Publications by authors named "Olivier Fain"

331 Publications

Chronic Villitis of unknown etiology (VUE): Obstetrical features, outcome and treatment.

J Reprod Immunol 2021 11 23;148:103438. Epub 2021 Oct 23.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, service de Médecine Interne (DMU i3), F-75012, Paris, France.

Villitis of unknown etiology (VUE) is characterized by lympho-histiocytic infiltrates, which are predominant within the villous stroma. VUE can be of low grade i.e. affecting less than 10 contiguous villi or high grade with either patchy or diffuse subgroups (the later concerning more than 30 % of distal villi). Several other placental lesions could be associated with VUE, in particular in diffuse subgroups, such as diffuse perivillous fibrin deposition and chronic intervillositis. One of the most characteristic features of VUE is the late onset of fetal growth restriction after 32 weeks of gestation, and earlier detection of villitis should first raise an infectious origin. High grade VUE has been associated with fetal growth restriction, prematurity, fetal deaths, recurrent pregnancy loss, central nervous system injury and is characterized by relatively high risk of recurrence (25-50 %). Prospective and well-designed studies are necessary to determine the real prevalence of these adverse pregnancy events associated with VUE. Data about the management of VUE are extremely scarce and thus no recommendation based on the literature review could be actually done.
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http://dx.doi.org/10.1016/j.jri.2021.103438DOI Listing
November 2021

Myeloid Clonal Infiltrate Identified With Next-Generation Sequencing in Skin Lesions Associated With Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: A Case Series.

Front Immunol 2021 4;12:715053. Epub 2021 Oct 4.

Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Service de Médecine Interne et Inflammation-[Département Médico-Universitaire (DMU)-i3], Université Paris 06, Paris, France.

Background: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with cutaneous manifestations. Next-generation sequencing (NGS) is a tool capable of identifying clonal myeloid cells in the skin infiltrate and thus better characterize the link between hematological diseases and skin lesions.

Objective: To assess whether skin lesions of MDS/CMML are clonally related to blood or bone marrow cells using NGS.

Methods: Comparisons of blood or bone marrow and skin samples NGS findings from patients presenting with MDS/CMML and skin lesions in three French hospitals.

Results: Among the 14 patients recruited, 12 patients (86%) had mutations in the skin lesions biopsied, 12 patients (86%) had a globally similar mutational profile between blood/bone marrow and skin, and 10 patients (71%) had mutations with a high variant allele frequency (>10%) found in the myeloid skin infiltrate. Mutations in and , both in four patients, were the most frequent. Two patients harbored a mutation on hematopoietic samples.

Limitations: Limited number of patients and retrospective collection of the data. Blood and skin sampling were not performed at the exact same time point for two patients.

Conclusion: Skin lesions in the setting of MDS/CMML are characterized by a clonal myeloid infiltrate in most cases.
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http://dx.doi.org/10.3389/fimmu.2021.715053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521190PMC
December 2021

Clinical and prognostic significance of antinuclear antibodies in primary antiphospholipid syndrome: A multicenter retrospective study.

Joint Bone Spine 2021 Oct 14;89(2):105297. Epub 2021 Oct 14.

Service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), hôpital Saint-Antoine, Sorbonne université, AP-HP, 75012 Paris, France. Electronic address:

Introduction: The antiphospholipid syndrome (APS) (1) is defined by the development of vascular thrombosis, or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). Antinuclear antibodies (ANA) can be detected in primary APS patients without any clinical systemic autoimmune disease. The presence of ANA antibodies could confer a specific phenotype in primary APS.

Objective: To evaluate the characteristics of APS patients with antinuclear antibodies without other autoimmune disease (ANA positive APS patients) in comparison with primary APS without ANA or secondary APS patients with associated systemic lupus erythematosus (SLE).

Methods: Clinical and biologic data from 195 APS were retrospectively collected and patients were classified as primary APS with positive ANA (ANA-positive APS), primary APS without any ANA (ANA-negative APS), and SLE-associated APS (SLE-APS).

