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The Pre-treatment Gut Microbiome is Associated with Lack of Response to Methotrexate in New Onset Rheumatoid Arthritis
Artacho, Alejandro; Isaac, Sandrine; Nayak, Renuka; Flor-Duro, Alejandra; Alexander, Margaret; Koo, Imhoi; Manasson, Julia; Smith, Philip B; Rosenthal, Pamela; Homsi, Yamen; Gulko, Percio; Pons, Javier; Puchades-Carrasco, Leonor; Izmirly, Peter; Patterson, Andrew; Abramson, Steven B; Pineda-Lucena, Antonio; Turnbaugh, Peter J; Ubeda, Carles; Scher, Jose U
OBJECTIVES/OBJECTIVE:Although oral methotrexate (MTX) remains the anchor drug for RA, up to 50% of patients do not achieve a clinically adequate outcome. Concomitantly, there is a lack of prognostic tools for treatment response prior to drug initiation. Here we study whether inter-individual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA (NORA). METHODS:16S rRNA gene and shotgun metagenomic sequencing were performed on the baseline gut microbiomes of drug-naïve, NORA patients (n=26). Results were validated in an additional independent cohort (n=21). To gain insight into potential microbial mechanisms, ex vivo experiments coupled with metabolomics analysis evaluated the association between microbiome-driven MTX depletion and clinical response. RESULTS:Our analysis revealed significant associations between the abundance of gut bacterial taxa and their genes with future clinical response, including orthologs related to purine and methotrexate metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicts lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pre-treatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes. CONCLUSIONS:Together, these results provide the first step towards predicting lack of response to oral MTX in NORA patients and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.
PMID: 33314800
ISSN: 2326-5205
CID: 4717542
Prevalence of Systemic Lupus Erythematosus in the United States: Estimates from a Meta-Analysis of the Centers for Disease Control and Prevention National Lupus Registries
Izmirly, Peter M; Parton, Hilary; Wang, Lu; McCune, W Joseph; Lim, S Sam; Drenkard, Cristina; Ferucci, Elizabeth D; Dall'Era, Maria; Gordon, Caroline; Helmick, Charles G; Somers, Emily C
OBJECTIVE:Epidemiologic data for systemic lupus erythematosus (SLE) is limited, particularly for racial/ethnic subpopulations in the United States (U.S.). Leveraging data from the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population-based SLE registries, a meta-analysis estimating U.S. SLE prevalence was performed. METHODS:The CDC National Lupus Registry network included four registries in unique states and a fifth in the Indian Health Service (IHS). All registries used the 1997 revised American College of Rheumatology (ACR) classification criteria for the SLE case definition. Case finding spanned either 2002-2004 or 2007-2009. A random effects model was employed given heterogeneity across sites. Applying sex/race-stratified estimates to the 2018 Census population, an estimate for the number of SLE cases in the U.S. was generated. RESULTS:5,417 cases fulfilled the ACR SLE classification criteria. Pooled prevalence from the four state-specific registries was 72.8/100,000 (95%CI:65.3,81.0), 9 times higher for females than males (128.7 vs 14.6), and highest among Black females (230.9), followed by Hispanic (120.7), white (84.7) and Asian/Pacific Islander females (84.4). Male prevalence was highest in Black males (26.7) followed by Hispanic (18.0), Asian/Pacific Islander (11.2), and white males (8.9). The American Indian/Alaska Native had the highest race-specific SLE estimates for females (270.6/100,000) and males (53.8/100,000). In 2018, 204,295 persons (95% CI:160,902,261,725) in the U.S. fulfilled ACR SLE classification criteria. CONCLUSIONS:A coordinated network of population-based SLE registries provided more accurate estimates for SLE prevalence and numbers affected in the U.S.
PMID: 33474834
ISSN: 2326-5205
CID: 4762822
European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance
Aringer, Martin; Brinks, Ralph; Dörner, Thomas; Daikh, David; Mosca, Marta; Ramsey-Goldman, Rosalind; Smolen, Josef S; Wofsy, David; Boumpas, Dimitrios T; Kamen, Diane L; Jayne, David; Cervera, R; Costedoat-Chalumeau, Nathalie; Diamond, Betty; Gladman, Dafna D; Hahn, Bevra; Hiepe, Falk; Jacobsen, Søren; Khanna, Dinesh; Lerstrøm, Kirsten; Massarotti, Elena; McCune, Joseph; Ruiz-Irastorza, Guillermo; Sanchez-Guerrero, Jorge; Schneider, Matthias; Urowitz, Murray; Bertsias, George; Hoyer, Bimba F; Leuchten, Nicolai; Schmajuk, Gabriela; Tani, Chiara; Tedeschi, Sara K; Touma, Zahi; Anic, Branimir; Assan, Florence; Chan, Tak Mao; Clarke, Ann Elaine; Crow, Mary K; Czirják, László; Doria, Andrea; Graninger, Winfried; Halda-Kiss, Bernadett; Hasni, Sarfaraz; Izmirly, Peter M; Jung, Michelle; Kumánovics, Gábor; Mariette, Xavier; Padjen, Ivan; Pego-Reigosa, José M; Romero-Diaz, Juanita; Rúa-Figueroa, Ãñigo; Seror, Raphaèle; Stummvoll, Georg H; Tanaka, Yoshiya; Tektonidou, Maria G; Vasconcelos, Carlos; Vital, Edward M; Wallace, Daniel J; Yavuz, Sule; Meroni, Pier Luigi; Fritzler, Marvin J; Naden, Ray; Costenbader, Karen; Johnson, Sindhu R
BACKGROUND/OBJECTIVES/OBJECTIVE:The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. METHODS:We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. RESULTS:Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement. CONCLUSIONS:Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.
