Publications by authors named "Bertrand Godeau"

154 Publications

Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Haematologica 2021 Feb 25. Epub 2021 Feb 25.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), F-75012, Paris.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.
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http://dx.doi.org/10.3324/haematol.2020.272559DOI Listing
February 2021

Thrombocytopenia following Pfizer and Moderna SARS/CoV-2 vaccination.

Am J Hematol 2021 Feb 19. Epub 2021 Feb 19.

Division of Pediatric Hematology/Oncology, New York Presbyterian Hospital, New York, NY.

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http://dx.doi.org/10.1002/ajh.26132DOI Listing
February 2021

Romiplostim in adults with newly diagnosed or persistent immune thrombocytopenia.

Expert Rev Hematol 2020 12 30;13(12):1319-1332. Epub 2020 Nov 30.

Division of Hematology, Massachusetts General Hospital, Harvard Medical School , Boston, MA, USA.

: Three distinct phases are recognized in immune thrombocytopenia (ITP): newly diagnosed (≤3 months after diagnosis), persistent (>3-12 months after diagnosis), and chronic (>12 months). Several international guidelines/expert recommendations have been released in the past 2 years regarding the treatment of newly diagnosed/persistent ITP. : Across the guidelines/expert recommendations, thrombopoietin receptor agonists (TPO-RAs), including romiplostim (the focus of this review), are recommended in newly diagnosed or persistent ITP for patients who fail to respond to corticosteroids or intravenous immunoglobulin (or where these are contraindicated). To identify data relating to romiplostim in adults with newly diagnosed or persistent ITP, we conducted a search of PubMed (with no time limit applied) and abstracts from 2019 EHA/ASH meetings using the term 'romiplostim.' : The findings from nine clinical trials, six real-world studies and ten case reports provide insight into the early use of romiplostim, which could help to reduce exposure to the adverse effects associated with prolonged corticosteroid use, as well as reduce the risk of severe bleeding. Additionally, given the durable responses observed in patients with newly diagnosed/persistent ITP, as well as the potential for treatment-free responses following discontinuation, romiplostim might help to avoid the need for subsequent treatment.
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http://dx.doi.org/10.1080/17474086.2020.1850253DOI Listing
December 2020

Procalcitonin to Reduce Antibiotic Exposure during Acute Chest Syndrome in Adult Patients with Sickle-Cell Disease.

J Clin Med 2020 Nov 19;9(11). Epub 2020 Nov 19.

DHU A-TVB, Service de Médecine Intensive Réanimation, 51 Avenue du Maréchal de Lattre de Tassigny, AP-HP Hôpitaux Universitaires Henri Mondor, 94010 Créteil, France.

Acute chest syndrome (ACS) is a major complication of sickle-cell disease. Bacterial infection is one cause of ACS, so current guidelines recommend the routine use of antibiotics. We performed a prospective before-after study in medical wards and an intensive-care unit (ICU). During the control phase, clinicians were blinded to procalcitonin concentration results. We built an algorithm using the obtained measurements to hasten antibiotic cessation after three days of treatment if bacterial infection was not documented, and procalcitonin concentrations were all <0.5 μg/L. During the intervention period, the procalcitonin algorithm was suggested to physicians as a guide for antibiotic therapy. The primary endpoint was the number of days alive without antibiotics at Day 21. One-hundred patients were analyzed (103 ACS episodes, 60 in intervention phase). Possible or proven lung infection was diagnosed during 13% of all ACS episodes. The number of days alive without antibiotics at Day 21 was higher during the intervention phase: 15 [14-18] vs. 13 [13,14] days ( = 0.001). More patients had a short (≤3 days) antibiotic course during intervention phase: 31% vs 9% ( = 0.01). There was neither infection relapse nor pulmonary superinfection in the entire cohort. A procalcitonin-guided strategy to prescribe antibiotics in patients with ACS may reduce antibiotic exposure with no apparent adverse outcomes.
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http://dx.doi.org/10.3390/jcm9113718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699579PMC
November 2020

High dose romiplostim as a rescue therapy for adults with severe bleeding and refractory immune thrombocytopenia.

Am J Hematol 2021 02 23;96(2):E43-E46. Epub 2020 Nov 23.

Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France.

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http://dx.doi.org/10.1002/ajh.26040DOI Listing
February 2021

Use of Biologics to Treat Relapsing and/or Refractory Eosinophilic Granulomatosis With Polyangiitis: Data From a European Collaborative Study.