Results: Fourty patients (21%) were classified into ANA-positive APS group, 77 (39%) in ANA-negative APS and 78 (40%) in SLE-APS. In ANA-positive APS patients, 20 patients (51%) had arterial thrombosis, 14 (41%) had veinous thrombosis and 19% had obstetrical complications. There was no difference between the three groups for the frequency of thrombotic manifestations and obstetrical complications. ANA-positive APS patients had more non-criteria manifestations than ANA-negative APS (48% versus 25%; P≤0.01). ANA-positive APS had more triple aPL positivity (59% versus 18%; P<0.001) and more thrombosis and obstetrical recurrences (63% versus 36%; P<0.01) in comparison with ANA-negative APS patients. ANA-positive APS had more triple aPL positivity than SLE-APS patients (54% versus 33%; P<0.05). ANA-positive APS and SLE-APS patients had similar clinical manifestations, and recurrences. Despite a limited follow-up (28 months (11-50)) none of the ANA-positive APS develop SLE. Antiplatelet and anticoagulant therapies were similar for the three groups. SLE-APS patients received more immunomodulatory therapies.

Conclusion: ANA positivity in patients with APS enables to individualize a subset of patients with a more severe phenotype. Whereas the ANA positivity does not seem to be associated with the risk to develop SLE, prospective studies with a longer follow-up are necessary, in particular to evaluate the effect of additional therapies in this subset of APS.
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http://dx.doi.org/10.1016/j.jbspin.2021.105297DOI Listing
October 2021

Bartonella and Coxiella infections presenting as systemic vasculitis: case series and review of literature.

Rheumatology (Oxford) 2021 Sep 9. Epub 2021 Sep 9.

Département de Médecine Interne, Centre de Référence National pour les maladies auto-immunes systémiques rares, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.

Objectives: Coxiella and Bartonella sp. display particular tropism for endothelial or endocardial tissues and an abnormal host response to infections with induced autoimmunity. We aimed, through a case series combined with a comprehensive literature review, to outline characteristics of Coxiella and Bartonella infections presenting as systemic vasculitis.

Methods: We retrospectively included cases of definite Coxiella and Bartonella infections presenting with vasculitis features and performed a comprehensive literature review.

Results: Six cases of Bartonella infections were added to 18 cases from literature review. Causative pathogens were mainly B. henselae. Bartonella infection mimicked anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis in 83% with PR3-ANCA and presented as cryoglobulinemic vasculitis in 8%. Glomerulonephritis was present in 92%, and 88% had endocarditis. Complement fractions were low in 82% and rheumatoid factor positive in 85%. Kidney biopsies showed cell proliferation, mostly crescentic, with pauci-immune glomerulonephritis in 29%. Outcome was favorable, with the use of antibiotics alone in one third. Five cases of Coxiella infections were added to 16 from literature review. Sixteen had small-vessel vasculitides, mainly cryoglobulinemia vasculitis in 75%. One patient had polyarteritis nodosa-like vasculitis and four large-vessel vasculitis. Outcome was good except for one death. A highly sensitive next generation sequencing analysis on 3 Coxiella and 2 Bartonella-related vasculitides biopsies did not find any bacterial DNA.

Conclusion: Coxiella and Bartonella are both able to induce vasculitis but display distinct vasculitis features. Bartonella mimics PR3-ANCA-associated vasculitis in the setting of endocarditis, whereas Coxiella may induce vasculitis involving all vessel sizes.
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http://dx.doi.org/10.1093/rheumatology/keab691DOI Listing
September 2021

Lymphoma complicating rheumatoid arthritis: results from a French case-control study.

RMD Open 2021 09;7(3)

Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicetre, Île-de-France, France

Objectives: To study the characteristics of B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin lymphoma complicating rheumatoid arthritis (RA) and to identify RA-related factors associated with their occurrence.

