Searched for: in-biosketch:yes
person:merrij01
Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study
Buyon, Jill P; Kim, Mimi Y; Guerra, Marta M; Laskin, Carl A; Petri, Michelle; Lockshin, Michael D; Sammaritano, Lisa; Branch, D Ware; Porter, T Flint; Sawitzke, Allen; Merrill, Joan T; Stephenson, Mary D; Cohn, Elisabeth; Garabet, Lamya; Salmon, Jane E
Background: Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern. Objective: To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE. Design: Prospective cohort. Setting: Multicenter. Patients: 385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE study. Exclusion criteria were urinary protein-creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy. Measurements: APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA). Results: APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 x 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%. Limitation: Patients with high disease activity were excluded. Conclusion: In pregnant patients with inactive or stable mild or moderate SLE, severe flares are infrequent, and absent specific risk factors, outcomes are favorable. Primary Funding Source: National Institutes of Health.
PMCID:5113288
PMID: 26098843
ISSN: 1539-3704
CID: 1641432
Impact of early disease factors on metabolic syndrome in systemic lupus erythematosus: data from an international inception cohort
Parker, Ben; Urowitz, Murray B; Gladman, Dafna D; Lunt, Mark; Donn, Rachelle; Bae, Sang-Cheol; Sanchez-Guerrero, Jorge; Romero-Diaz, Juanita; Gordon, Caroline; Wallace, Daniel J; Clarke, Ann E; Bernatsky, Sasha; Ginzler, Ellen M; Isenberg, David A; Rahman, Anisur; Merrill, Joan T; Alarcon, Graciela S; Fessler, Barri J; Fortin, Paul R; Hanly, John G; Petri, Michelle; Steinsson, Kristjan; Dooley, Mary Anne; Manzi, Susan; Khamashta, Munther A; Ramsey-Goldman, Rosalind; Zoma, Asad A; Sturfelt, Gunnar K; Nived, Ola; Aranow, Cynthia; Mackay, Meggan; Ramos-Casals, Manuel; van Vollenhoven, Ronald F; Kalunian, Kenneth C; Ruiz-Irastorza, Guillermo; Lim, S Sam; Kamen, Diane L; Peschken, Christine A; Inanc, Murat; Bruce, Ian N
BACKGROUND: The metabolic syndrome (MetS) may contribute to the increased cardiovascular risk in systemic lupus erythematosus (SLE). We examined the association between MetS and disease activity, disease phenotype and corticosteroid exposure over time in patients with SLE. METHODS: Recently diagnosed (<15 months) patients with SLE from 30 centres across 11 countries were enrolled into the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort from 2000 onwards. Baseline and annual assessments recorded clinical, laboratory and therapeutic data. A longitudinal analysis of factors associated with MetS in the first 2 years of follow-up was performed using random effects logistic regression. RESULTS: We studied 1150 patients with a mean (SD) age of 34.9 (13.6) years and disease duration at enrolment of 24.2 (18.0) weeks. In those with complete data, MetS prevalence was 38.2% at enrolment, 34.8% at year 1 and 35.4% at year 2. In a multivariable random effects model that included data from all visits, prior MetS status, baseline renal disease, SLICC Damage Index >1, higher disease activity, increasing age and Hispanic or Black African race/ethnicity were independently associated with MetS over the first 2 years of follow-up in the cohort. CONCLUSIONS: MetS is a persistent phenotype in a significant proportion of patients with SLE. Renal lupus, active inflammatory disease and damage are SLE-related factors that drive MetS development while antimalarial agents appear to be protective from early in the disease course.
PMCID:4515988
PMID: 24692585
ISSN: 0003-4967
CID: 986612
Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells
Coit, Patrick; Renauer, Paul; Jeffries, Matlock A; Merrill, Joan T; McCune, W Joseph; Maksimowicz-McKinnon, Kathleen; Sawalha, Amr H
Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10(-6)). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.