PMID: 33568386
ISSN: 1468-2060
CID: 4793292
Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease
Haberman, Rebecca H; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B; Tuen, Michael; Koralov, Sergei B; Atreya, Raja; Tascilar, Koray; Allen, Joseph R; Castillo, Rochelle; Cornelius, Amber R; Rackoff, Paula; Solomon, Gary; Adhikari, Samrachana; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Neurath, Markus; Abramson, Steven B; Schett, Georg; Mulligan, Mark J; Scher, Jose U
Objective/UNASSIGNED:To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods/UNASSIGNED:Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results/UNASSIGNED:Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions/UNASSIGNED:In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES/UNASSIGNED:These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.
PMCID:8132259
PMID: 34013285
ISSN: n/a
CID: 4877422
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
Passively acquired lupus in the fetus and neonate
Chapter by: Buyon, Jill P.; Wainwright, Benjamin J.; Saxena, Amit; Izmirly, Peter
in: Lahita"™s Systemic Lupus Erythematosus by
[S.l.] : Elsevier, 2021
pp. 325-363
ISBN: 9780128205839
CID: 5198842
EVALUATION OF SARS-COV-2 IGG ANTIBODY REACTIVITY IN A MULTI-RACIAL/ETHNIC COHORT OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS [Meeting Abstract]
Saxena, A; Guttmann, A; Masson, M; Kim, M Y; Haberman, R H; Castillo, R; Scher, J U; Deonaraine, K K; Engel, A J; Michael, Belmont H; Blazer, A D; Buyon, J P; Fernandez-Ruiz, R; Izmirly, P M
Background Patients with Systemic Lupus Erythematosus (SLE) represent a unique population at risk for COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. This study was initiated to evaluate for the presence of SARS-CoV-2 IgG antibodies in SLE patients with and without prior COVID-19-related symptoms or COVID-19 RT PCR testing. Methods A total of 329 patients with SLE from two cohorts, one serially monitored for COVID-19 in Spring 2020 (the Web-based Assesment of Autoimmune, Immune-Mediated and Rheumatic Patients (WARCOV) and one undergoing routine surveillance (NYU Lupus Cohort) were tested for SARS-CoV-2 IgG via commercially available immunoassays processed through hospital or outpatient laboratories between April 29, 2020 and February 9, 2021. Results Overall, 16% of 329 patients had a reactive SARSCoV- 2 IgG antibody test. Seropositive patients were more likely to be Hispanic. Other demographic variables, lupus-specific factors and immunosuppressant use were not associated with reactivity. Of the 29 patients with prior RT-PCR confirmed COVID-19, 83% developed an antibody response despite 62% being on immunosuppressants. Six percent of patients who had symptoms suspicious for COVID-19 but negative concurrent RT-PCR testing developed an antibody response. Twenty-three percent of patients who had COVID- 19-related symptoms but no RT-PCR testing and 5% of patients who had no symptoms of COVID-19 developed an antibody response. Among patients initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially. In COVID- 19-confirmed patients high percentages had antibody positivity beyond 30 weeks from disease onset, 88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks. Conclusions Most patients with SLE and confirmed COVID- 19 were able to produce a serologic response despite use of a variety of immunosuppressants. These findings provide reassurances regarding the efficacy of humoral immunity and possible reinfection protection in patients with SLE
EMBASE:638287648
ISSN: 2053-8790
CID: 5292912
INCIDENCE OF SYSTEMIC LUPUS ERYTHEMATOSUS IN THE UNITED STATES: ESTIMATES FROM A METAANALYSIS OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION NATIONAL LUPUS REGISTRIES [Meeting Abstract]
Izmirly, P M; Ferucci, E D; Somers, E C; Wang, L; McCune, J W; Sam, Lim S; Drenkard, C; Dall'Era, M; Gordon, C; Helmick, C G; Parton, H
