Publications by authors named "Louis Terriou"

93 Publications

Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

J Clin Immunol 2022 Jun 23. Epub 2022 Jun 23.

Université de Lille, UFR Médecine, 59000, Lille, France.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4: p = 0.005; CD8: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.
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http://dx.doi.org/10.1007/s10875-022-01299-1DOI Listing
June 2022

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

Clin Exp Rheumatol 2022 Jul 16;40(7):1336-1342. Epub 2022 May 16.

CHU Rennes, Service de Médecine Interne et Immunologie Clinique, Inserm, CIC 1414, Rennes, France.

Objectives: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE.

Methods: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders.

Results: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83).

Conclusions: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.
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http://dx.doi.org/10.55563/clinexprheumatol/nbn38dDOI Listing
July 2022

Characteristics, management and outcome of acquired amegakaryocytic thrombocytopenia.

Br J Haematol 2022 08 10;198(3):595-599. Epub 2022 May 10.

Service de Médecine Interne, Centre de Référence des Cytopénies Auto-immunes de l'adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Est Créteil (UPEC), Créteil, France.

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http://dx.doi.org/10.1111/bjh.18235DOI Listing
August 2022

Tolerance of bradykinin-releasing drugs in patients with acquired C1 inhibitor deficiency: a case series and review of the literature.

Eur J Dermatol 2022 02;32(1):49-55

CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France, Centre de Référence des Angiœdèmes à Kinines, F-59000 Lille, France, University Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France, Inserm, F-59000 Lille, France.

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http://dx.doi.org/10.1684/ejd.2021.4175DOI Listing
February 2022

Profuse telangiectasias in an immunocompetent patient misleading presentation revealing a hepatosplenic-Tγδ-cell lymphoma.

Clin Case Rep 2022 Mar 11;10(3):e05503. Epub 2022 Mar 11.

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 Univ. Lille Inserm, CHU Lille Lille France.

Here we present the case of an hepato-splenic-Tγδ-cell lymphoma interestingly occurring in a non-immunocompromised patient, with profuse telangiectasias giving originally misleading orientation towards the diagnosis of B angiotropic lymphoma.
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http://dx.doi.org/10.1002/ccr3.5503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915152PMC
March 2022

Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

J Allergy Clin Immunol Pract 2022 05 21;10(5):1356-1364.e2. Epub 2022 Jan 21.

Department of Internal Medicine, Montpellier University Hospital, Montpellier, France.

Background: Mast cells are key players in innate immunity and the T2 adaptive immune response. The latter counterbalances the T1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published.

Objective: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting.

Methods: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies.

Results: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden).

Conclusions: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.
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http://dx.doi.org/10.1016/j.jaip.2021.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780123PMC
May 2022

Paroxysmal nocturnal hemoglobinuria and vascular liver disease: Eculizumab therapy decreases mortality and thrombotic complications.

Am J Hematol 2022 04 31;97(4):431-439. Epub 2022 Jan 31.

Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.

A total of 2%-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study was aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry, who had VLD diagnosed between 1997 and 2019 is considered. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48) and median follow-up VLD diagnosis 4.7 years (1.2-9.5), were included. Clone size was 80% (70-90), median hemoglobin concentration was 10.0 g/dl (8-11), and lactate dehydrogenase (LDH) was 736 IU (482-1744). Forty-two patients (68%) had eculizumab; median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus nonexposed period: 2.6 versus 8.7 per 100 (PY), incidence rate ratio (IRR) was 0.29, 95% CI (0.1-0.9), p = .035. Thrombosis recurrence occurred less frequently during the exposure to eculizumab: 0.5 versus 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end points (i.e., bleeding, arterial ischemic lesions, infection, and liver complications) were less common during the exposure to eculizumab, although not reaching statistical significance. Six-year thrombosis-free survival was 70%, 95% CI [0.60-0.83] for PNH cohort and 83%, 95% CI [0.70-1.00] for non-PNH Envie 2 patients, (p < .001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD.
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http://dx.doi.org/10.1002/ajh.26474DOI Listing
April 2022

Risk factors for severe neonatal thrombocytopenia in cases of maternal immune thrombocytopenia.

Acta Paediatr 2022 May 31;111(5):985-991. Epub 2022 Jan 31.

Department of Obstetrics, Lille University Hospital, Lille, France.

