Publications by authors named "Nathalie Costedoat-Chalumeau"

196 Publications

Serum Interleukin-26 Is a New Biomarker for Disease Activity Assessment in Systemic Lupus Erythematosus.

Front Immunol 2021 14;12:663192. Epub 2021 May 14.

Univ Angers, CHU Angers, INSERM, CRCINA, Angers, France.

Objective: Interleukin-26 (IL-26) has a unique ability to activate innate immune cells due to its binding to circulating double-stranded DNA. High levels of IL-26 have been reported in patients with chronic inflammation. We aimed to investigate IL-26 levels in patients with systemic lupus erythematosus (SLE).

Methods: IL-26 serum levels were quantified by ELISA for 47 healthy controls and 109 SLE patients previously enrolled in the PLUS study. Performance of IL-26 levels and classical markers (autoantibodies or complement consumption) to identify an active SLE disease (SLE disease activity index (SLEDAI) score > 4) were compared.

Results: IL-26 levels were significantly higher in SLE patients than in controls (4.04 ± 11.66 and 0.74 ± 2.02 ng/mL; p = 0.005). IL-26 levels were also significantly higher in patients with active disease than those with inactive disease (33.08 ± 21.06 vs 1.10 ± 3.80 ng/mL, p < 0.0001). IL-26 levels correlated with SLEDAI score and the urine protein to creatinine ratio (uPCR) (p < 0.001). Patients with high IL-26 levels had higher SLEDAI score, anti-DNA antibodies levels, and uPCR (p < 0.05). They presented more frequently with C3 or C4 complement consumption. Lastly, IL-26 showed stronger performance than classical markers (complement consumption or autoantibodies) for active disease identification.

Conclusions: Our results suggest that, in addition to classical SLE serological markers, the measurement of IL-26 levels may be a useful biomarker for active disease identification in SLE patients.
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http://dx.doi.org/10.3389/fimmu.2021.663192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160525PMC
May 2021

Impact of hydroxychloroquine used as DMARD on SARS-CoV-2 tests and infection evolution in a population of 871 patients with inflammatory rheumatic and musculoskeletal diseases.

Joint Bone Spine 2021 May 26;88(6):105226. Epub 2021 May 26.

Université de Lille, Inserm, CHU Lille, Service de Médecine Interne et Immunologie Clinique, Centre de référence des maladies autoimmunes systémiques rares du Nord et Nord-Ouest de France (CeRAINO), U1286-INFINITE-Institute for Translational Research in Inflammation, 59000 Lille, France.

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http://dx.doi.org/10.1016/j.jbspin.2021.105226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152361PMC
May 2021

Case 294.

Radiology 2021 Jun;299(3):727-729

From the Departments of Radiology (M.G., M.B., M.P.R.) and Internal Medicine (N.C.C.), Cochin Hospital, APHP Centre, 27 Rue du Fg St Jacques, Paris 75014, France; and Université de Paris, Paris, France (M.B., N.C.C., M.P.R.).

History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 10/L (normal range, 150-400 × 10/L), a C-reactive protein level of 158 mg/L (normal range, <5 mg/L) and a d-dimer level of 2000 mg/L (normal range, <500 mg/L). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, <0.3 g/day), and a high serum troponin level of 1066 ng/L (normal range, <14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4).
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http://dx.doi.org/10.1148/radiol.2021203170DOI Listing
June 2021

What are the topics you care about making trials in lupus more effective? Results of an Open Space meeting of international lupus experts.

Lupus Sci Med 2021 May;8(1)

Policlinic and Hiller Research Unit, Heinrich Heine University Düsseldorf, Dusseldorf, Nordrhein-Westfalen, Germany.

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about 'What are the topics you care about for making trials in lupus more effective?'. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs.
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http://dx.doi.org/10.1136/lupus-2021-000506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141446PMC
May 2021

Evaluation of the severe preeclampsia classification criterion for antiphospholipid syndrome in a study of 40 patients.

Arthritis Res Ther 2021 05 4;23(1):134. Epub 2021 May 4.

