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Angiogenic Factor Imbalance Early in Pregnancy Predicts Adverse Outcomes in Patients with Lupus and Antiphospholipid Antibodies: Results of the PROMISSE Study
Kim, Mimi Y; Buyon, Jill P; Guerra, Marta M; Rana, Sarosh; Zhang, Dongsheng; Laskin, Carl A; Petri, Michelle; Lockshin, Michael D; Sammaritano, Lisa R; Branch, D Ware; Porter, T Flint; Merrill, Joan T; Stephenson, Mary D; Gao, Qi; Karumanchi, S Ananth; Salmon, Jane E
BACKGROUND: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high risk population. In non-autoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. OBJECTIVE: To determine whether early dysregulation of circulating angiogenic factors, can predict APO in high risk SLE and/or APL pregnancies. STUDY DESIGN: We used data and samples from the PROMISSE Study (Predictors of pRegnancy Outcome: BioMarkers In antiphospholipid antibody Syndrome and Systemic Lupus Erythematosus), a multi-center prospective study that enrolled 492 pregnant women with SLE and/or APL between September 2003 and August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured monthly and subjects followed for APO, classified as severe (PE<34 weeks, fetal/neonatal death, indicated pre-term delivery <30 weeks) or moderate (PE>/=34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). RESULTS: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and sEng levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio=17.3 comparing highest and lowest quartiles, 95% CI: 3.5-84.8; positive predictive value (PPV)=61%; negative predictive value (NPV)=93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/ml) and sFlt1 in highest quartile (>1872 pg/ml; odds ratio=31.1; 95% CI: 8.0-121.9; PPV=58%; NPV=95%). Severe APO rate in this high risk subgroup was 94% (95%CI: 70%-99.8%), if lupus anticoagulant or history of high blood pressure is additionally present. In contrast, among patients with both sFlt1 <1872 pg/ml and PlGF >70.3 pg/ml, rate of severe APO was only 4.6% (95% CI: 2.1%- 8.6%). CONCLUSIONS: Circulating angiogenic factors measured during early gestation have a high negative predictive value in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of healthcare resources.
PMCID:4698098
PMID: 26432463
ISSN: 1097-6868
CID: 1790132
A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE)
Kalunian, Kenneth C; Merrill, Joan T; Maciuca, Romeo; McBride, Jacqueline M; Townsend, Michael J; Wei, Xiaohui; Davis, John C; Kennedy, William P
OBJECTIVES/OBJECTIVE:To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon α (anti-IFN-α) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE). METHODS:Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2). BACKGROUND:Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM). RESULTS:Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ~10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups. CONCLUSIONS:The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT00962832.
PMID: 26038091
ISSN: 1468-2060
CID: 4874562
Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus
Gerosa, Maria; Poletti, Barbara; Pregnolato, Francesca; Castellino, Gabriella; Lafronza, Annalisa; Silani, Vincenzo; Riboldi, Piersandro; Meroni, Pier Luigi; Merrill, Joan T
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.