Methods: A multicentre case-control study was performed in France. Cases were patients with RA fulfilling ACR-EULAR 2010 criteria in whom B-cell NHL or Hodgkin lymphoma developed after the diagnosis of RA. For each case, 2 controls were assigned at random from the ESPOIR cohort and were matched on age at lymphoma diagnosis (cases)/age at the 10-year follow-up visit in the cohort (controls). Case and control characteristics were compared to identify parameters associated with the occurrence of lymphoma.

Results: 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphoma (DLBCL, n=27, 50.0%). On immunochemistry, 4 of 27 (14.8%) lymphoma cases were positive for Epstein-Barr virus. On univariate analysis, factors associated with the occurrence of lymphoma were male sex (OR 3.3, 95% CI 1.7 to 6.7), positivity for ACPA (OR 5.1, 95% CI 2.0 to 15.7) and rheumatoid factor (OR 3.9, 95% CI 1.6 to 12.2), and erosions on radiographs (OR 3.8, 95% CI 1.7 to 8.3) and DAS28 (OR 2.0, 95% CI 1.5 to 2.7), both at the time of matching. Methotrexate, TNF blockers and a number of previous biologics were not associated with the occurrence of lymphoma. On multivariable analysis, erosions and DAS28 remained significantly associated with increased risk of lymphoma.

Conclusion: Lymphomas complicating RA are mostly DLBCL. Risk of lymphoma in patients with RA was increased with markers of disease activity and severity, which supports the paradigm of a continuum between autoimmunity and lymphomagenesis in RA.
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http://dx.doi.org/10.1136/rmdopen-2021-001698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413949PMC
September 2021

TFH cells in systemic sclerosis.

J Transl Med 2021 08 30;19(1):375. Epub 2021 Aug 30.

INSERM UMRs 938, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Université, 75012, Paris, France.

Systemic sclerosis is an autoimmune disease characterized by excessive dermal fibrosis with progression to internal organs, vascular impairment and immune dysregulation evidenced by the infiltration of inflammatory cells in affected tissues and the production of auto antibodies. While the pathogenesis remains unclear, several data highlight that T and B cells deregulation is implicated in the disease pathogenesis. Over the last decade, aberrant responses of circulating T follicular helper cells, a subset of CD4 T cells which are able to localise predominantly in the B cell follicles through a high level of chemokine receptor CXCR5 expression are described in pathogenesis of several autoimmune diseases and chronic graft-versus-host-disease. In the present review, we summarized the observed alteration of number and frequency of circulating T follicular helper cells in systemic sclerosis. We described their role in aberrant B cell activation and differentiation though interleukine-21 secretion. We also clarified T follicular helper-like cells involvement in fibrogenesis in both human and mouse model. Finally, because T follicular helper cells are involved in both fibrosis and autoimmune abnormalities in systemic sclerosis patients, we presented the different strategies could be used to target T follicular helper cells in systemic sclerosis, the therapeutic trials currently being carried out and the future perspectives from other auto-immune diseases and graft-versus-host-disease models.
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http://dx.doi.org/10.1186/s12967-021-03049-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407089PMC
August 2021

Efficacy and safety of TNF-α antagonists and tocilizumab in Takayasu arteritis: Multicenter retrospective study of 209 patients.

Rheumatology (Oxford) 2021 Aug 7. Epub 2021 Aug 7.

Service de Médecine Interne et Immunologie Clinique Groupe Hospitalier UNEOS Metz-Vantoux, France.

Objective: To assess safety and efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK).

