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Dive into the research topics where Anca Askanase is active.

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Featured researches published by Anca Askanase.


Journal of Immunology | 2000

Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-alpha by macrophages.

María-Eugenia Miranda-Carús; Anca Askanase; Robert R. Clancy; Francis Di Donato; Tseng-Ming Chou; Matthew Libera; Edward K. L. Chan; Jill P. Buyon

Despite the near universal association of congenital heart block and maternal Abs to SSA/Ro and SSB/La, the intracellular location of these Ags has made it difficult to substantiate their involvement in pathogenicity. To define whether components of the SSA/Ro-SSB/La complex, which translocate during apoptosis, are indeed accessible to extracellular Abs, two approaches were taken: immunoprecipitation of surface biotinylated proteins and scanning electron microscopy. Human fetal cardiocytes from 16–24-wk abortuses were cultured and incubated with staurosporine to induce apoptosis. Surface biotinylated 48-kDa SSB/La was reproducibly immunoprecipitated from apoptotic, but not nonapoptotic cardiocytes. Surface expression of SSA/Ro and SSB/La was further substantiated by scanning electron microscopy. Gold particles (following incubation with gold-labeled sera containing various specificities of anti-SSA/Ro-SSB/La Abs and murine mAb to SSB/La and 60-kDa SSA/Ro) were consistently observed on early and late apoptotic cardiocytes. No particles were seen after incubation with control antisera. To evaluate whether opsonized apoptotic cardiocytes promote inflammation, cells were cocultured with macrophages. Compared with nonapoptotic cardiocytes or apoptotic cardiocytes incubated with normal sera, apoptotic cardiocytes preincubated with affinity-purified Abs to SSB/La, 52-kDa SSA/Ro, or 60-kDa SSA/Ro increased the secretion of TNF-α from cocultured macrophages. In summary, apoptosis results in surface accessibility of all SSA/Ro-SSB/La Ags for recognition by circulating maternal Abs. It is speculated that in vivo such opsonized apoptotic cardiocytes promote an inflammatory response by resident macrophages with damage to surrounding conducting tissue.


Lupus | 2002

Spectrum and progression of conduction abnormalities in infants born to mothers with anti-SSA/Ro-SSB/La antibodies

Anca Askanase; Deborah M. Friedman; J. Copel; M R Dische; Anne M. Dubin; T J Starc; Margaret Katholi; Jill P. Buyon

The classic cardiac manifestation of neonatal lupus is congenitalheart block, attributed to antibodymediated inflammation and subsequent fibrosis of the atrioventricular(AV) node. In consideringthe pathologic process of injury it may be that tissue damage results in a range of conduction abnormalities. Identification of less-advanced degrees of block or of fibrosis around the AV node without any conduction abnormality on EKG would support this pathologic model, and serve as a potential marker for treatment if the conduction defect could be shown to progress. To ascertain the spectrum of arrhythmias associated with maternal anti-SSA/Ro-SSB/La antibodies, records of all children enrolled in the Research Registry for Neonatal Lupus were reviewed. Of 187 children with congenital heart block whose mothers have anti-SSA/Ro-SSB/La antibodies, nine had a prolonged PR interval on EKG at birth, four of whom progressed to more advanced AV block. A child whose younger sibling had third degree block was diagnosed with first degree block at age 10 years at the time of surgery for a broken wrist. Two children diagnosed in utero with second degree block were treated with dexamethasone and reverted to normal sinus rhythm by birth, but ultimately progressed to third degree block. Four children had second degree block at birth: of these, two progressed to third degree block. Sinus bradycardia (< 100 bpm) was present in three (3.8%) of 78 fetuses for whom atrial rates were recorded by echocardiogram. Of 40 neonates for whom EKGs were available, the mean atrial rate was 137± 20 bpm (range 75–200). These data have important research and clinical implications. In contrast to the AV node, permanent sinoatrial nodal involvement is not clinically apparent. Perhaps many fetuses sustain mild inflammation, but resolution is variable, as suggested by the presence of incomplete AV block. Since subsequent progression of less-advanced degrees of block can occur, an EKG should be performed on all infants born to mothers with anti-SSA/Ro-SSB/La antibodies.


Lupus | 2013

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE

Mary Anne Dooley; F Houssiau; Cynthia Aranow; David D’Cruz; Anca Askanase; D. Roth; Z.J. Zhong; S. Cooper; William W. Freimuth; Ellen M. Ginzler

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.