AP-HP, Cochin Hospital, Internal Medicine Department, Centre de référence maladies auto-immunes et systémiques rares d'Ile de France, Paris, France.

Background: The criteria for antiphospholipid syndrome (APS) include severe preeclampsia and/or placental insufficiency leading to preterm delivery before 34 weeks of gestation, but this APS manifestation has been rarely studied. Thus, we report a series of severe preeclampsia occurred in patients with APS.

Methods: We retrospectively analysed data of women with APS (Sydney criteria) who experienced severe preeclampsia with delivery before 34 weeks' gestation between 2000 and 2017 at five French internal medicine departments and one Italian rheumatology unit.

Results: The 40 women had a mean age of 30.5 ± 4.6 years at their first episode of preeclampsia; 21 were nulligravid (52.5%), 12 (30%) had already been diagnosed with APS, and 21 (52.5%) had a triple-positive antiphospholipid (aPL) antibody test. Preeclampsia occurred at a median gestational age of 25.5 weeks (IQR 23-29). It was associated with HELLP in 18 cases (45%), eclampsia in 6 (15%), placental abruption in 3 (7.5%), catastrophic APS in 3 (7.5%), and foetal and neonatal death in 11 and 15 cases. Overall, 14 (35%) children survived, born at a median gestational age of 31 weeks. Among other APS criteria, 16 women (40%) experienced at least one thrombosis, 17 (42.5%) an intrauterine foetal death, and 19 (47.5%) at least one episode of HELLP during follow-up (median 5 years, IQR = 2-8). None had three or more consecutive miscarriages. Notably, 12 women (30%) had systemic lupus erythematosus.

Conclusions: Severe preeclampsia led to high mortality in the offspring. Almost half of these women experienced other APS features, but not three consecutive miscarriages.
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http://dx.doi.org/10.1186/s13075-021-02518-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094564PMC
May 2021

SLE-DAS in the First Trimester of Gestation Predicts Maternal Lupus Flares Later in Pregnancy.

Front Pharmacol 2021 16;12:660123. Epub 2021 Apr 16.

Rheumatology Unit, Department of Medicine, DIMED, University of Padova, Padova, Italy.

Systemic Lupus Erythematosus (SLE) mainly occurs during childbearing age. Remission or low disease activity state (LDAS) before conception are recommended by experts to achieve a favourable lupus pregnancy outcome but little is known on the best way to evaluate remission or activity status during pregnancy. We tested SLE-disease activity score (SLE-DAS) in the first trimester as predictor of maternal flares and obstetrical complications in 2nd and 3rd trimester in a cohort of SLE pregnant women. Inclusion criteria were: 1) women ≥ 18 years; 2) affected with SLE (SLICC 2012); 3) enrolled in two referral centers (Italy and France) 4) with an ongoing singleton pregnancy at 12 weeks (only one pregnancy per patient). Disease activity was assessed at first trimester of pregnancy, using SLE-pregnancy disease activity index (SLEPDAI) and retrospectively applying SLE-DAS. Maternal lupus flares at 2nd and 3rd trimester were defined by the SELENA-SLEDAI Flare Index (SFI). Adverse pregnancy outcome (APO) included: fetal and neonatal death, placental insufficiency with premature delivery <37 weeks, and small for gestational age (SGA) (≤3rd percentile). We included 158 pregnant patients affected with SLE. At first trimester the median SLEPDAI (IQR) was 2 (0-4) and the median SLE-DAS (IQR) 1.32 (0.37-2.08). At least one flare occurred in 25 (15.8%) women during the 2nd and 3rd trimester. APO occurred in 19 (12.0%) patients. A significant correlation between SLE-DAS and SLEPDAI was found in this cohort (Spearman's = 0.97, Figure 1). At multivariate analysis, both SLE-DAS and SLEPDAI predicted maternal flares (adjOR = 1.2; 95% CI = 1.0-1.3, = 0.02; adjOR 1.3, 95% CI = 1.1-1.6 per unit increase, = 0.01, respectively). SLE-DAS and SLEPDAI were associated with APO at univariate analysis ( = 0.02). SLE-DAS was highly correlated with SLEPDAI and its use in the first trimester predicted maternal flares in the 2nd and 3rd trimester, making SLE-DAS a reliable instrument to measure SLE activity during pregnancy.
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http://dx.doi.org/10.3389/fphar.2021.660123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085518PMC
April 2021

Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.