Methods And Results: Two-hundred nine patients with TAK [median age of 29 years [7-62], and 186 (89%) females] were included. They received either TNF-α antagonists [n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5)], or tocilizumab [n = 77 (37%) with 121 lines; intravenous and subcutaneous in 95 and 26 cases, respectively]. A complete response at 6 months was evidenced in 101/152 (66%) on TNF-α antagonists and 75/107 (70%) on tocilizumab, respectively. Age ≥ 30 years [OR = 2.09 [1.09; 3.99]] was associated with complete response, whereas vascular signs [0.26 [0.1; 0.65]], baseline prednisone ≥ 20 mg/day [0.51 [0.28; 0.93]] were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvements [HR 2.44 (1.06; 5.65) and 3.66 (1.18; 11.4), respectively], and systemic signs at baseline [HR 2.01 (1.30; 3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNFα antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biological-targeted therapies of whom 37 (21%) and 21 (17%), (p= 0.4) on TNF-α antagonists and tocilizumab, respectively.

Conclusion: This large multicentre study shows high efficacy of biological-targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.
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http://dx.doi.org/10.1093/rheumatology/keab635DOI Listing
August 2021

Regulatory B cell imbalance correlates with Tfh expansion in systemic sclerosis.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):20-24. Epub 2021 Jul 28.

INSERM U938, Centre de Recherche Saint-Antoine, Paris; Sorbonne Université, Paris, and Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), AP-HP, Hôpital Saint-Antoine, Paris, France.

Objectives: Systemic sclerosis (SSc) is an autoimmune disease with fibrosis, microangiopathy and immune dysfunction. B cell abnormalities characterised by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of SSc. We previously identified an expansion of functional and activated circulating T follicular helper (cTfh) cells in SSc patients. The aim of this study was to analyse the frequency of regulatory B (Breg) cell subsets and the correlation with Tfh in SSc patients.

Methods: Circulating Breg cells CD24hiCD38hi and CD27+CD24hi levels and cTfh cells CD4+CXCR5+PD1+ were determined by cytometry in 50 SSc patients and 32 healthy subjects.

Results: The frequency of Breg cells CD24hiCD38hi and CD24hiCD27+ was significantly reduced in patients with SSc as compared to controls (p=0.02 and p<0.001, respectively). In contrast, when examining the CD21low B cell subset, the frequency was significantly increased in SSc patients compared to healthy controls, (p<0.001). There was no difference in Breg cell levels in patients with diffuse SSc and limited SSc. However, CD24hiCD27+ Breg cell frequency was significantly decreased in SSc patients with pulmonary arterial hypertension (p=0.014), but not in patients with interstitial lung disease (p=0.058). Furthermore, we observed a negative correlation between cTfh and CD24hiCD27+ Breg cell levels in SSc patients but not in healthy controls (p=0.02).

Conclusions: These results suggest that Breg cell subsets may participate in the regulation of cTfh and disease severity. Decreased CD24hiCD27+ Breg cell frequency may contribute to the development of SSc.
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August 2021

Acute Myocarditis Revealing Adult-Onset Still's Disease.

JACC Case Rep 2021 Jul 5;3(7):1002-1006. Epub 2021 May 5.

Department of Cardiology, Saint-Antoine and Tenon Hospitals, Assistance Publique-Hôpitaux de Paris and Sorbonne University, Paris, France.

A 34-year-old man presented with fever, palpitations, maculopapular rash, pharyngitis, left cheilitis, and bilateral gonalgia. High-sensitivity troponin I concentration was 4,900 ng/l. Transthoracic echocardiogram revealed reduced global longitudinal strain. Cardiac magnetic resonance imaging showed acute myocarditis. Adult-onset Still's disease was diagnosed, and treatment with intravenous corticosteroids and tocilizumab was initiated. ().
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http://dx.doi.org/10.1016/j.jaccas.2021.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311366PMC
July 2021

Prevalence of cardiovascular risk factors, the use of statins and of aspirin in Takayasu Arteritis.

Sci Rep 2021 07 13;11(1):14404. Epub 2021 Jul 13.

AP-HP, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU i3), Hôpital Saint-Antoine, Sorbonne Université, 75012, Paris, France.