Aim: Maternal immune thrombocytopenia (ITP) may induce neonatal thrombocytopenia (nTP), which carries a risk of neonatal haemorrhagic complications. Some risk factors for nTP have reached consensus such as maternal splenectomy and previous severe nTP, while others such as maternal platelet count have not.

Methods: We conducted a retrospective cohort study in a university hospital, including 145 neonates of mothers with ITP. We assessed the risk of severe nTP and bleeding complications.

Results: Severe nTP in the first 24 h after birth was more common in case of maternal splenectomy (OR = 4.4) and a previous severe nTP (OR = 46.9). Severe nTP at nadir (lowest platelet count during the initial postnatal days) was more frequent in cases of a previous neonate with severe nTP (OR = 42), maternal treatment during pregnancy (OR = 2.4) and a low maternal platelet count during pregnancy or at delivery. These risk factors were not significantly associated with an increased risk of neonatal haemorrhagic complications.

Conclusion: In our population, we confirm the risk of severe nTP in case of maternal splenectomy or previous nTP. By monitoring the platelet count to its nadir, we identified three additional risk factors: maternal treatment during pregnancy and low maternal platelet count during pregnancy or low maternal platelet count at delivery.
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http://dx.doi.org/10.1111/apa.16252DOI Listing
May 2022

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

N Engl J Med 2022 01;386(1):11-23

From the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint-Louis Hospital and Université de Paris (R.P.L., F.S.F., C.F., G.S.), and the Adolescent and Young Adult Hematology Unit, Saint-Louis Hospital (F.R.), Paris, the Hematology Department, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (C.R., S.T.), Centre Hospitalier Universitaire Lyon Sud, Lyon (F.B., A.P.), Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut-Lévêque, Pessac (E.F., L.C.), the Department of Clinical Hematology, Rennes University Hospital, Rennes (J.-B.M.), Service d'Hématologie, Hôpital Jean Minjoz, Besançon (E.D.), and Hôpital Claude Huriez, Lille (L.T.) - all in France; the Clinical Study Unit, European Society for Blood and Marrow Transplantation (R.P.L., A.K., S.I., S.R.T., I.S.-O., C.F., C.D., A.M.R.), and the Department of Hematology, Leiden University Medical Center (C.J.M.H., J.M.L.T.), Leiden, the Department of Hematology, University Medical Center Utrecht, Utrecht (R.A.P.R.), the Department of Hematology, University Medical Center Groningen, Groningen (M.R.G.), and the Department of Clinical Hematology, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam (E.N.) - all in the Netherlands; the Department of Haematological Medicine, King's College Hospital NHS Foundation Trust (A.K., R.C., A.E.S., P.M., J.C.W.M., G.J.M.), and Barts Health NHS Trust, St. Bartholomew's Hospital (J.C.), London, the Department of Haematology, St. James's University Hospital, Leeds (M.G., T.M., A.H., P.M.), and the Centre for Clinical Haematology, Nottingham University Hospital, Nottingham (N.H.R.) - all in the United Kingdom; the Department of Biology, Università Tor Vergata (S.I.), and the Department of Translational and Precision Medicine, Division of Hematology, Sapienza University (A.P.I., U.L.R.), Rome, Ematologia e Centro Trapianti, IRCCS Ospedale Policlinico San Martino (E.A., M.T.L.), and the Hematology Unit, IRCCS Istituto Giannina Gaslini (E.P., C.D.), Genoa, Unità Operativa Complessa di Ematologia, Unità Operativa Complessa di Fisiopatologia delle Anemie, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan (W.B.), the Department of Clinical Medicine and Surgery, Federico II University, Naples (S.M., L.M., F.C., C.F., A.M.R.), and Ematologia e Trapianto Emopoietico, Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati, Avellino (L.M., C.F., A.M.R.) - all in Italy; University Hospital Donostia, San Sebastián (J.C.V.), the Department of Hematology, Catalan Institute of Oncology Bellvitge Hospital-Hospital Duran i Reynals, L'Hospitalet de Llobregat (A.S.), Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Barcelona (B.X.), and Servicio de Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Valencia (I.J.) - all in Spain; and the Department of Hematology, University Hospital Basel, Basel, Switzerland (B.D., J.R.P.).

Background: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.

Methods: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.

Results: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.

Conclusions: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).
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http://dx.doi.org/10.1056/NEJMoa2109965DOI Listing
January 2022

USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.