Rheumatology (Oxford) 2021 Apr 19. Epub 2021 Apr 19.

Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

Objectives: To characterize the clinical and biological course, management and response to treatment in Systemic Lupus Erythematosus (SLE)-associated Pure Red Cell Aplasia (PRCA).

Methods: Nationwide multicentre retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone-marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection.

Results: We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level and reticulocyte and differential erythroblast count were 39.2 ± 13.2 years, 62 ± 20 g/L, 9.1 ± 7.6 x 109/L and 2.8 ± 2.5%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range: 2-11). Corticosteroid therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, five (21%) partial response and two (8%) treatment failure. In total, 21 (87%) patients required red-blood-cell transfusion; five had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization.

Conclusion: SLE-associated PRCA is a severe condition. Repeated red-blood-cell transfusions and several lines of immunosuppressant therapy are mostly required with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.
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http://dx.doi.org/10.1093/rheumatology/keab363DOI Listing
April 2021

Catastrophic antiphospholipid syndrome and posterior ocular involvement: case series of 11 patients and literature review.

Retina 2021 Apr 2. Epub 2021 Apr 2.

AP-HP, Cochin Hospital, Internal Medicine department, Centre de référence maladies auto-immunes et systémiques rares de l'Ile de France, Paris, France. Université Paris-Descartes, Paris, France. AP-HP, Cochin Hospital, Ophthalmology Department, Paris, France. Centre Hospitalier Saint Joseph Saint Luc, Internal medicine department, Lyon, France. Foch Hospital, Internal Medicine department, Suresnes, France. AP-HP, Henri Mondor Hospital, Internal Medicine department, Creteil, France. AP-HP, La Pitié-Salpêtrière Hospital, Internal Medicine department, Centre de référence maladies auto-immunes et systémiques rares de l'Ile de France, Paris, France. Normandie Université, UNIROUEN, Inserm U1096, Rouen university hospital, department of internal medicine, vascular and thrombosis unit, 76000 Rouen, France. Univ. Lille ; INSERM U1167 ; CHU Lille, Internal Medicine department, Centre National de Référence Maladies Systémiques et Auto-Immunes Rares, European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases (ReCONNECT), F-59000 Lille, France Department of Internal Medicine, CHU de Saint-Etienne, France. Université Paris Descartes-Sorbonne Paris Cité, Paris, France ; INSERM U 1153, Center for Epidemiology and Statistics, Sorbonne Paris Cité (CRESS), Paris, France.

Purpose: To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome (CAPS).

Methods: Retrospective case series of patients presenting with CAPS and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at CAPS diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best corrected visual acuity (BCVA).

Results: This study included 23 patients (11 cases treated by the authors and 12 published case reports), 21 (91%) of them female. Their median age at diagnosis was 28 years (range 16-79). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n=11, 48%), and/or retinal vasculitis (n = 1, 4%). Final BCVA was not significantly worse than BCVA at diagnosis (P = 0.16). Retinal vascular occlusions were associated with poorer final visual acuity than choroidopathy (P = 0.002). After a median follow-up of 14 months [2-132], nearly half the patients (n = 11, 48%) had permanent vision loss including BCVA < 20/400 for 4 patients.

Conclusion: Posterior ophthalmic manifestations of CAPS were mainly bilateral retinal vascular occlusion, which had the worst visual prognosis, followed by choroidopathy and retinal vasculitis. Permanent visual loss was common.
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http://dx.doi.org/10.1097/IAE.0000000000003185DOI Listing
April 2021

Is the presence of antiphospholipid antibodies a poor prognostic factor for patients with hemolysis, elevated liver enzymes, and low platelet count syndrome?