The aim of this study was to assess the prevalence of cardiovascular risk factors in TAK, to describe the use of aspirin and statins and the risk factors associated with vascular ischemic complications and relapses. We conducted a retrospective study on TAK patients diagnosed between 2010 and 2018. Demographic, clinical, laboratory data and treatments were evaluated at diagnosis and during the follow-up. We included fifty-two TAK patients with median age 37.5 years [range 16-53] and 43 (83%) women. At diagnosis, cardiovascular risk factors were present in 32 (62%) patients: hypertension (n = 20, 38%), hyperlipidemia (n = 8, 15%), tobacco use (n = 16, 31%). During the median 4-year follow-up [range 0.1-17 years], 17 (33%) patients had at least one ischemic event and 15 (29%) patients needed endovascular procedure. Whereas TAK patients with cardiovascular risk factors were more frequently on statins and anti-hypertensive drugs, they have higher rates of cumulative ischemic complications (5 (24%) versus 21 (67%); p = 0.004), but similar rates of aspirin-treated patients. Patients who have developed vascular ischemic events were more frequently smokers (53% versus 20%; p = 0.03). The vascular complication-free survival was not significantly different in TAK patients with or without statins or aspirin at diagnosis. During the follow-up, 27 (52%) patients had at least one relapse, and the relapse-free survival was not significantly different in patients treated with statins or aspirin. Cardiovascular risk factors in TAK have to be strictly controlled since these risk factors could be associated with increased risk of ischemic complications.
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http://dx.doi.org/10.1038/s41598-021-93416-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277815PMC
July 2021

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

Clin Transl Allergy 2021 Jun;11(4):e12035

BioCryst Pharmaceuticals, Durham, North Carolina, USA.

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE.

Methods: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness.

Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline.

Conclusions: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE.

Trial Registration: The study is registered with ClinicalTrials.gov (NCT03472040).
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http://dx.doi.org/10.1002/clt2.12035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221587PMC
June 2021

Unexplained recurrent implantation failures: Predictive factors of pregnancy and therapeutic management from a French multicentre study.

J Reprod Immunol 2021 06 22;145:103313. Epub 2021 Mar 22.

Sorbonne Université, APHP, Service de Médecine Interne, Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DMU i3), F-75012, Paris, France. Electronic address:

Introduction: Recurrent implantation failure is defined as the absence of pregnancy after at least three transfers of good-quality embryos after in vitro fecundation/intracytoplasic sperm injection.

Aim: The aim of this study was to describe a multicentre cohort of women with unexplained RIF, to analyse the factors associated with clinical pregnancy and to evaluate the immunomodulatory therapies efficacy.

Methods: Women were consecutively recruited from university departments with unexplained RIF.

Results: Sixty-four women were enrolled with mean age 36 ± 3 years. The rates of clinical pregnancy in 64 women were compared in untreated and treated cycles and according to therapies used during the last prospectively followed embryo transfer. A clinical pregnancy after the transfer was noted in 56 % pregnancies on intralipids and in 50 % on prednisone, versus 5 % in untreated ones (p < 0.001). The 340 embryo transfers of these 64 women resulted in 68 clinical pregnancies and 18 live births. Clinical pregnancies were significantly more frequent in treated versus untreated embryo transfers (44 % vs 9 %; p < 0.001) with odds ratio at 8.13 (95 % CI 4.49-14.72, p < 0.0001). Cumulative pregnancy rates were higher for steroid-treated transfers than for untreated transfers when considering overall transfers before and after using steroids and also only those under steroids. Cumulative pregnancy rates were not different from steroid- and intralipid-treated embryo transfers CONCLUSIONS: In this multicentre study of women with unexplained RIF, use of immunomodulatory treatments before embryo transfer resulted in higher clinical pregnancy. Randomised, well-designed studies in well-defined population of RIF women are necessary to confirm our preliminary data.
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http://dx.doi.org/10.1016/j.jri.2021.103313DOI Listing
June 2021

Unexplained recurrent miscarriages: predictive value of immune biomarkers and immunomodulatory therapies for live birth.