J Clin Med 2021 Nov 27;10(23). Epub 2021 Nov 27.

Service de Médecine Interne, AP-HP, Hôpital Saint Antoine, Sorbonne Université, 75012 Paris, France.

Background: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).

Objectives: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.

Methods: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.

Results: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.

Conclusions: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.
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http://dx.doi.org/10.3390/jcm10235586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658409PMC
November 2021

Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a 2-center experience.

Blood Adv 2022 02;6(3):998-1003

Département de médecine interne et d'immunologie clinique, Université de Lille,  Inserm, Centre Hospitalier Universitaire (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, Institute for Translational Research in Inflammation (INFINITE), Lille, France.

The recently described vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1. Patients with VEXAS syndrome display late-onset autoinflammatory symptoms, usually refractory to treatment, and hematologic abnormalities. The identification of an easily-accessible specific marker (UBA1 mutations) is of particular interest as it allows the convergence of various inflammatory and hematological symptoms in a unique clinico-biological entity and gives the opportunity to design specific treatment strategies. Here we retrospectively identified 6 patients with VEXAS syndrome who underwent allogeneic hematopoietic stem cell transplantation (ASCT). To date, no treatment guidelines have been validated. In 4 patients, ASCT was guided by life-threatening autoinflammatory symptoms that were refractory to multiple therapies. Three patients are in durable complete remission 32, 38, and 37 months after ASCT. Two others are in complete remission response after 3 and 5 months. One unfortunately died post-ASCT. This report suggests that ASCT could be a curative option in patients with VEXAS syndrome and severe manifestations. Considering the complications and side effects of the procedure as well as the existence of other potential treatment, clinical trials are needed to define the subgroup of patients who will benefit from this strategy and its place in the therapeutic arsenal against VEXAS syndrome.
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http://dx.doi.org/10.1182/bloodadvances.2021004749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945317PMC
February 2022

Splenectomy for primary immune thrombocytopenia revisited in the era of thrombopoietin receptor agonists: New insights for an old treatment.

Am J Hematol 2022 01 26;97(1):10-17. Epub 2021 Oct 26.

Service de Médecine Interne et Immunopathologie-IUCT Oncopole, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs.
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http://dx.doi.org/10.1002/ajh.26378DOI Listing
January 2022

Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry.

Br J Haematol 2022 02 14;196(4):969-974. Epub 2021 Oct 14.

Department of Internal Medicine, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Sorbonne University, Paris, France.

Azacitidine can be effective in myelodysplastic syndromes (MDS) associated with inflammatory/autoimmune diseases. Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) is a new monogenic autoinflammatory syndrome caused by somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutation, often associated with MDS, whose treatment is difficult and not yet codified. Based on a French nationwide registry of 116 patients with VEXAS, we report the efficacy and safety of azacitidine treatment in 11 patients with VEXAS with MDS. Clinical response of VEXAS to azacitidine was achieved in five patients (46%), during 6, 8+, 12, 21, 27+ months respectively, suggesting that azacitidine can be effective in selected patients with VEXAS and associated MDS.
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http://dx.doi.org/10.1111/bjh.17893DOI Listing
February 2022

Safety of anti-SARS-CoV-2 vaccination for patients with immune thrombocytopenia.

Br J Haematol 2021 12 31;195(5):703-705. Epub 2021 Aug 31.

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.17813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8653340PMC
December 2021

[Autologous hematopoietic cells for severe autoimmune diseases: Guidelines of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) for immune monitoring and biobanking].

Bull Cancer 2021 Dec 14;108(12S):S72-S81. Epub 2021 Jul 14.

AP-HP, hôpital Saint-Louis, unité de médecine interne (UF 04): CRMR MATHEC, Maladies auto-immunes et thérapie cellulaire, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), 75010 Paris, France; Université de Paris, Institut de recherche Saint-Louis, recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France; McGill University, Department of Medicine, H3A 1A1, Montreal, Canada. Electronic address:

