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Assessment of fluorinated steroids to avert progression and mortality in anti-SSA/Ro-associated cardiac injury limited to the fetal conduction system

Izmirly, Peter M; Saxena, Amit; Sahl, Sara K; Shah, Ummara; Friedman, Deborah M; Kim, Mimi Y; Buyon, Jill P
OBJECTIVES: Extension of disease beyond the atrioventricular (AV) node is associated with increased mortality in cardiac neonatal lupus (NL). Treatment of isolated heart block with fluorinated steroids to prevent disease progression has been considered but published data are limited and discordant regarding efficacy. This study evaluated whether fluorinated steroids given to manage isolated advanced block prevented development of disease beyond the AV node and conferred a survival benefit. METHODS: In this retrospective study of cases enrolled in the Research Registry for NL, inclusion was restricted to anti-SSA/Ro-exposed cases presenting with isolated advanced heart block in utero who either received fluorinated steroids within 1 week of detection (N=71) or no treatment (N=85). Outcomes evaluated were: development of endocardial fibroelastosis, dilated cardiomyopathy and/or hydrops fetalis; mortality and pacemaker implantation. RESULTS: In Cox proportional hazards regression analyses, fluorinated steroids did not significantly prevent development of disease beyond the AV node (adjusted HR=0.90; 95% CI 0.43 to 1.85; p=0.77), reduce mortality (HR=1.63; 95% CI 0.43 to 6.14; p=0.47) or forestall/prevent pacemaker implantation (HR=0.87; 95% CI 0.57 to 1.33; p=0.53). No risk factors for development of disease beyond the AV node were identified. CONCLUSIONS: These data do not provide evidence to support the use of fluorinated steroids to prevent disease progression or death in cases presenting with isolated heart block.
PMCID:5167557
PMID: 26835701
ISSN: 1468-2060
CID: 1933092

Mortality in Systemic Lupus Erythematosus: an Updated Review

Fors Nieves, Cesar E; Izmirly, Peter M
Both systemic lupus erythematosus (SLE) and its treatments can contribute to increased mortality rates. The focus of this review is recent studies on mortality and comorbidities during the last 5 years from around the world. The authors conducted a literature review, using PUBMED, for articles relating to SLE mortality with a specific focus on literature published within the last 5 years. Our analysis found that while mortality in SLE patients continues to improve, there are differences in survival based on ethnicity, socioeconomic status, age, and gender. The most common cause of mortality is cardiovascular disease, followed closely by infection and severe disease activity. To conclude, while there have been significant advances in the treatment of SLE and its associated comorbidities, increased mortality remains a major concern in patient management.
PMID: 26984805
ISSN: 1534-6307
CID: 2030522

Autoimmune congenital heart block: complex and unusual situations

Brito-Zeron, P; Izmirly, P M; Ramos-Casals, M; Buyon, J P; Khamashta, M A
Autoimmune congenital heart block (ACHB) is an immune-mediated cardiac disease included among the manifestations collectively referred to as neonatal lupus. The placental transference of maternal Ro/La autoantibodies may damage the conduction tissues during fetal development leading to blocking of signal conduction at the atrioventricular (AV) node in an otherwise structurally normal heart. Irreversible complete AV block is the main cardiac manifestation of ACHB, but some babies may develop endocardial fibroelastosis, valvular insufficiency, and/or frank cardiomyopathies with significantly reduced cardiac function requiring transplant. The severity of ACHB is illustrated by a global mortality rate of 20% and pacemaker rates of at least 64%, often within the first year of life. This review analyses the main complex and/or unusual clinical situations associated with ACHB, including unusual maternal immunological profiles, infrequent maternal autoimmune diseases, cardiac damage unrelated to AV block, fetal invasive management, late complications after birth, risk of congenital heart block (CHB) in ovodonation and in vitro fertilization techniques, the role of maternal features other than autoimmunity, the influence of the birth order or the risk of CHB in twins and triplets.
PMID: 26762645
ISSN: 1477-0962
CID: 1911402

Early diagnosis of primary Sjogren's syndrome: EULAR-SS task force clinical recommendations

Brito-Zeron, Pilar; Theander, Elke; Baldini, Chiara; Seror, Raphaele; Retamozo, Soledad; Quartuccio, Luca; Bootsma, Hendrika; Bowman, Simon J; Dorner, Thomas; Gottenberg, Jacques-Eric; Mariette, Xavier; Bombardieri, Stefano; de Vita, Salvatore; Mandl, Thomas; Ng, Wan-Fai; Kruize, Aike A; Tzioufas, Athanasios; Vitali, Claudio; Buyon, Jill; Izmirly, Peter; Fox, Robert; Ramos-Casals, Manuel; On Behalf Of The Eular Sjogren Syndrome Task Force
Sjogren's syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying 'occult' SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.
PMID: 26691952
ISSN: 1744-8409
CID: 1884132