Am J Obstet Gynecol 2021 Apr 1. Epub 2021 Apr 1.

Internal Medicine and Clinical Immunology Department, Reference Center for Rare Systemic Autoimminue Diseases of North and Northwest France (CeRAINO), European Reference Network on Rare Connective Tissues and Musculoskeletal Diseases (ReCONNECT), Centre Hospitalier Universitaire de Lille, Lille, France.

Background: The characteristics of antiphospholipid syndrome-associated hemolysis, elevated liver enzymes, and low platelet count syndrome are poorly described, likely because of the low frequency of this combination of syndromes.

Objective: This study aimed to compare the characteristics and prognosis of hemolysis, elevated liver enzymes, and low platelet count syndrome in patients with and without antiphospholipid syndrome.

Study Design: In this multicenter, case-control study, adult women diagnosed with hemolysis, elevated liver enzymes, and low platelet count syndrome before 34 weeks' gestation and who were also tested for antiphospholipid antibodies according to international diagnostic recommendations were included. Cases labeled "HELLP-APS+" were defined as patients who fulfilled the international classification criteria for antiphospholipid syndrome; they were retrospectively recruited by screening the 672 patients with antiphospholipid syndrome in our antiphospholipid syndrome database. Control cases labeled "HELLP-APS-" were defined as patients who did not fulfill the criteria for antiphospholipid syndrome; they were retrospectively recruited from our hospital admission database.

Results: Overall, 71 patients were included (mean age, 30±5 years), with 23 patients in the hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome group and 48 patients in the hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome group. The live birth rate was significantly lower for patients with hemolysis, elevated liver enzymes, and low platelet count with antiphospholipid syndrome than for those with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (43.5% vs 89.4%; P<.001). The patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome gave birth prematurely more often than the patients without antiphospholipid syndrome (24 weeks' gestation; 22.0-28.0 weeks vs 30 weeks' gestation; 27.0-33.0 weeks; P<.001). Among the patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome, 39% required an induced abortion owing to hemolysis, elevated liver enzymes, and low platelet count syndrome severity vs 8.5% of the patients with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (P=.006). The intensive care unit admission rate was 61.9% in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome, which was significantly higher than the rate of 27.7% in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (P=.007). None of the mothers died.

Conclusion: Our results suggest that the presence of antiphospholipid syndrome is a poor prognostic factor for both the mother and fetus in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome.
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http://dx.doi.org/10.1016/j.ajog.2021.03.039DOI Listing
April 2021

Evolution of kidney antibody secreting cells molecular signature in lupus patients with active nephritis upon immunosuppressive therapy.

Arthritis Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

Institut Necker Enfants Malades, INSERM U1151/CNRS UMS 8253, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objectives: To characterize kidney and urine antibody secreting cells (ASC) from patients with active lupus nephritis (LN), before and after induction therapy.

Methods: We included patients with biopsy proven active LN and performed anti-CD138 staining of kidney biopsy samples to visualize ASC. We performed single-cell gene expression profiling on sorted ASC from fresh biopsy samples by multiplex RT-PCR. We used a gene set allowing the study of ASC maturation from plasmablast to long-lived plasma cells. We quantified urine ASC from untreated LN patients at diagnosis and after 6 months of prospective follow up during induction therapy.

Results: The number of kidney CD138+ ASC in 46 untreated LN patients correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASC from 3 untreated patients had a plasmablast molecular signature, contrasting with ASC from 4 patients refractory to immunosuppressant drugs that expressed long-lived plasma cells genes and clustered with long-lived bone marrow plasma cells from 2 healthy donors. Some urine ASC with plasmablast signature were detected in patients with untreated active LN. The presence of urine ASC at 6 months was associated with treatment failure.

Conclusion: These results suggest a potential interest of ASC-directed therapy in refractory LN.
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http://dx.doi.org/10.1002/art.41703DOI Listing
March 2021

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance.

Ann Rheum Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Medicine, Division of Rheumatology, University of California at San Francisco and the VA Medical Center, San Francisco, California, USA.