Annals of the Rheumatic Diseases | 2010

Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine

Peter M. Izmirly; Mimi Y. Kim; Carolina Llanos; Phuong U Le; Marta M. Guerra; Anca Askanase; Jane E. Salmon; Jill P. Buyon

Background Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody-associated cardiac manifestations of NL (cardiac-NL). Methods Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/Ro/SSB/La antibodies at pregnancy, confirmation of medication use and childs outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007. Results Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Cases and controls were similar with respect to demographic and antibody status. Multivariable analysis adjusting for birth year, maternal race/ethnicity, antibody status, non-fluorinated steroid use and prior cardiac-NL risk yielded an OR associated with HCQ use of 0.46 (95% CI 0.18 to 1.18; p=0.10). Conclusion This case–control study suggests that, in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL. Prospective studies are needed for confirmation.


Journal of Autoimmunity | 2013

Cancer risk in systemic lupus: An updated international multi-centre cohort study

Sasha Bernatsky; Rosalind Ramsey-Goldman; Jeremy Labrecque; Lawrence Joseph; Jean François Boivin; Michelle Petri; Asad Zoma; Susan Manzi; Murray B. Urowitz; Dafna D. Gladman; Paul R. Fortin; Ellen M. Ginzler; Edward H. Yelin; Sang-Cheol Bae; Daniel J. Wallace; Steven M. Edworthy; Søren Jacobsen; Caroline Gordon; Mary Anne Dooley; Christine A. Peschken; John G. Hanly; Graciela S. Alarcón; Ola Nived; Guillermo Ruiz-Irastorza; David A. Isenberg; Anisur Rahman; Torsten Witte; Cynthia Aranow; Diane L. Kamen; Kristjan Steinsson

OBJECTIVE To update estimates of cancer risk in SLE relative to the general population. METHODS A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkins lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.


Arthritis & Rheumatism | 2014

Treatment of Lupus Nephritis with Abatacept: The Abatacept and Cyclophosphamide Combination Efficacy and Safety Study

Anca Askanase; Margie Byron; Lynette Keyes-Elstein; Patricia Cagnoli; W. Joseph McCune; W. Winn Chatham; Gabriel Contreras; David I. Daikh; Maria Dall'Era; David Wofsy; Anne Davidson; Betty Diamond; Meggan Mackay; Linna Ding; Wendy Gao; Mary Anne Dooley; Hilda Fragoso-Loyo; Jorge Sanchez-Guerrero; David R. Karp; Nancy J. Olsen; Meenakshi Jolly; Kenneth C. Kalunian; Diane L. Kamen; Iris Lee; Marc C. Levesque; S. Sam Lim; Cesar Ramos-Remus; Brad H. Rovin; Peter Sayre; Dawn Smilek

To assess the efficacy and safety of a 24‐week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce “clinical tolerance,” defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy.


Journal of Immunology | 2002

Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro-SSB/La antibody-mediated congenital heart block

Robert R. Clancy; Anca Askanase; Raj P. Kapur; Efstathia Chiopelas; Natalie Azar; M. Eugenia Miranda-Carus; Jill P. Buyon

The signature lesion of autoantibody-associated congenital heart block (CHB) is fibrosis of the conducting tissue. To date, participation of myofibroblasts in the cascade to injury has been unexplored. The importance of myofibroblast/macrophage cross-talk is demonstrated by the novel finding of these cell types in the heart of a neonate dying of CHB. This clue to pathogenesis prompted consideration of the mechanism by which maternal anti-SSA/Ro-SSB/La Abs initiate an inflammatory response and promote fibrosis. Isolated cardiocytes from 16–24 wk abortuses were rendered apoptotic by exposure to poly (2-) hydroxyethylmethacrylate; flow cytometry confirmed surface expression of Ro/La. Apoptotic cardiocytes were incubated with affinity-purified Abs to 52 and 60 kDa Ro from CHB mothers (opsonized) or IgG fractions from healthy donors (nonopsonized). Macrophages cultured with opsonized apoptotic cardiocytes expressed proinflammatory markers, supported by a three-fold increase in active αVβ3 integrin. Fetal cardiac fibroblasts exposed to supernatants obtained from macrophages incubated with opsonized apoptotic cardiocytes (but not nonopsonized) dramatically increased expression of the myofibroblast marker α-smooth muscle actin (SMAc). The “opsonized” supernatant reversed an inhibitory effect of the “nonopsonized” supernatant on proliferation of fibroblasts (120 vs 69%, p < 0.05). Parallel experiments examined the effects of two cytokines and their neutralizing Abs on fibroblasts. TGFβ1 increased SMAc staining but decreased proliferation. TNF-α did not affect either readout. Addition of anti-TGFβ1 Abs to the “opsonized” supernatant blocked SMAc expression but increased proliferation, while anti-TNF-α blocking Abs had no effects. These data suggest that transdifferentiation of cardiac fibroblasts to a scarring phenotype is a pathologic process initiated by maternal Abs.