Background Epidemiologic data on systemic lupus erythematosus (SLE) are limited, particularly for racial/ethnic subpopulations in the United States (U.S.). This meta-analysis leveraged data from the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population-based SLE registries to estimate the general and by sex, race/ethnicity incidence of SLE in the U.S. Methods The CDC registries were established in Michigan, Georgia, California, New York and through the Indian Health Service (IHS). Registries used the 1997 revised ACR classification criteria for SLE as their case definition, and the surveillance time periods ranged from 2002-2009. Age-standardized incidence rates were stratified by sex and race/ethnicity from the state-based registries; the American Indian/Alaska Native (AI/AN) estimate was based only on the IHS registry that covered multiple states. For pooling data across the four sites with data on different racial/ethnic groups, we used Cochran's Q and I statistic to test for heterogeneity across sites. Due to significant heterogeneity, we used a random effects model to calculate pooled incidence, which allows for more variation across sites. We then extrapolated to the 2018 Census population data according to sex and race-stratified groups, including data from the IHS registry, and summed the stratum-specific estimates to provide a total population estimate of incident SLE cases in the U.S. Results The registries contributed 1,057 classified cases of SLE from a mix of urban and rural areas. From the meta-analysis of the four state-based registries, the overall incidence was 5.1 (95%CI4.6,5.6) per 100,000 person-years. The incidence among females was about 7 times higher than males (8.7 vs 1.2). In the meta-analysis, the incidence rate was highest among Black females (15.9,95%CI12.5,20.3), followed by Asian/Pacific Islander females (7.6,95%CI5.5,10.4), Hispanic females (6.8,95%CI6.2,7.6), and White females (5.7,95% CI4.9,6.7). Among males, the incidence rate was highest among Black males (2.4,95%CI1.8,3.0) followed by Hispanic males (0.9,95%CI0.4,1.9), White males (0.8,95%CI0.6,1.1), and Asian/Pacific Islander males (0.4,95%CI0.2,0.6). The AI/ AN incidence estimates, had the second highest rates of SLE among females (10.4,95%CI6.6,14.6) and highest for males (3.8, 95%CI1.6,7.8). Applying our sex- and race-specific incidence estimates to the corresponding population denominators from 2018 Census data, we estimated that 14,263 new persons (12,560 females and 1,703 males) in the U.S. were diagnosed with SLE and fulfill the ACR classification criteria, table 1. Conclusion A coordinated network of population-based SLE registries provided more accurate estimates of the incidence of SLE and the numbers of new individuals affected with SLE in the U.S. in 2018
EMBASE:638287621
ISSN: 2053-8790
CID: 5292932
COVID-19 in Patients with Inflammatory Arthritis: A Prospective Study on the Effects of Comorbidities and DMARDs on Clinical Outcomes
Haberman, Rebecca H; Castillo, Rochelle; Chen, Alan; Yan, Di; Ramirez, Deborah; Sekar, Vaish; Lesser, Robert; Solomon, Gary; Niemann, Andrea L; Blank, Rebecca B; Izmirly, Peter; Webster, Dan E; Ogdie, Alexis; Troxel, Andrea B; Adhikari, Samrachana; Scher, Jose U
OBJECTIVE:To characterize the hospitalization and death rates among patients with inflammatory arthritis affected by COVID-19 and to analyze the associations between comorbidities and immunomodulatory medications and infection outcomes. METHODS:Clinical, demographic, maintenance treatment, and disease course data and outcomes of individuals with inflammatory arthritis (IA; rheumatoid arthritis and spondylarthritis) with symptomatic COVID-19 infection were prospectively assessed via web-based questionnaire followed by individual phone calls and electronic medical record review. Baseline characteristics and medication use were summarized for hospitalized and ambulatory patients, and outcomes were compared for each medication class using multivariable logistic regression. RESULTS:A total of 103 patients with IA were included in the study (n=80 confirmed and n=23 highly suspicious for COVID-19). Twenty-six percent of participants required hospitalization, and 4% died. Patients who warranted hospitalization were significantly more likely to be older (P<0.001) and have comorbid hypertension (P=0.001) and chronic obstructive pulmonary disease (P=0.022). IA patients taking oral glucocorticoids had a higher likelihood of being admitted for COVID-19 (P<0.001) while those on maintenance anti-cytokine biologic therapies did not. CONCLUSION/CONCLUSIONS:In patients with underlying IA, COVID-19 outcomes were worse in those receiving glucocorticoids but not in patients on maintenance anti-cytokine therapy. Further work is needed to understand whether immunomodulatory therapies affect COVID-19 incidence.
PMID: 32725762
ISSN: 2326-5205
CID: 4557002