Arthritis Rheumatol 2021 Mar 23;73(3):498-503. Epub 2021 Jan 23.

National Referral Center for Rare Systemic and Autoimmune Diseases, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France.

Objective: To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: A retrospective European collaborative study was conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease.

Results: Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range [IQR] 5-13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1-4.5) and the median BVAS in the MEPO group was 2 (IQR 1-5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0-4.5) and at 12 months (median 0, IQR 0-2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)-dependent asthma, patients who received MEPO had a much better GC-sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively.

Conclusion: These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC-dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first-line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.
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http://dx.doi.org/10.1002/art.41534DOI Listing
March 2021

Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial.

Haematologica 2020 08 13. Epub 2020 Aug 13.

Centre Hospitalier Universitaire Henri-Mondor, Université Paris Est Creteil, Creteil, France.

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety.
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http://dx.doi.org/10.3324/haematol.2020.259481DOI Listing
August 2020

Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study.

Blood 2020 Dec;136(26):3056-3061

Department of Internal Medicine, National Reference Center for Immune Cytopenias, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Creteil, Créteil, France.

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.
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http://dx.doi.org/10.1182/blood.2020007594DOI Listing
December 2020

Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series.

Br J Haematol 2020 08 4;190(4):e224-e229. Epub 2020 Aug 4.

Department of Internal Medicine, National Referral Center for Adult's Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France.

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http://dx.doi.org/10.1111/bjh.17024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404899PMC
August 2020

Letter responds to the comment in 'immune thrombocytopenia of haematological immune-related adverse events in cancer immunotherapy: Most and mighty'.

Eur J Cancer 2020 07 26;134:60-61. Epub 2020 May 26.

Hôpitaux de Paris, Hôpital Bicêtre, Médecine Interne et Immunologie Clinique, F-94275, Le Kremlin-Bicêtre, France; INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, F-94276, Le Kremlin-Bicêtre, France; Université Paris Sud, UMR 1184, F-94276, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, F-92265, Fontenay-aux-Roses, France.

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http://dx.doi.org/10.1016/j.ejca.2020.03.012DOI Listing
July 2020

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.

BMJ 2020 May 14;369:m1844. Epub 2020 May 14.

Centre for Clinical Epidemiology, Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris, Centre of Research in Epidemiology and Statistics, Paris, France.

Objective: To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.

Design: Comparative observational study using data collected from routine care.

Setting: Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.

Participants: 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.

Interventions: Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).

Main Outcome Measures: The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.

Results: In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.

Conclusions: Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.
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http://dx.doi.org/10.1136/bmj.m1844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221472PMC
May 2020

Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine.

Ann Rheum Dis 2020 06 24;79(6):837-839. Epub 2020 Apr 24.

Sorbonne Université, Assistance Publique - Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-217566DOI Listing
June 2020

Utilization of intravenous or subcutaneous immunoglobulins in secondary immune deficiency (ULTIMATE): A retrospective multicenter study.

Clin Immunol 2020 06 11;215:108419. Epub 2020 Apr 11.

Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Service de Médecine Interne, Hôpital Henri Mondor, AP-HP, Créteil, France. Electronic address:

Introduction: We conducted a retrospective multicenter cohort study of patients receiving Immunoglobulin replacement therapy (IgRT) for secondary immune deficiency (SID) during 2012.

Methods: Data were retrospectively collected from the first dose of Ig administered in 2012 to 1 year afterward in terms of the indication for IgRT, as well as efficacy and safety.

Results: In total, 16 hospitals participated in the study, and 368 patients were included. Indications for IgRT were non-Hodgkin lymphoma (82 [22.3%] patients), multiple myeloma (76 [20.7%]), chronic lymphocytic leukemia (64 [17.4%]) and other (79 [21.5%]). Only 89 (24.2%) patients received IgRT according to 2011 European Medical Agency (EMA) recommendations; 196 (53.3%) received prophylactic antibiotics and 262 (76.2%) had an IgG level < 4 g/L before IgRT initiation.

Conclusion: In this study, whatever the criteria, only 24.2% of patients with SID who received IgRT met EMA recommendations, which suggests a misuse of IgRT in SID.
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http://dx.doi.org/10.1016/j.clim.2020.108419DOI Listing
June 2020

Analysis of risk factors for complications and adverse obstetrical outcomes in women with Takayasu arteritis: a French retrospective study and literature review.

Clin Rheumatol 2020 Sep 23;39(9):2707-2713. Epub 2020 Mar 23.

Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne, Hôpital Avicenne, Université Paris 13, 93000, Bobigny, France.

Objective: Takayasu arteritis (TAK) is a large vessel vasculitis affecting young women of childbearing age. The outcome of pregnancies in TAK patients, factors associated with maternal and foetal complications and adverse outcomes were analysed.

Methods: All pregnancies in women with a TAK diagnosis were retrospectively included from 20 French hospitals providing care for TAK, until August 2015.

Results: The study consisted of 43 pregnancies in 33 women, including 29 with a pre-existing TAK diagnosis and 4 diagnosed during pregnancy. Complications were observed in 20 pregnancies (47%), including 35% with arterial hypertension (n = 15), 9% with pre-eclampsia (n = 4), 2% with HELLP syndrome (n = 1) and 14% with intrauterine growth restriction (IUGR, n = 6, leading in one case to a medically indicated termination of pregnancy). There were 42 live births (98%) at a median term of 38 [27-42] weeks gestation including 9 before 37 weeks (21%). The median birth weight was 2940 [610-4310] grams. Five children (12%) required transfer to a neonatal intensive care unit. One premature boy (27 weeks gestation) died after 2 days. Treatment during pregnancy included steroids (n = 25/43; 58%), azathioprine (n = 9/43; 21%) and infliximab (n = 1/43; 2%). The risk of developing arterial hypertension during pregnancy was associated with previous chronic arterial hypertension and with an infra-diaphragmatic vasculitis injury (P = 0.01 and P = 0.04, respectively). No correlation was reported between TAK activity and any of the obstetrical complications described in the study.

Conclusion: This study showed a high rate of adverse obstetrical complications without significant impact on live birth rates. Pregnancy did not appear to influence TAK disease activity. Key Points • We observed a high rate of adverse obstetrical complications in women with Takayasu arteritis; however, the rate of live births was high. Pregnancy did not appear to influence TA disease activity.
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http://dx.doi.org/10.1007/s10067-020-05024-4DOI Listing
September 2020

Matrix therapy is a cost-effective solution to reduce amputation risk and improve quality of life: pilot and case studies.

Regen Med Res 2019 10;7. Epub 2019 Dec 10.

OTR3, SAS, 4 rue Française, 75001 Paris, France - CRRET (EA 4397/ERL CNRS 9215), Université Paris-Est, Créteil 94010, France.

Introduction: Chronic, non-healing ulcers remain one of the most challenging clinical situations for health care practitioners. Often, conventional treatments fail and lead to amputation, further decreasing the patient's quality of life and resulting in enormous medical expenditures for healthcare systems. Here we evaluated the use of and cost-effectiveness of the RGTA (ReGeneraTing Agents) medical device CACIPLIQ20 (OTR4120) for chronic lower-extremity ulcers in patients with Leriche and Fontaine Stage IV peripheral arterial disease who were not eligible for revascularization.

Methods: This uncontrolled pilot study included 14 chronic lower extremity ulcers in 12 patients in one hospital. The pilot study included 12 patients with TcPO < 20 mm Hg and ABPI < 0.5 who had either a minimum of one chronic lower extremity ulcer or a chronic ulcer related to amputation. OTR4120 was applied twice a week or until complete healing, for up to 12 weeks. Ulcer surface area reduction (%)after 2, 4, 8 and 12 weeks, appearance after 4 weeks, and healing after 12 weeks were measured and recorded.

Results: A 35% reduction in ulcer size was achieved after 4 weeks. 7 (50%) out of 14 ulcers completely healed within 1 to 3 months of treatment.

Discussion: OTR4120 is an effective therapeutic option for patients with chronic lower extremity ulcers, can provide major improvement of quality of life and has the added benefit of being a significant cost-effective solution for healthcare systems.
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http://dx.doi.org/10.1051/rmr/190002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902838PMC
December 2019

Updated international consensus report on the investigation and management of primary immune thrombocytopenia.

Blood Adv 2019 11;3(22):3780-3817

Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.
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http://dx.doi.org/10.1182/bloodadvances.2019000812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880896PMC
November 2019

Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux.

Am J Hematol 2019 12 8;94(12):1314-1324. Epub 2019 Oct 8.

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.

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option.
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http://dx.doi.org/10.1002/ajh.25632DOI Listing
December 2019

Second-line and beyond: treatment options for primary persistent and chronic immune thrombocytopenia.

Platelets 2020 5;31(3):291-299. Epub 2019 Jul 5.