Background/objectives: 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.
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http://dx.doi.org/10.1136/annrheumdis-2020-219373DOI Listing
February 2021

Improving medication adherence in patients with lupus nephritis.

Kidney Int 2021 02;99(2):285-287

Service de Rhumatologie, Cliniques Universitaires Saint-Luc, 10 avenue Hippocrate, 1200 Bruxelles, Belgique; Pôle de pathologies rhumatismales inflammatoires et systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Louvain-la-Neuve, Belgium.

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http://dx.doi.org/10.1016/j.kint.2020.10.037DOI Listing
February 2021

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

Nat Rev Rheumatol 2021 03 6;17(3):177-184. Epub 2021 Jan 6.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.
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http://dx.doi.org/10.1038/s41584-020-00565-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786339PMC
March 2021

Longitudinal Analysis of Fetal Ventricular Rate for Risk Stratification in Immune Congenital Heart Block.

Fetal Diagn Ther 2021 9;48(1):1-8. Epub 2020 Dec 9.

Obstetrics, Fetal Medicine and Surgery, Hôpital Necker Enfants Malades, Paris, France,

Objectives: To assess the perinatal risks of immune complete congenital heart block (iCCHB) based on the longitudinal analysis of fetal heart rate.

Methods: Retrospective analysis of a cohort of grade III congenital heart block diagnosed in utero, in the absence of associated cardiac defect, with positive maternal serum antibodies. Longitudinal measurements of the fetal heart rate were used to estimate the average slope of ventricular rate as a function of gestational age. We then defined the following prognostic stratification based on longitudinal follow-up observations: the high-rate (HR) group included cases for which all prenatal ventricular rate measurements were above the age-specific mean of our population of iCCHB and the low-rate (LR) group included those with at least one observation below the mean during follow-up. The 2 groups were compared to analyze the potential relationship between prenatal ventricular rate and adverse neonatal outcome defined by in utero or perinatal death, neonatal heart rate <50 bpm, or hemodynamic failure requiring emergency pacing.

Results: Forty-four cases were studied. Overall, the average heart rate significantly decreased during gestation from 65 bpm at 20 weeks to 55 bpm at 38 weeks. The HR and LR groups included 18 (41%) and 26 (59%) cases, respectively. Adverse perinatal outcome occurred in 1/18 (6%) and 22/26 (85%) cases in the HR and LR groups, respectively (p < 0.001). In the HR group, 33% of cases remained nonpaced at >6 months. The positive predictive values and negative predictive values for adverse perinatal outcome in the LR group were 85% (22/26) and 94% (17/18), respectively (100 and 80% <30 weeks and 88 and 78% at ≥30 weeks).

Conclusions: The prognostic classification we developed based on longitudinal heart rate assessment may be used in the late 2nd or early 3rd trimester to identify iCCHB cases at high risk of adverse perinatal outcome. This prognostic stratification should help refine counseling and perinatal management earlier in pregnancy instead of waiting for late gestation or predelivery assessment.
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http://dx.doi.org/10.1159/000507811DOI Listing
December 2020

Pulmonary hypertension associated with congenital heart block and neonatal lupus syndrome: A series of four cases.

Lupus 2021 Feb 16;30(2):307-314. Epub 2020 Nov 16.

M3C-Necker, Hôpital Universitaire Necker-Enfants malades, Paris, France.

Objective: Neonatal lupus syndrome has multisystemic manifestations among which pulmonary involvement has been rarely reported. We describe the clinical presentation, management, and outcome of a series of four neonates who developed reversible pulmonary hypertension associated with auto-immune congenital complete heart block.

Method: Data from the French registry of neonatal lupus syndrome were retrospectively reviewed.