Am J Reprod Immunol 2021 08 12;86(2):e13425. Epub 2021 Apr 12.

Sorbonne Université Service de Gynécologie Obstétrique, Hôpital Armand-Trousseau, Paris, France.

Introduction: Recurrent miscarriages are defined as three or more early miscarriages before 12 weeks of gestation. The aim of this study was to describe a cohort of women with unexplained recurrent miscarriages, evaluate several potential biomarkers of immune origin, and describe the outcome of pregnancies under immunomodulatory therapies.

Methods: Women having a history of at least 3 early miscarriages without any etiology were recruited from 3 university hospitals.

Results: Among 101 women with recurrent miscarriages, overall, 652 pregnancies have been included in the analysis. Women which experienced miscarriages were older (33.3 ± 5.4 versus 31.9 ± 6.7; p = 0.03), with history of more pregnancies (4 (2-6) versus 3.5 (1-5.75); p 0.0008), and less frequently the same partner (406 (74%) versus 79 (86%); p=0.01). There was no difference in the level and frequencies of biomarkers of immune origin (NK, lymphocyte, gamma globulins and blood cytokine levels and endometrial uNK activation status), except the higher rates of positive antinuclear antibodies in women with live birth (12 (13%) versus 36 (7%); p=0.03). Among the 652 pregnancies, 215 (33%) have been treated and received either aspirin/low weighted molecular heparin (LMWH) and/or combined to different lines of immunomodulatory treatment. Patients with pregnancy under treatment had a significantly higher rate of cumulative live birth rate than those with untreated ones (43.0% vs 34.8%; p = 0.04). When compared to patients with untreated pregnancies, patients with steroids during the pregnancy had twice more chances to obtain live birth (OR 2.0, CI95% 1.1 - 3.7, p = 0.02).

Conclusions: Unexplained recurrent miscarriages could have improved obstetrical outcome under immunomodulatory therapies and in particular steroids.
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http://dx.doi.org/10.1111/aji.13425DOI Listing
August 2021

COVID-19 as a trigger of acute attacks in people with hereditary angioedema.

Clin Exp Allergy 2021 07 4;51(7):947-950. Epub 2021 Apr 4.

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

Acute attacks could occur during the convalescent phase of COVID-19 illness, more commonly in patients with a history of frequent attacks. However it is unclear whether the acute attacks during the convalescent phase are specifically triggered by COVID-19 or not.
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http://dx.doi.org/10.1111/cea.13870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250827PMC
July 2021

VEXAS syndrome: still expanding the clinical phenotype.

Rheumatology (Oxford) 2021 09;60(9):e321-e323

Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department, Hôpital Saint Antoine.

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http://dx.doi.org/10.1093/rheumatology/keab225DOI Listing
September 2021

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

Haematologica 2021 05 1;106(5):1414-1422. Epub 2021 May 1.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094121PMC
May 2021

Apremilast in Refractory Behçet's Syndrome: A Multicenter Observational Study.

Front Immunol 2020 4;11:626792. Epub 2021 Feb 4.

Sorbonne Universités AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, Paris, France.

Objective: Mucocutaneous and joint disorders are the most common manifestations in Behçet's syndrome (BS) and are frequently clustered in the so-called minor forms of BS. There remains a need for safe and effective treatment for joint lesions in BS. We report the long-term safety and effectiveness of apremilast in refractory joint and mucocutaneous manifestations of BS.

Methods: French nationwide multicenter study including 50 BS patients with either active joint and/or mucocutaneous manifestations resistant to colchicine and/or DMARDs. Patients received apremilast 30 mg twice a day. Primary effectiveness endpoint was the proportion of patients with complete response (CR) of articular symptoms at month 6 (M6), defined as resolution of inflammatory arthralgia and arthritis, with joint count equal to zero.