PMCID:4497927
PMID: 26005050
ISSN: 1095-9157
CID: 4874552
Mood Disorders in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study
Hanly, John G; Su, Li; Urowitz, Murray B; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Bernatsky, Sasha; Clarke, Ann E; Wallace, Daniel J; Merrill, Joan T; Isenberg, David A; Rahman, Anisur; Ginzler, Ellen M; Petri, Michelle; Bruce, Ian N; Dooley, M A; Fortin, Paul; Gladman, Dafna D; Sanchez-Guerrero, Jorge; Steinsson, Kristjan; Ramsey-Goldman, Rosalind; Khamashta, Munther A; Aranow, Cynthia; Alarcon, Graciela S; Fessler, Barri J; Manzi, Susan; Nived, Ola; Sturfelt, Gunnar K; Zoma, Asad A; van Vollenhoven, Ronald F; Ramos-Casals, Manuel; Ruiz-Irastorza, Guillermo; Lim, S Sam; Kalunian, Kenneth C; Inanc, Murat; Kamen, Diane L; Peschken, Christine A; Jacobsen, Soren; Askanase, Anca; Theriault, Chris; Thompson, Kara; Farewell, Vernon
OBJECTIVE: To examine the frequency, characteristics, and outcome of mood disorders, as well as clinical and autoantibody associations, in a multiethnic/racial, prospective inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: Patients were assessed annually for mood disorders (4 types, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 18 other neuropsychiatric events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 subscales, mental and physical component summary scores were collected. Time to event, linear and ordinal regressions, and multi-state models were used as appropriate. RESULTS: Among the 1,827 patients with SLE, 88.9% were female, and 48.9% were Caucasian. The mean +/- SD age of the patients was 35.1 +/- 13.3 years, disease duration was 5.6 +/- 4.8 months, and the length of followup was 4.7 +/- 3.5 years. During the course of the study, 863 (47.2%) of the 1,827 patients had 1,627 neuropsychiatric events. Mood disorders occurred in 232 (12.7%) of 1,827 patients, and 98 (38.3%) of 256 mood disorder events were attributed to SLE. The estimated cumulative incidence of any mood disorder after 10 years was 17.7% (95% confidence interval 15.1, 20.2%). A greater risk of mood disorder was associated with concurrent neuropsychiatric events (P = 0.01), and a lower risk was associated with Asian race/ethnicity (P = 0.01) and treatment with immunosuppressive drugs (P = 0.003). Mood disorders were associated with lower mental health and mental component summary scores but not with the SLEDAI-2K, SDI, or lupus autoantibodies. Among the 232 patients with depression, 168 (72.4%) were treated with antidepressants. One hundred twenty-six (49.2%) of 256 mood disorders resolved in 117 (50.4%) of 232 patients. CONCLUSION: Mood disorders, the second most frequent neuropsychiatric event in patients with SLE, have a negative impact on health-related quality of life and improve over time. The lack of association with global SLE disease activity, cumulative organ damage, and lupus autoantibodies emphasizes the multifactorial etiology of mood disorders and a role for non-lupus-specific therapies.
PMCID:4485527
PMID: 25778456
ISSN: 2326-5205
CID: 1649452
Connective tissue diseases: Is SLE many single-organ diseases or an overlapping spectrum? [Comment]
Merrill, Joan T
PMID: 25939416
ISSN: 1759-4804
CID: 2650282
Variations of BOLD: Can hydroxychloroquine be temporarily stopped during clinical trials in SLE? [Meeting Abstract]
Merrill, J. T.; Thanou, A.; Carthen, F.; Kamp, S.; Buyon, J. P.
ISI:000360421900126
ISSN: 0392-856x
CID: 2961922
Genetic association of CD247 (CD3zeta) with SLE in a large-scale multiethnic study
Martins, M; Williams, A H; Comeau, M; Marion, M; Ziegler, J T; Freedman, B I; Merrill, J T; Glenn, S B; Kelly, J A; Sivils, K M; James, J A; Guthridge, J M; Alarcon-Riquelme, M E; Bae, S-C; Kim, J-H; Kim, D; Anaya, J-M; Boackle, S A; Criswell, L A; Kimberly, R P; Alarcon, G S; Brown, E E; Vila, L M; Petri, M A; Ramsey-Goldman, R; Niewold, T B; Tsao, B P; Gilkeson, G S; Kamen, D L; Jacob, C O; Stevens, A M; Gaffney, P M; Harley, J B; Langefeld, C D; Fesel, C
A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3zeta chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3zeta are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 x 10(-4) < P < 4.15 x 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 x 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 x 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 x 10(-3) < P< 3.97 x 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 x 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.
PMCID:4371129
PMID: 25569266
ISSN: 1476-5470
CID: 2627972
Differential expression of the transcription factor ARID3a in lupus patient hematopoietic progenitor cells
Ratliff, Michelle L; Ward, Julie M; Merrill, Joan T; James, Judith A; Webb, Carol F
Although hematopoietic stem/progenitor cells (HSPCs) are used for transplantation, characterization of the multiple subsets within this population in humans has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in humans have not been defined. We previously showed increased numbers of ARID3a(+) B cells in nearly half of systemic lupus erythematosus (SLE) patients, and total numbers of ARID3a(+) B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HSPCs in either healthy controls or SLE patients. Numbers of ARID3a(+) HSPCs in SLE patients were increased over numbers of ARID3a(+) cells in healthy controls. Although all SLE-derived HSPCs exhibited poor colony formation in vitro compared with controls, SLE HSPCs with high numbers of ARID3a(+) cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HSPCs with high numbers of ARID3a(+) cells also more readily generated autoantibody-producing cells than HSPCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HSPCs could be informative for applications requiring transplantation of those cells.