Service de Médecine Interne, Centre 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.

Less than 40% of patients with newly diagnosed adult immune thrombocytopenia will show spontaneous recovery within 12 months. Therefore, second-line treatments are frequently used to maintain a hemostatic platelet count or at best to cure the disease, with as few adverse effects as possible. Nevertheless, we lack head-to-head comparison studies of the different available treatments. Moreover, physicians have no robust predictors of response to guide decision-making on an individual basis. Therefore, there is no consensus, and decisions when to treat and with which drug must be individualized and shared with the patient based on factors related to the patient and the available second-line treatments. The main treatments used, based on their good benefit-risk ratio, are splenectomy, rituximab, and thrombopoietin-receptor agonists, but their prescription should be avoided in some situations and can be limited due to cost or to health authorities' restrictions on funding the last two drugs. This review presents the various second-line treatments used in primary persistent or chronic immune thrombocytopenia in adults and discusses their prescription in general and specific situations.
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http://dx.doi.org/10.1080/09537104.2019.1636018DOI Listing
September 2020

Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia.

Ther Adv Hematol 2019 9;10:2040620719837906. Epub 2019 May 9.

ASST San Gerardo Hospital, Monza, Italy.

Primary immune thrombocytopenia (ITP) is a bleeding disorder that conventionally has been treated with steroids or other immunosuppressive treatments. The introduction of thrombopoietin receptor agonists (TPO-RAs), which increase platelet production, dramatically changed the treatment landscape for ITP by providing patients with well-tolerated, long-term treatment options. Two TPO-RAs, eltrombopag and romiplostim, have been approved in the United States and European Union for the treatment of ITP. Some patients do not benefit from the first TPO-RA they receive, so it is assumed that the alternate TPO-RA would have the same outcome. However, eltrombopag and romiplostim have distinct pharmacodynamic and pharmacokinetic properties and may have different tolerability and efficacy in individual patients with ITP. Published retrospective studies showed that >75% of patients who switched to the alternate TPO-RA maintained or achieved a response with the new treatment. Notably, most patients who switched due to lack of efficacy with the first TPO-RA responded to the alternate TPO-RA, which demonstrates an absence of cross-resistance between the two drugs. Therefore, switching to the alternate TPO-RA if the first TPO-RA fails to demonstrate a response should be considered before the use of a less-preferable option.
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http://dx.doi.org/10.1177/2040620719837906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515841PMC
May 2019

Bortezomib and dexamethasone, an original approach for treating multi-refractory warm autoimmune haemolytic anaemia.

Br J Haematol 2019 10 2;187(1):124-128. Epub 2019 Jun 2.

Service de Médecine Interne, Centre national de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

We report the off-label use of bortezomib combined with dexamethasone in eight adults with severe and multi-refractory warm auto-immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1-4) cycles. After a median follow-up of 14 (6-36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults.
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http://dx.doi.org/10.1111/bjh.16009DOI Listing
October 2019

Thrombopoietin receptor agonists: ten years later.

Haematologica 2019 06 9;104(6):1112-1123. Epub 2019 May 9.

Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.

The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety and tolerability. TPO-RA were shown to be effective in reducing bleeding and the need for concomitant or rescue medication. Many other investigations of their mechanism of effect, prospective and retrospective trials, and studies focusing on toxicity have been performed widening our knowledge of these two agents. Initial concerns on issues such as myelofibrosis have not been confirmed. Only a small number of patients develop moderate-severe reticulin fibrosis and/or collagen fibrosis; however, these are usually reversed after discontinuation of TPO-RA. Studies indicate, however, that TPO-RA may increase the risk of venous thromboembolism. Both TPO-RA are currently approved in patients with chronic ITP aged >1-year who are refractory to at least one other treatment. Eltrombopag has acquired two additional indications: severe aplastic anemia refractory to first-line treatment and hepatitis C patients undergoing treatment with interferon-ribavirin. Despite these wide-ranging studies, important questions still need to be answered. This summary review on TPO-RA will summarize what is known regarding efficacy in ITP, evaluate safety concerns in more depth, and focus on the questions that remain.
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http://dx.doi.org/10.3324/haematol.2018.212845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545830PMC
June 2019

Update in Neurocritical Care: a summary of the 2018 Paris international conference of the French Society of Intensive Care.

Ann Intensive Care 2019 Apr 16;9(1):47. Epub 2019 Apr 16.

Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070, Brussels, Belgium.