Results: Between 2000 and March 2020, 231 children were included in the French registry, four/73 followed in our institution developed pulmonary hypertension. Diagnosis was suspected on transthoracic echocardiography at a median age of 42 days [range 10-58], and confirmed by right heart catheterization in all; 2 of them where paced at time of diagnosis and 2 were not. All had some degree of hypoxemia and respiratory distress. Hypoxemia was always reversible under O et NO. Lung CT demonstrated ground glass anomalies in all. One patient had a lung biopsy consistent with pulmonary hypertension secondary to lung disease. Management included immunosuppressive therapy in 3 associated with sildenafil in 2. Pulmonary hypertension resolved in all at a median age of 4 weeks [range 3-6] after treatment initiation and after one year for the one child who did not receive specific treatment.

Conclusion: Clinical, hemodynamical, imaging and histological findings advocate for pulmonary hypertension associated with respiratory disease as a rare manifestation of neonatal lupus syndrome.
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http://dx.doi.org/10.1177/0961203320973073DOI Listing
February 2021

Different Control Populations May Lead to Different Understanding of Hydroxychloroquine Blood Levels as a Risk Factor for Retinopathy: Comment on the Article by Petri et al.

Arthritis Rheumatol 2021 04 22;73(4):715. Epub 2021 Feb 22.

Centre de Référence des Maladies Auto-Immunes, et Systémiques Rares d'Ile de France, Cochin Hospital AP-HP, Université de Paris, and INSERM Unité 1153 Center for Epidemiologyand Statistics, Paris, France.

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http://dx.doi.org/10.1002/art.41588DOI Listing
April 2021

EULAR recommendations for a core data set for pregnancy registries in rheumatology.

Ann Rheum Dis 2021 01 14;80(1):49-56. Epub 2020 Oct 14.

Epidemiology and Health Care Research, German Rheumatism Research Center Berlin, Berlin, Germany.

Background And Objective: There is an urgent need for robust data on the trajectories and outcomes of pregnancies in women with inflammatory rheumatic diseases (IRD). In particular when rare outcomes or rare diseases are to be investigated, collaborative approaches are required. However, joint data analyses are often limited by the heterogeneity of the different data sources.To facilitate future research collaboration, a European League Against Rheumatism (EULAR) Task Force defined a core data set with a minimum of items to be collected by pregnancy registries in rheumatology covering the period of pregnancy and the 28-day neonatal phase in women with any underlying IRD.

Methods: A stepwise process included a two-round Delphi survey and a face-to-face meeting to achieve consensus about relevant items.

Results: A total of 64 multidisciplinary stakeholders from 14 different countries participated in the two rounds of the Delphi process. During the following face-to-face meeting of the EULAR Task Force, consensus was reached on 51 main items covering 'maternal information', 'pregnancy' and 'treatment'. Generic instruments for assessment are recommended for every item. Furthermore, for the five most frequent IRDs rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and other connective tissue diseases, disease-specific laboratory markers and disease activity measurements are proposed.

Conclusion: This is the first consensus-based core data set for prospective pregnancy registries in rheumatology. Its purpose is to stimulate and facilitate multinational collaborations that aim to increase the knowledge about pregnancy course and safety of treatment in women with IRDs during pregnancy.
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http://dx.doi.org/10.1136/annrheumdis-2020-218356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788063PMC
January 2021

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

Arthritis Res Ther 2020 09 25;22(1):223. Epub 2020 Sep 25.

UPMC, Université Paris 6, Paris, France.

Background: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients.

Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.

Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).

Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.
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http://dx.doi.org/10.1186/s13075-020-02291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517694PMC
September 2020

Pregnancy rates and outcomes in early axial spondyloarthritis: An analysis of the DESIR cohort.

Joint Bone Spine 2021 Mar 15;88(2):105075. Epub 2020 Sep 15.

Rheumatology department, Cochin Hospital, Paris, France; INSERM U-1153, Center for Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris-Sorbonne, Paris, France.

Objectives: Only scarce data is available regarding pregnancy outcomes in early axSpA, particularly little is known about the impact of disease activity. The objective is to identify (a) the factors associated with the occurrence of a clinical pregnancy during follow-up and (b) the risk factors for an unfavorable pregnancy outcome (e.g. miscarriage, medical termination or pre-term delivery) in an early axSpA population.