PMCID:4297684
PMID: 25535283
ISSN: 1550-6606
CID: 4874532
The IRF5-TNPO3 association with systemic lupus erythematosus (SLE) has two components that other autoimmune disorders variably share
Kottyan, Leah C; Zoller, Erin E; Bene, Jessica; Lu, Xiaoming; Kelly, Jennifer A; Rupert, Andrew M; Lessard, Christopher J; Vaughn, Samuel E; Marion, Miranda; Weirauch, Matthew T; Namjou, Bahram; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G; Hirschfield, Gideon M; Xie, Gang; Coltescu, Catalina; Amos, Chris; Li, He; Ice, John A; Nath, Swapan K; Mariette, Xavier; Rischmueller, Maureen; Lester, Sue; Brun, Johan G; Goransson, Lasse G; Harboe, Erna; Omdal, Roald; Cunninghame-Graham, Deborah S; Vyse, Tim; Miceli-Richard, Corinne; Brennan, Michael T; Lessard, James A; Wahren-Herlenius, Marie; Kvarnstrom, Marika; Illei, Gabor G; Witte, Torsten; Jonsson, Roland; Eriksson, Per; Nordmark, Gunnel; Anaya, Juan-Manuel; Rhodus, Nelson L; Segal, Barbara M; Merrill, Joan T; James, Judith A; Guthridge, Joel M; Scofield, R Hal; Alarcon-Riquelme, Marta; Bae, Sang-Cheol; Boackle, Susan A; Criswell, Lindsey A; Gilkeson, Gary; Kamen, Diane L; Jacob, Chaim O; Kimberly, Robert; Brown, Elizabeth; Edberg, Jeffrey; Alarcon, Graciela S; Reveille, John D; Vila, Luis M; Petri, Michelle; Ramsey-Goldman, Rosalind; Freedman, Barry I; Niewold, Timothy; Stevens, Anne M; Tsao, Betty P; Ying, Jun; Mayes, Maureen D; Gorlova, Olga Y; Wakeland, Ward; Radstake, Timothy; Martin, Ezequiel; Martin, Javier; Siminovitch, Katherine; Moser Sivils, Kathy L; Gaffney, Patrick M; Langefeld, Carl D; Harley, John B; Kaufman, Kenneth M
Exploiting genotyping, DNA sequencing, imputation, and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE) we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3,230 IRF5-TNPO3 high quality, common variants across five ethnicities in 8,395 SLE cases and 7,367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (p-valuemeta=6x10-49; OR=1.38-1.97). The second genetic effect spanned an 85.5 kb, 24 variant haplotype that included the genes IRF5 and TNPO3 (p-valuesEU=10-27-10-32, OR=1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjogren's syndrome and systemic sclerosis while only the IRF5-TNPO3 gene-spanning haplotype is associated in primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
PMCID:4275071
PMID: 25205108
ISSN: 0964-6906
CID: 1181522
Electrocardiographic findings in systemic lupus erythematosus: Data from an international inception cohort
Bourre-Tessier, Josiane; Urowitz, Murray B; Clarke, Ann E; Bernatsky, Sasha; Krantz, Mori J; Huynh, Thao; Joseph, Lawrence; Belisle, Patrick; Bae, Sang-Cheol; Hanly, John G; Wallace, Daniel J; Gordon, Caroline; Isenberg, David; Rahman, Anisur; Gladman, Dafna D; Fortin, Paul R; Merrill, Joan T; Romero-Diaz, Juanita; Sanchez-Guerrero, Jorge; Fessler, Barri; Alarcon, Graciela S; Steinsson, Kristjan; Bruce, Ian N; Ginzler, Ellen; Dooley, Mary Anne; Nived, Ola; Sturfelt, Gunnar; Kalunian, Kenneth; Ramos-Casals, Manuel; Petri, Michelle; Zoma, Asad; Pineau, Christian A
Objective: To estimate the early prevalence of various electrocardiographic (ECG) abnormalities in patients with SLE and to evaluate possible associations between repolarization changes (increased corrected QT, QTc, and QT dispersion, QTd) and clinical and laboratory variables, including the anti-Ro/SSA level and specificity (52 or 60KDa). Methods: We studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (SLEDAI-2K), disease damage (SLICC/ACR DI), and laboratory data from the baseline or first follow-up visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross-sectional associations between anti-Ro/SSA and ECG repolarization abnormalities. Results: For the 779 patients included, mean age (SD) was 35.6 years (13.8), 88.4% were women, and mean disease duration was 10.5 months (14.4). Mean SLEDAI-2K was 5.4 (5.6) and mean SLICC/ACR DI was 0.5 (1.0). ECG abnormalities were frequent and included non-specific ST-T changes (30.9%), possible left ventricular hypertrophy (5.4%) and supraventricular arrhythmias (1.3%). A QTc >/= 440ms was found in 15.3%, while QTc >/= 460ms was found in 5.3%. Mean (SD) QTd was 34.2ms (14.7) and QTd >/= 40ms was frequent (38.1%). Neither the specificity, nor the level of anti-Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total DI was significantly associated with a QTc interval exceeding 440 ms (OR 1.38 95% CI 1.06, 1.79). Conclusion: A substantial proportion of recent-onset SLE patients exhibit repolarization abnormalities although severe abnormalities were rare. (c) 2014 American College of Rheumatology.
PMID: 24838943
ISSN: 2151-464x
CID: 1065332