The 2018 Paris Intensive Care symposium entitled "Update in Neurocritical Care" was organized in Paris, June 21-22, 2018, under the auspices of the French Intensive Care Society. This 2-day post-graduate educational symposium comprised several chapters, aiming first to provide all-board intensivists with current standards for the clinical assessment of altered consciousness states (including coma and delirium) and peripheral nervous system in critically ill patients, monitoring of brain function (specifically, electro-encephalography) and best practices for sedation-analgesia-delirium management. An update on the treatment of specific severe brain pathologies-including ischaemic/haemorrhagic stroke, cerebral venous thrombosis, hypoxic-ischaemic brain injury, immune-mediated and infectious encephalitis and refractory status epilepticus-was also provided. Finally, we discuss how to approach some difficult decisions, namely the role of decompressive craniectomy and prognostication models in patients with head injury. For each chapter, the scope of the present review was to provide important issues and key messages, provide most recent and relevant literature in the field, and briefly describe new developments in the field.
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http://dx.doi.org/10.1186/s13613-019-0523-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468018PMC
April 2019

Clinical spectrum, evolution, and management of autoimmune cytopenias associated with angioimmunoblastic T-cell lymphoma.

Eur J Haematol 2019 Jul 30;103(1):35-42. Epub 2019 May 30.

Service de médecine interne, Hôpital Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Est, Créteil, France.

Objective: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear.

Method: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio).

Results: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse.

Conclusion: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity.
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http://dx.doi.org/10.1111/ejh.13239DOI Listing
July 2019

Orbital mass in ANCA-associated vasculitides: data on clinical, biological, radiological and histological presentation, therapeutic management, and outcome from 59 patients.

Rheumatology (Oxford) 2019 09;58(9):1565-1573

Department of Internal Medicine, National Referral Center for Systemic and Autoimmune Diseases, Hôpital de la Pitié-Salpêtrière, Paris.

Objective: Orbital mass is a rare and sight-threatening manifestation of ANCA-associated vasculitides, which remains a therapeutic challenge. We aimed to describe the presentation, therapeutic management and outcome of ANCA-associated vasculitides-related orbital mass.

Methods: We conducted a French nationwide retrospective study of patients with orbital mass in the setting of ANCA-associated vasculitides according to ACR criteria and/or Chapel Hill Consensus Conference definitions.

Results: Fifty-nine patients [33 women, median age 46 (range 7-90) years] were included. Fifty-six (95%) patients had granulomatosis with polyangiitis, two eosinophilic granulomatosis with polyangiitis and one microscopic polyangiitis. Orbital mass was unilateral in 47 (80%) cases, and seemed to develop from ENT involvement in most cases. Orbital mass biopsy was available in 32 (54%) patients, showing lymphoplasmacytic infiltration in 65%, fibrosis in 55%, granulomas in 48% and vasculitis in 36%. All patients but one received glucocorticoids as first-line therapy associated with immunosuppressive agents in 82%, mainly cyclophosphamide. Response to therapy was noted in 52% of patients treated with cyclophosphamide compared with 91% of those treated with rituximab. Twenty-seven (46%) patients required a second-line therapy because of relapse (59%) or refractory course (41%). Sequelae included visual impairment in 28%, with definitive blindness in 17%. Refractory course was associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.

Conclusion: Orbital mass is associated with refractory course and high frequency of sequelae, especially blindness. Refractory course is associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.
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http://dx.doi.org/10.1093/rheumatology/kez071DOI Listing
September 2019

Characteristics, risk factors and management of venous thromboembolism in immune thrombocytopenia: a retrospective multicentre study.

Intern Med J 2019 09;49(9):1154-1162

Department of Internal Medicine, Reference Center of Autoimmune Cytopenias, University Hospital Henri-Mondor, Créteil, France.

Background: An increased risk of thrombosis has been reported in immune thrombocytopenic purpura (ITP), but the characteristics, risk factors of occurrence, recurrence and management of venous thromboembolic events (VTE) have been poorly investigated.

Aims: To describe VTE and ITP characteristics, distribution of VTE risk factors and their impact on VTE features and recurrence.

Methods: A retrospective study of patients with ITP and VTE registered in databases of three reference French centres of ITP.