Autologous hematopoietic cell transplantation (AHCT) is a new treatment option for patients with severe autoimmune diseases (AD), based on the use of intensive or myeloablative chemotherapy to eradicate the pathogenic autoreactive immune cells and to allow the installation of a new and tolerant immune system during immune reconstitution process. Immune reconstitution analysis after AHCT is required for patients clinical follow-up and to further identify biological and immunological markers of the clinical response to develop individualized AHCT protocols. These MATHEC-SFGM-TC good clinical practice guidelines were developed by a multidisciplinary group of experts including members of the french reference center for stem Cell Therapy in Auto-immune Diseases (MATHEC), hematologists from the French speaking Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and experts in immune monitoring and biobanking. The objectives are to provide practical recommandations for immune monitoring and biobanking of samples in patients with AD undergoing AHCT, for routine care purposes and investigational studies.
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http://dx.doi.org/10.1016/j.bulcan.2021.03.020DOI Listing
December 2021

Correspondence in reference to the previously published Epub manuscript: immune thrombocytopenic purpura after SARS-CoV-2 vaccine.

Br J Haematol 2021 09 10;194(6):e93-e95. Epub 2021 Jun 10.

Department of Internal Medicine and Clinical Immunology, University of Lille, CHU Lille, Lille, F-59000, France.

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http://dx.doi.org/10.1111/bjh.17628DOI Listing
September 2021

Long term outcomes of the French ASTIS systemic sclerosis cohort using the global rank composite score.

Bone Marrow Transplant 2021 09 9;56(9):2259-2267. Epub 2021 Jun 9.

Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC, AP-HP, Hôpital Saint-Louis, Paris, France.

Two randomised trials (ASTIS, SCOT) of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) versus monthly Cyclophosphamide for severe Systemic Sclerosis (SSc) patients used similar inclusion criteria, but different primary endpoints: event-free-survival (EFS) at 24 months in ASTIS versus the global rank composite score (GRCS) at 54 months in SCOT. Here we analysed the French ASTIS cohort (n = 49) outcome using the same GRCS endpoint as reported in SCOT. All patients, randomised to AHSCT (n = 26) or Cyclophosphamide (n = 23), were evaluated for the non-parametric GRCS endpoint based on: death, EFS, forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 60 months. Secondary endpoints were: EFS, overall survival (OS), HAQ DI and organ status. In intention-to-treat analysis, the GRCS demonstrated superiority for AHSCT (median: 9 versus -19, p = 0.018), mRSS (Δ mRSS: -16 versus -9, p = 0.02), and HAQ-DI (ΔHAQ-DI: -0.89 versus -0.2, p = 0.05) with no significant difference in OS, EFS, lung, heart and kidney function between the groups. In conclusion, this study demonstrates long term benefits of non-myeloablative AHSCT when assessed by the five longitudinal measures within GRCS affording direct primary endpoint comparison between ASTIS and SCOT.
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http://dx.doi.org/10.1038/s41409-021-01355-1DOI Listing
September 2021

Mutant UBA1 and Severe Adult-Onset Autoinflammatory Disease.

N Engl J Med 2021 Jun;384(22):2163-2164

Lille University Hospital, Lille, France

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http://dx.doi.org/10.1056/NEJMc2102124DOI Listing
June 2021

Splenectomy for haemophagocytic lymphohistiocytosis of unknown origin: risks and benefits in 21 patients.

Br J Haematol 2021 08 7;194(3):638-642. Epub 2021 May 7.

Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, INSERM U1163, Imagine Institut, Sorbonne Paris University, Paris, France.

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http://dx.doi.org/10.1111/bjh.17497DOI Listing
August 2021

Systemic Pulmonary Events Associated with Myelodysplastic Syndromes: A Retrospective Multicentre Study.

J Clin Med 2021 Mar 10;10(6). Epub 2021 Mar 10.

Department of Internal Medicine and Clinical Immunology, National Reference Centre for Rare Systemic Autoimmune Disease North and North-West of France, University of Lille, CHU Lille, F-59000 Lille, France.