Rheumatology | 2016

The frequency and outcome of lupus nephritis: results from an international inception cohort study

John G. Hanly; Aidan G. O'Keeffe; Li Su; Murray B. Urowitz; Juanita Romero-Diaz; Caroline Gordon; Sang-Cheol Bae; Sasha Bernatsky; Ann E. Clarke; Daniel J. Wallace; Joan T. Merrill; David A. Isenberg; Anisur Rahman; Ellen M. Ginzler; Paul R. Fortin; Dafna D. Gladman; Jorge Sanchez-Guerrero; Michelle Petri; Ian N. Bruce; Mary Anne Dooley; Rosalind Ramsey-Goldman; Cynthia Aranow; Graciela S. Alarcón; Barri J. Fessler; Kristjan Steinsson; Ola Nived; Gunnar Sturfelt; Susan Manzi; Munther A. Khamashta; Ronald F. van Vollenhoven

OBJECTIVE To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort. METHODS Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores. RESULTS There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR <30 ml/min at diagnosis had lower SF-36 physical component summary scores (P < 0.01) and lower Physical function, Physical role and Bodily pain scores. Over time, patients with abnormal eGFR and proteinuria had lower SF-36 mental component summary (P ≤ 0.02) scores compared to patients with normal values. CONCLUSION LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.


Arthritis & Rheumatism | 2010

Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block

Peter M. Izmirly; Carolina Llanos; Lela A. Lee; Anca Askanase; Mimi Y. Kim; Jill P. Buyon

OBJECTIVE Cutaneous disease associated with placental transport of maternal anti-SSA/Ro or anti-SSB/La antibodies is transient, and children often appear to be otherwise healthy. However, the impact of this manifestation of neonatal lupus (NL) on the risk of cardiac disease occurring in a future pregnancy is critical for family counseling and for powering preventive trials. The purpose of this study was to determine the recurrence rates of NL, with specific focus on cardiac NL following cutaneous NL in a child enrolled in the Research Registry for Neonatal Lupus (RRNL). METHODS Fifty-eight families who were enrolled in the RRNL met the following inclusion criteria for our study: maternal anti-SSA/Ro or anti-SSB/La antibodies, a child with cutaneous NL, and a pregnancy subsequent to the child with cutaneous NL. RESULTS The majority of the 58 mothers (78%) were Caucasian. Of 77 pregnancies that occurred following the birth of a child with cutaneous NL, the overall recurrence rate for any manifestation of NL was 49% (95% confidence interval [95% CI] 37-62%); 14 pregnancies (18.2%) were complicated by cardiac NL, 23 (29.9%) by cutaneous NL, and 1 (1.3%) by hematologic/hepatic NL. A subset analysis was restricted to the 39 children who were born after the initial child with cutaneous NL had been enrolled in the RRNL. The overall recurrence rate for NL was 36% (95% CI 20-52%); 5 pregnancies (12.8%) were complicated by cardiac NL and 9 (23.1%) by cutaneous NL. There were no significant differences in the following maternal risk factors for having a subsequent child with cardiac or cutaneous NL: age, race/ethnicity, anti-SSB/La status, diagnosis, use of nonfluorinated steroids, or breastfeeding. The sex of the subsequent fetus did not influence the development of cardiac or cutaneous NL. CONCLUSION Based on data from this large cohort, the identification of cutaneous NL in an anti-SSA/Ro antibody-exposed infant is particularly important, since it predicts a 6-10-fold risk of a subsequent child developing cardiac NL.


Annals of the Rheumatic Diseases | 2014

Lymphoma risk in systemic lupus: effects of disease activity versus treatment

Sasha Bernatsky; Rosalind Ramsey-Goldman; Lawrence Joseph; Jean François Boivin; Karen H. Costenbader; Murray B. Urowitz; Dafna D. Gladman; Paul R. Fortin; Ola Nived; Michelle Petri; Søren Jacobsen; Susan Manzi; Ellen M. Ginzler; David A. Isenberg; Anisur Rahman; Caroline Gordon; Guillermo Ruiz-Irastorza; Edward H. Yelin; Sang-Cheol Bae; Daniel J. Wallace; Christine A. Peschken; Mary Anne Dooley; Steven M. Edworthy; Cynthia Aranow; Diane L. Kamen; Juanita Romero-Diaz; Anca Askanase; Torsten Witte; Susan G. Barr; Lindsey A. Criswell

Objective To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). Methods We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogrens syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses. Results We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls. Conclusions In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

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Susan Manzi

Allegheny Health Network

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Ellen M. Ginzler

SUNY Downstate Medical Center

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Cynthia Aranow

The Feinstein Institute for Medical Research

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Mary Anne Dooley

University of North Carolina at Chapel Hill

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Daniel J. Wallace

Cedars-Sinai Medical Center

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Michelle Petri

Johns Hopkins University School of Medicine

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