidence and transient elevation of autoantibodies post mRNA COVID-19 vaccination in inflammatory arthritis

Blank, Rebecca B; Haberman, Rebecca H; Qian, Kun; Samanovic, Marie; Castillo, Rochelle; Jimenez Hernandez, Anthony; Vasudevapillai Girija, Parvathy; Catron, Sydney; Uddin, Zakwan; Rackoff, Paula; Solomon, Gary; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Mulligan, Mark J; Hu, Jiyuan; Scher, Jose U
OBJECTIVES/OBJECTIVE:Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. METHODS:Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. RESULTS:Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, p= 0.014). Incidence of de novo anti-cyclic citrullinated protein (CCP) seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titer, transient, and not associated with increase in IA flares. CONCLUSIONS:In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population.
PMID: 35640110
ISSN: 1462-0332
CID: 5235902

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

COVID-19 outcomes in patients with psoriasis and psoriatic arthritis: A prospective cohort study

Yan, Di; Kolla, Avani M; Young, Trevor; Fried, Lauren; Shankar, Shruthi; Rangel, Lauren; Yin, Lu; Castillo, Rochelle; Steuer, Alexa; Svigos, Katerina; Izmirly, Peter; Sekar, Vaish; Lesser, Robert; Solomon, Gary; Blank, Rebecca B; Haberman, Rebecca H; Neimann, Andrea L; Scher, Jose U
PMCID:8958163
PMID: 35373153
ISSN: 2666-3287
CID: 5219542

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
PMCID:9275793
PMID: 35856060
ISSN: 2665-9913
CID: 5279052