Although pulmonary events are considered to be frequently associated with malignant haemopathies, they have been sparsely studied in the specific context of myelodysplastic syndromes (MDS). We aimed to describe their different types, their relative proportions and their relative effects on overall survival (OS). We conducted a multicentre retrospective cohort study. Patients with MDS (diagnosed according to the 2016 WHO classification) and pulmonary events were included. The inclusion period was 1 January 2007 to 31 December 2017 and patients were monitored until August 2019. Fifty-five hospitalized patients were included in the analysis. They had 113 separate pulmonary events. Thirteen patients (23.6%) had a systemic autoimmune disease associated with MDS. Median age at diagnosis of MDS was 77 years. Median time to onset of pulmonary events was 13 months. Pulmonary events comprised: 70 infectious diseases (62%); 27 interstitial lung diseases (23.9%), including 13 non-specific interstitial pneumonias and seven secondary organizing pneumonias or respiratory bronchiolitis-interstitial lung diseases; 10 pleural effusions (8.8%), including four cases of chronic organizing pleuritis with exudative effusion; and six pulmonary hypertensions (5.3%). The median OS of the cohort was 29 months after MDS diagnosis but OS was only 10 months after a pulmonary event. The OS was similar to that of the general myelodysplastic population. However, the occurrence of a pulmonary event appeared to be either an accelerating factor of death or an indicator for the worsening of the underlying MDS in our study. More than a third of pulmonary events were non-infectious and could be systemic manifestations of MDS.
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http://dx.doi.org/10.3390/jcm10061162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999053PMC
March 2021

Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature.

Front Immunol 2020 18;11:558811. Epub 2020 Dec 18.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, France.

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4 lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4 plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4 plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10 [5.7 10-1.79 10]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10 [2.0 10-6.0 10]), a polyclonal setting in which all IgG4 plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10 at diagnosis and 1.0 10 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4 plasma cell proliferation.
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http://dx.doi.org/10.3389/fimmu.2020.558811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793697PMC
May 2021

ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder.

Cell Rep Med 2020 12 22;1(9):100158. Epub 2020 Dec 22.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.
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http://dx.doi.org/10.1016/j.xcrm.2020.100158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762771PMC
December 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

[Crohn's disease and autologous hemapoietic cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2020 Dec 14;107(12S):S140-S150. Epub 2020 Oct 14.

Centre de référence des maladies auto-immunes systémiques rares d'Île-de-France, hôpital St-Louis (AP-HP), unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF 04), 1, avenue Claude-Vellefaux, 75010 Paris, France; Université Paris-Denis-Diderot, institut de recherche Saint-Louis, EA 3518, Sorbonne Paris Cité, France; McGill University, department of internal medicine, Montreal, Canada. Electronic address:

Crohn's Disease (CD) is an auto-inflammatory disease, which may involve the entire gastro-intestinal tract. CD is diagnosed on several clinical, biological, endoscopic and histological criteria. First line therapy is based on oral or iv steroids. In case of steroids dependence or resistance, several types of immunosuppressive or immunomodulating therapies are available: classical antimetabolites (thiopurines or methotrexate) or monoclonal antibodies against TNFα, against interleukin 12/23 or against integrin. Nonetheless, Crohn's disease may remain active despite the use of several lines of therapy. In such cases, autologous hematopoietic cell transplantation (AHCT) is an effective therapeutic option in highly selected CD patients with specific criteria. The MATHEC-SFGM-TC Good Clinical Practice Guidelines (GCPG) were developed by a multidisciplinary group of experts including gastroenterologists, hematologists and members of the reference center for stem cell therapy in auto-immune diseases (MATHEC), including members of the French groupe d'étude thérapeutique des affections inflammatoires du tube digestif(GETAID) under the auspices of the French speaking Society of bone marrow transplantation and cellular therapy (SFGM-TC). The aim of the present guidelines is to define the eligibility criteria for CD patients when candidates to AHCT, the procedures for mobilization of hematopoietic stem cell (HSC), conditioning regimen and standardized follow-up after AHCT including monitoring of gastroenterological treatments during AHCT and thereafter throughout all follow-up.
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http://dx.doi.org/10.1016/j.bulcan.2020.08.009DOI Listing
December 2020

Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study.

Semin Arthritis Rheum 2020 10 11;50(5):879-884. Epub 2020 Jul 11.

Department of Internal Medicine, Assistance Publique-Hôpitaux de Marseille, Hôpital La Timone, Marseille, France.

Introduction: Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) PATIENTS AND METHODS: Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features.

Results: Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21-90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behçet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1-162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11-3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21-9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank <0.05).

Conclusion: This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.
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http://dx.doi.org/10.1016/j.semarthrit.2020.07.002DOI Listing
October 2020

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

Blood 2020 12;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

Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

Am J Hematol 2020 11 19;95(11):1314-1323. Epub 2020 Sep 19.

Department of Hematology, INSERM U 1052, CRCL, Centre Léon Bérard, Lyon, France.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.
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http://dx.doi.org/10.1002/ajh.25945DOI Listing
November 2020
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