Results: Among 49 patients, 66 VTE were recorded. The platelet count at the time of the first VTE was <100 × 10 /L for 28/43 (65%) patients. In total, 19/48 (40%) patients had at least one positive antiphospholipid test result. For the 10 VTE occurring in eight patients with platelet count <50 × 10 /L, ITP treatment was efficient in 7. One haemorrhagic complication associated with anticoagulant (AC) therapy was recorded. For 31/49 (63%) patients, long-term AC therapy could have been discussed after the first VTE, but only 13 received it. A second VTE occurred in 13 (27%) patients. The risk of recurrence was increased in patients with unprovoked VTE before ITP diagnosis or active cancer.

Conclusion: VTE in ITP mainly occurred in the presence of multiple risk factors of TE. A low platelet count does not protect against VTE. Management with AC therapy despite persistently low platelet count seems possible. Risk of VTE recurrence is high, particularly with a history of unprovoked VTE or active cancer. In this setting, indefinite AC therapy could be discussed.
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http://dx.doi.org/10.1111/imj.14269DOI Listing
September 2019

Clinical and biological features in -hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients.

Haematologica 2019 08 17;104(8):1554-1564. Epub 2019 Jan 17.

Laboratoire d'Hématologie, Center Hospitalier Universitaire (CHU) Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. -hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In -related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that -hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of -hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.
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http://dx.doi.org/10.3324/haematol.2018.205328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669138PMC
August 2019

Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study.

Lancet Haematol 2019 Jan 4;6(1):e48-e57. Epub 2018 Dec 4.

Service de Médecine Interne and Immunologie Clinique, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; Université Paris Sud, Centre de Recherche en Immunologie des Infections Virales et des Maladies Auto-Immunes, INSERM, Le Kremlin-Bicêtre, France; Division d'Immunovirologie, Commissariat à l'Energie Atomique et aux Energies Alternatives, Fontenay-aux-Roses, France.

Background: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1.

Methods: In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry.

Findings: We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients.

Interpretation: Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted.

Funding: Gustave Roussy and Gustave Roussy Immunotherapy Program.
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http://dx.doi.org/10.1016/S2352-3026(18)30175-3DOI Listing
January 2019

Severe, non specific symptoms in non-typhoidal Salmonella infections in adult patients with sickle cell disease: a retrospective multicentre study.

Infect Dis (Lond) 2018 Nov - Dec;50(11-12):822-830. Epub 2018 Oct 14.

a Service de Médecine Interne, Centre de Référence des Cytopénies Auto-Immunes de l'Adulte, Hôpital Henri-Mondor , Créteil , France.

Background: Non-typhoidal salmonellosis (NTS) often occurs in children with sickle-cell disease (SCD) and remains a significant cause of mortality in developing countries. However, there is lack of reports on the clinical presentation, outcome and complications of NTS in adults with SCD.

Methods: We performed a chart review between 2006 and 2016 of adults SCD diagnosed with NTS in 3 referral centers monitoring approximately 3500 SCD adults.

Results: Twenty-three episodes of NTS were diagnosed among 22 SCD adults. Diagnosis was challenging: 65% (n = 15/23) of patients presented with vaso-occlusive crisis (VOC) and 30% had no fever. Isolated serotypes were: ser. Enteritidis (n = 8), ser. Typhimurium (n = 6), others (n = 3). We identified two patterns of infections: (1) bacteremic NTS (n = 15) with (n = 9) or without secondary foci of infections (n = 6); (2) non-bacteremic NTS with extra-intestinal foci of infection (n = 8), including primary bones/joints infections (n = 5). Half of patients with osteo-articular localization (n = 6/13) had a previous history of osteonecrosis (n = 2) or osteomyelitis (n = 4) at the same site. Morbidity was high, 6 patients (26%) were admitted to the intensive care unit, 14 patients (61%) required RBC transfusion for VOC. Half of the episodes (n = 12) required surgery (n = 10) or interventional radiology (n = 2) to control the infection. One patient presented a relapse of NTS bacteraemia one year after the first episode.

Conclusions: Besides bloodstream infections, clinical presentation of NTS in adults with SCD is non-specific at admission. A triad including bacteraemia, secondary focis of infection and bone localizations was observed in 30% of cases.
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http://dx.doi.org/10.1080/23744235.2018.1500706DOI Listing
April 2019

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists.

Rheumatology (Oxford) 2018 Aug;57(8):1432-1438

Internal Medicine, French Referral Centre for Adult Immune Cytopenia, Henri Mondor Hospital, AP-HP, UPEC University, Créteil, France.

Objectives: The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP.

Methods: This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP.

Results: We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs.

Conclusion: Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.
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http://dx.doi.org/10.1093/rheumatology/key119DOI Listing
August 2018