In search of an antibody specificity highly predictive of congenital heart block

Izmirly, Peter M; Saxena, Amit
PMCID:4854070
PMID: 27158527
ISSN: 2053-8790
CID: 2106472

Neonatal Lupus: Clinical Spectrum, Biomarkers, Pathogenesis, and Approach to Treatment

Chapter by: Buyon, JP; Saxena, A; Izmirly, PM
in: Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects by
pp. 451-461
ISBN: 9780128020098
CID: 2169102

Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro-Associated Cardiac Neonatal Lupus

Saxena, Amit; Izmirly, Peter M; Han, Sung Won; Briassouli, Paraskevi; Rivera, Tania L; Zhong, Hua; Friedman, Deborah M; Clancy, Robert M; Buyon, Jill P
BACKGROUND: Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, and cardiac dysfunction: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D. OBJECTIVES: Identification of maternal and fetal biomarkers associated with development and morbidity of cardiac NL should provide clues to pathogenesis with translational implications for management. METHODS: Cord (139) and maternal (135) blood samples collected during pregnancies at risk for cardiac NL were available for study. Levels of cord and maternal CRP, cord NT-proBNP, and cord troponin I were evaluated using multiplex assays. Cord and maternal vitamin D were assessed by liquid chromatography-mass spectrometry. MMP-2, uPA, uPAR, and plasminogen were evaluated using ELISA. RESULTS: Cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in cardiac NL-affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of cardiac NL development, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality in cardiac NL. Maternal CRP and cord troponin I levels did not differ between the groups. Cord and maternal vitamin D levels were not significantly associated with cardiac NL, but average maternal vitamin D level during pregnancy was positively associated with longer time to postnatal pacemaker placement. CONCLUSIONS: These data support the association of fetal reactive inflammatory and fibrotic components with development and morbidity of cardiac NL. Following CRP and NT-proBNP levels after birth can potentially monitor severity and progression of cardiac NL. MMP-2 and the uPA/uPAR/plasminogen cascade provide therapeutic targets to decrease fibrosis. Although decreased vitamin D did not confer increased risk, given the positive influence on postnatal outcomes, maternal levels should be optimized.
PMCID:4545752
PMID: 26293764
ISSN: 1558-3597
CID: 1732472

TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus

Doerner, Jessica L; Wen, Jing; Xia, Yumin; Paz, Karin Blecher; Schairer, David; Wu, Lan; Chalmers, Samantha A; Izmirly, Peter; Michaelson, Jennifer S; Burkly, Linda C; Friedman, Adam J; Putterman, Chaim
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-kappaB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.
PMCID:4504782
PMID: 25826425
ISSN: 1523-1747
CID: 1669512

Serum biomarkers of inflammation, fibrosis, and cardiac function associate with diagnosis and severity of cardiac neonatal lupus [Meeting Abstract]

Saxena, A.; Izmirly, P. M.; Han, S.; Briassouli, P.; Rivera, T. L.; Zhong, H.; Friedman, D.; Clancy, R. M.; Buyon, J. P.
ISI:000360421900257
ISSN: 0392-856x
CID: 2961932

The clinical spectrum of autoimmune congenital heart block

Brito-Zeron, Pilar; Izmirly, Peter M; Ramos-Casals, Manuel; Buyon, Jill P; Khamashta, Munther A
Autoimmune congenital heart block (CHB) is an immune-mediated acquired disease that is associated with the placental transference of maternal antibodies specific for Ro and La autoantigens. The disease develops in a fetal heart without anatomical abnormalities that could otherwise explain the block, and which is usually diagnosed in utero, but also at birth or within the neonatal period. Autoantibody-mediated damage of fetal conduction tissues causes inflammation and fibrosis and leads to blockage of signal conduction at the atrioventricular (AV) node. Irreversible complete AV block is the principal cardiac manifestation of CHB, although some babies might develop other severe cardiac complications, such as endocardial fibroelastosis or valvular insufficiency, even in the absence of cardiac block. In this Review, we discuss the epidemiology, classification and management of women whose pregnancies are affected by autoimmune CHB, with a particular focus on the autoantibodies associated with autoimmune CHB and how we should test for these antibodies and diagnose this disease. Without confirmed effective preventive or therapeutic strategies and further research on the aetiopathogenic mechanisms, autoimmune CHB will remain a severe life-threatening disorder.
PMCID:5551504
PMID: 25800217
ISSN: 1759-4804
CID: 1513872