PMCID:4740786
PMID: 26870034
ISSN: 1664-3224
CID: 4874602
Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results
Yelnik, Cecile M; Laskin, Carl A; Porter, T Flint; Branch, D Ware; Buyon, Jill P; Guerra, Marta M; Lockshin, Michael D; Petri, Michelle; Merrill, Joan T; Sammaritano, Lisa R; Kim, Mimi Y; Salmon, Jane E
OBJECTIVE: We previously reported that lupus anticoagulant (LAC) is the main predictor of poor pregnancy outcome in antiphospholipid antibody (aPL)-positive patients. We sought to confirm this finding in an independent group of patients who were subsequently recruited into the PROMISSE study. METHODS: The PROMISSE study is a multicentre, prospective, observational study of pregnancy outcomes in women with aPL and/or systemic lupus erythematosus (SLE) that enrolled patients from 2003 to 2015. All consecutive, aPL-positive patients from the PROMISSE study who completed their pregnancy between April 2011 and January 2015 (after the previous PROMISSE report) are included in the current report. Patients were followed monthly until delivery, and aPL was tested at first, second and third trimesters of pregnancy and at 12 weeks post partum. Adverse pregnancy outcomes (APOs) were defined as fetal death after 12 weeks of gestation, neonatal death, delivery prior to 36 weeks of gestation due to pre-eclampsia or placental insufficiency or small-for-gestational age (birth weight <5th percentile). RESULTS: Forty-four aPL-positive patients are included in this paper. Thirteen patients had APOs, which occurred in 80% of cases during the second trimester of pregnancy. LAC was present in 69% of patients with APOs compared with 27% of patients without APOs (p=0.01). No association was found between anticardiolipin antibodies (aCL) or anti-beta2 glycoprotein I antibodies (abeta2GPI) IgG or IgM positivity and APOs. Definite antiphospholipid syndrome (history of thrombosis and/or pregnancy morbidity and aPL) was found in 92% of patients with any APOs compared with 45% of patients without APOs (p=0.004). Conversely, the frequency of SLE was not statistically different between those with and without APOs (30% vs 39%). CONCLUSIONS: Our findings, in an independent group of aPL-positive patients from the PROMISSE study, confirm that LAC, but not aCL and abeta2GPI, is predictive of poor pregnancy outcomes after 12 weeks of pregnancy. TRIAL REGISTRATION NUMBER: NCT00198068.
PMCID:4716418
PMID: 26835148
ISSN: 2053-8790
CID: 1931962
Heightened preclinical dysregulation of distinct adaptive and renal-associated mediators in patients who develop nephritis as they transition to systemic lupus erythematosus classification [Meeting Abstract]
Munroe, Melissa; Anderson, Jourdan R; Robertson, Julie M; Niewold, Timothy B; Tsokos, George C; Keith, Michael P; Merrill, Joan T; Buyon, Jill P; Harley, John B; James, Judith A
ISI:000380288300429
ISSN: 1550-6606
CID: 2220162
Why, why, why de-lupus (does so badly in clinical trials) [Editorial]
Isenberg, David A; Merrill, Joan T
PMID: 26786849
ISSN: 1744-8409
CID: 4874592
Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus
Zhao, Jian; Wu, Hui; Langefeld, Carl D; Kaufman, Kenneth M; Kelly, Jennifer A; Bae, Sang-Cheol; Alarcon, Graciela S; Anaya, Juan-Manuel; Criswell, Lindsey A; Freedman, Barry I; Kamen, Diane L; Gilkeson, Gary S; Jacob, Chaim O; James, Judith A; Merrill, Joan T; Gaffney, Patrick M; Sivils, Kathy Moser; Niewold, Timothy B; Petri, Michelle A; Song, Seung Taek; Jeong, Hye-Jin; Ramsey-Goldman, Rosalind; Reveille, John D; Scofield, R Hal; Stevens, Anne M; Boackle, Susan A; Vila, Luis M; Chang, Deh-Ming; Song, Yeong Wook; Vyse, Timothy J; Harley, John B; Brown, Elizabeth E; Edberg, Jeffrey C; Kimberly, Robert P; Hahn, Bevra H; Grossman, Jennifer M; Tsao, Betty P; La Cava, Antonio
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
PMCID:4658308
PMID: 26385092
ISSN: 1521-7035
CID: 2627912
Anifrolumab, an anti-interferon alpha receptor monoclonal antibody, in moderate to severe systemic lupus erythematosus (SLE) [Meeting Abstract]
Furie, R; Merrill, J T; Werth, V P; Khamashta, M; Kalunian, K; Brohawn, P; Illei, G; Drappa, J; Wang, L; Yoo, S