Methods: Observational prospective French cohort (DESIR) with 6 years of follow-up including 381 TNFi-naïve women with early axSpA. Factors associated with a clinical pregnancy occurring over follow-up and risk factors for an unfavorable pregnancy outcome were estimated by multivariable multilevel models (i.e. Frailty Shared Models and Mixed Models).

Results: During follow-up, 124 pregnancies occurred. Patients who got pregnant during follow-up were more likely to have discontinued their TNFi treatment in the 6 months preceding the pregnancy (HR=2.0 [95% CI 1.1-3.3], P=0.01) and to have an increased CRP at the previous visit (HR=1.7 [95% CI 1.2-2.5], P=0.01). Full-term delivery was by far the most frequent pregnancy outcome (75% of all pregnancies), and only NSAID use in the 6 months prior to the outcome was associated with an unfavorable outcome (OR=2.5 [95% CI 1.1-5.0], P=0.02). No association was found between TNFi use and an unfavorable pregnancy outcome.

Conclusion: Full-term delivery was the most frequent pregnancy outcome. NSAID use within 6 months of outcome, but not TNFi use, was associated with an unfavorable pregnancy outcome in this early axSpA cohort.
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http://dx.doi.org/10.1016/j.jbspin.2020.09.007DOI Listing
March 2021

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation.

Circ Arrhythm Electrophysiol 2020 10 9;13(10):e008686. Epub 2020 Sep 9.

New York University School of Medicine, New York, NY (R. Clancy, C.K.P., R. Cohen, M.M., B.J.W., A.S., P.M.I., J.P.B.).

Background: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy.

Methods: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies.

Results: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (=0.02, =0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (=0.04, =0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal.

Conclusions: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.
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http://dx.doi.org/10.1161/CIRCEP.120.008686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668319PMC
October 2020

Highly sensitive serum cardiac troponin T and cardiovascular events in patients with systemic lupus erythematosus (TROPOPLUS study).

Rheumatology (Oxford) 2021 03;60(3):1210-1215

Département de Médecine Interne, Hôpital Bichat, Assistance Publique Hôpitaux de Paris (APHP), Institut national de la santé et de la recherche médicale (INSERM) U1149, Université de Paris, France.

Objective: Identification of biological markers able to better stratify cardiovascular risks in SLE patients is needed. We aimed to determine whether serum cardiac troponin T (cTnT) levels measured with a highly sensitive assay [high sensitivity cTnT (HS-cTnT)] may predict cardiovascular events (CVEs) in SLE.

Method: All SLE patients included between 2007 and 2010 in the randomized, double-blind, placebo-controlled, multicentre PLUS trial were screened. Patients with no past history of CVE at inclusion and a follow-up period of >20 months were analysed. HS-cTnT concentration was measured using the electrochemiluminescence method on serum collected at PLUS inclusion. The primary outcome was the incident CVE. Factors associated with the primary outcome were identified and multivariate analysis was performed.

Results: Overall, 442 SLE patients (of the 573 included in the PLUS study) were analysed for the primary outcome with a median follow up of 110 (interquartile range: 99-120) months. Among them, 29 (6.6%) experienced at least one CVE that occurred at a median of 67 (interquartile range: 31-91) months after inclusion. Six out of 29 patients had more than one CVE. In the multivariate analysis, dyslipidaemia, age and HS-cTnT were associated with the occurrence of CVE. Kaplan-Meier analysis showed that a concentration of HS-cTnT > 4.27 ng/l at inclusion increased by 2.7 [hazard ratio 2.7 (95% CI: 1.3, 5.6), P =0.0083] the risk of CVE in SLE.

Conclusion: HS-cTnT measured in serum is the first identified biomarker independently associated with incident CVE in SLE patients.
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http://dx.doi.org/10.1093/rheumatology/keaa434DOI Listing
March 2021

Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities.

Ann Rheum Dis 2020 10 14;79(10):1333-1339. Epub 2020 Aug 14.

Rheumatology, Azienda Ospedaliero Universitaria Pisana, Pisa, Toscana, Italy.

Objectives: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria.

Methods: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated.

Results: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to <3 years (n=196) and ≥5 years (n=879). Among patients with 1 to <3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 81%). The EULAR/ACR criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). Among women, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% vs 83%) and better specificity than the SLICC criteria (94% vs 82%). Among white patients, the EULAR/ACR criteria had better sensitivity than the ACR criteria (95% vs 83%) and better specificity than the SLICC criteria (94% vs 83%). The EULAR/ACR criteria performed well among black patients (sensitivity of 98%, specificity 100%), and had better sensitivity than the ACR criteria among Hispanic patients (100% vs 86%) and Asian patients (97% vs 77%).

Conclusions: The EULAR/ACR 2019 criteria perform well among patients with early disease, men, women, white, black, Hispanic and Asian patients. These criteria have superior sensitivity than the ACR criteria and/or superior specificity than the SLICC criteria across many subgroups.
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http://dx.doi.org/10.1136/annrheumdis-2020-217162DOI Listing
October 2020

Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

J Am Coll Cardiol 2020 07;76(3):292-302

New York University School of Medicine, New York, New York. Electronic address: https://twitter.com/JillBuyonMD.

Background: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB).

Objectives: Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB.

Methods: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash.

Results: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4).

Conclusions: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).
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http://dx.doi.org/10.1016/j.jacc.2020.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394202PMC
July 2020

Exome sequencing for diagnosis of congenital hemolytic anemia.

Orphanet J Rare Dis 2020 07 8;15(1):180. Epub 2020 Jul 8.

Univ Paris Est Creteil, INSERM, IMRB, F-94010, Creteil, France.

Background: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis.

Results: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients.

Conclusion: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.
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http://dx.doi.org/10.1186/s13023-020-01425-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341591PMC
July 2020

Fluorinated steroids are not superior to any treatment to ameliorate the outcome of autoimmune mediated congenital heart block: a systematic review of the literature and meta-analysis.

Clin Exp Rheumatol 2020 Jul-Aug;38(4):783-791. Epub 2020 Jun 23.

Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Italy.

Objectives: Fluorinated steroids are largely the therapeutic approach of autoimmune mediated congenital heart block (CHB). We performed a meta-analysis to assess the efficacy of fluorinated steroids for the treatment of CHB.

Methods: Studies evaluating the efficacy of fluorinated steroids versus no treatment in CHB patients were identified in electronic databases. Random-effects model was used to pool odds ratio (OR) (with 95% CI) of live births as the primary outcome. ORs of CHB progression, pacemaker implantation and extranodal disease were the secondary outcome. Subgroup analysis according to CHB grade and study type was performed.

Results: Data from nine studies involving 747 patients were analysed. The overall live birth rates were 86.8% and 86.7%, respectively, in the fluorinated steroids exposed foetuses and in the non-exposed ones. Fluorinated steroids did not ameliorate overall survival in CHB (OR 1.02; 95% CI: 0.65-1.61) with any significant statistical heterogeneity between studies (I2 0%, p=0.45). No significant differences for the progression of CHB, the pacing and the presence of extranodal disease were observed. Subgroup analysis revealed a significant protective role of fluorinated steroids for survival in 3rd degree CHB and for pacing in monocentric studies, OR 4.07; 95% CI: 1.10-15.08 and OR 0.15; 95% CI: 0.02-0.99, respectively.

Conclusions: This meta-analysis shows that fluorinated steroids are not superior to any treatment in patients with CHB in terms of live birth, prevention of progression of incomplete CHB, pacemaker implantation and extranodal disease. Thus, considering their side effects, their use in CHB patients should be discouraged.
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September 2020

Commentary: First Report of the Italian Registry on Immune-Mediated Congenital Heart Block (Lu.Ne Registry).

Front Cardiovasc Med 2020 7;7:83. Epub 2020 May 7.

AP-HP, Cochin Hospital, Internal Medicine Department, Referral center for Rare Autoimmune and Systemic Diseases, Paris, France.

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http://dx.doi.org/10.3389/fcvm.2020.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221119PMC
May 2020