Background/Purpose: The efficacy and safety of anifrolumab (ANIFR), a type I IFN receptor antagonist, were assessed in a Phase II, randomized, double-blind, placebo-controlled study in SLE (NCT01438489). Methods: Three hundred and five adults with seropositive moderate to severe SLE despite standard of care medication were randomized and received intravenous (iv) ANIFR (300 mg, 1000 mg) or placebo (PBO) every 4 weeks for 48 weeks. Patients were stratified by SLEDAI score, oral corticosteroid (OCS) dose, and IFN gene signature (IFN high vs. IFN low) based on a 4-gene expression assay. Disease activity was assessed by SLEDAI-2K, BILAG 2004, Physician's Global Assessment, CLASI, BICLA, and 28-joint count. The primary endpoint was a composite of SRI(4) response at Day 169 with sustained reduction of OCS (<10 mg/day and 10 mg/day at baseline. Other efficacy measures of systemic and organ-specific disease activity and safety were also assessed at Day 365. Results: The primary endpoint at Day 169 was met by a greater proportion of ANIFR-treated patients vs. PBO (PBO: 17.6%; 300 mg: 34.3%, p=0.014; 1000 mg: 28.8%, p=0.063). At Day 365, the secondary SRI endpoint was met by 25.5% of PBO, 51.5% of 300 mg (p<0.001) and 38.5% of 1000 mg (p=0.048) patients. OCS reduction to <7.5 mg/day at Day 365 was achieved by 26.6% of PBO, 56.4% of 300 mg (p=0.001) and 31.7% of 1000 mg (p=0.595) patients. ANIFR demonstrated consistent benefit across multiple global and organ-specific measures at Day 365 (Table), as well as lower rates of BILAG moderate/severe flares/patient-year (PBO: 0.611; 300 mg: 0.266; 1000 mg: 0.391). 75% of patients were IFN high at baseline. The ANIFR efficacy observed in the entire cohort was similar or more pronounced in IFN high patients. Median suppression of 21 IFN-regulated genes was ~90% for both doses of ANIFR. Serious adverse events were reported in 18.8% of patients on PBO and 16.7% of patients in the pooled ANIFR groups. A higher frequency of influenza (most unconfirmed) (PBO: 1.0%; 300 mg: 6.1%; 1000 mg: 7.6%) and a dosage-dependent increase in Herpes zoster (PBO: 2.0%; 300 mg: 5.1%; 1000 mg: 9.5%) occurred in the ANIFR arms. Conclusion: Anifrolumab significantly reduced disease activity compared with PBO across multiple clinical endpoints. Enhanced effects in IFN high patients support the pathobiology of this treatment strategy. The lack of dose response can be explained by the nearly similar degrees of IFN gene signature inhibition achieved with the two anifrolumab doses. These data strongly support further development of anifrolumab. (Table Presented)
EMBASE:72097098
ISSN: 2326-5191
CID: 1903892
Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort
Bruce, Ian N; O'Keeffe, Aidan G; Farewell, Vern; Hanly, John G; Manzi, Susan; Su, Li; Gladman, Dafna D; 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; Petri, Michelle; Steinsson, Kristjan; Dooley, Mary Anne; 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, Sam; Kamen, Diane L; Peschken, Christine A; Inanc, Murat; Urowitz, Murray B
BACKGROUND AND AIMS: We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan-Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. RESULTS: We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs >/=1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to >/=1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). CONCLUSIONS: Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
PMCID:4552899
PMID: 24834926
ISSN: 0003-4967
CID: 1065302
Treatment of systemic lupus erythematosus patients with the BAFF antagonist "peptibody" blisibimod (AMG 623/A-623): results from randomized, double-blind phase 1a and phase 1b trials
Stohl, William; Merrill, Joan T; Looney, R John; Buyon, Jill; Wallace, Daniel J; Weisman, Michael H; Ginzler, Ellen M; Cooke, Blaire; Holloway, Donna; Kaliyaperumal, Arunan; Kuchimanchi, Kameswara Rao; Cheah, Tsui Chern; Rasmussen, Erik; Ferbas, John; Belouski, Shelley S; Tsuji, Wayne; Zack, Debra J
INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for >/= 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naive B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.
PMCID:4545922
PMID: 26290435
ISSN: 1478-6362
CID: 1742622