Results: At inclusion, the median tender and swollen joint count was of 4 [2-6] and 2 [1-2], respectively. The proportion of CR in joint disease at M6 was 65% (n = 15/23), and 17% (n = 4/23) were partial responders. CR of oral and genital ulcers, and pseudofolliculitis at M6 was 73% (n = 24/33), 94% (n = 16/17) and 71% (n = 10/14), respectively. The overall response at M6 was 74% for the entire cohort and 70% for the mucocutaneous-articular cluster (n = 27). The median Behçet's syndrome activity score significantly decreased during study period [50 (40-60) 20 (0-40); 0.0001]. After a median follow-up of 11 [6-13] months, 27 (54%) patients were still on apremilast. Reasons for apremilast withdrawal included adverse events (n = 15, 30%) and treatment failure (n = 8, 16%). Thirty-three (66%) patients experienced adverse events, mostly diarrhea (n = 19, 38%), nausea (n = 17, 34%) and headache (n = 16, 32%).

Conclusion: Apremilast seems effective in BS-related articular disease refractory to colchicine and DMARDs. Discontinuation rates were significantly higher than that reported in clinical trials.
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http://dx.doi.org/10.3389/fimmu.2020.626792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889954PMC
June 2021

Acute and Chronic Sarcoid Arthropathies: Characteristics and Treatments From a Retrospective Nationwide French Study.

Front Med (Lausanne) 2020 10;7:565420. Epub 2020 Dec 10.

Sorbonne Université, Service de médecine interne, Hôpital Saint-Antoine, DHU I2B: Inflammation, Immunopathologie, Biothérapie, APHP, Paris, France.

We aimed to analyze patients with acute and chronic joint involvements in sarcoidosis. This is a retrospective multicenter analysis of patients with proven sarcoidosis, as defined by clinical, radiological, and histological criteria, with at least one clinical and/or ultrasonographic synovitis. Thirty-nine patients with sarcoid arthropathy were included, and among them 19 had acute sarcoidosis (Lofgren's syndrome). Joint involvement and DAS44-CRP were not significantly different in acute and chronic sarcoid arthropathies. Acute forms were more frequent than chronic sarcoid arthropathy in Caucasians, without any difference of sex or age between these 2 forms. Joint involvement was frequently more symmetrical in acute than chronic forms (100 vs. 70%; < 0.05), with a more frequent involvement in wrists and ankles in acute forms, whereas the tender and swollen joint counts and the DAS44-CRP were similar between the 2 groups. Skin lesions were significantly more frequent in patients with acute forms [17 (89%) vs. 5 (25%); < 0.05] and were erythema nodosum in all patients with Löfgren's syndrome and sarcoid skin lesions in those with chronic sarcoidosis. Among 20 patients with chronic sarcoidosis, treatment was used in 17 (85%) cases, and consisted in NSAIDs alone ( = 5; 25%), steroids alone ( = 5; 25%), hydroxychloroquine ( = 2; 20%), methotrexate ( = 3; 15%), and TNF inhibitors ( = 2; 10%). A complete/partial joint response was noted in 14 (70%) cases with a DAS44-CRP reduction of 2.07 [1.85-2.44] (from 3.13 [2.76-3.42] to 1.06 [0.9-1.17]; < 0.05). Sarcoid arthropathies have different clinical phenotypes in acute and chronic forms and various treatment regimens such as hydroxychloroquine and methotrexate could be used in chronic forms.
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http://dx.doi.org/10.3389/fmed.2020.565420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758528PMC
December 2020

Endometriosis with infertility: A comprehensive review on the role of immune deregulation and immunomodulation therapy.

Am J Reprod Immunol 2021 03 19;85(3):e13384. Epub 2020 Dec 19.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, service de Médecine Interne and Inflammation, Paris, France.

Background: Endometriosis is a multifactorial pathology dependent on intrinsic and extrinsic factors, but the immune deregulation seems to play a pivotal role. In endometriosis-associated infertility, this could raise the benefit of immunomodulatory strategies to improve the results of ART. In this review, we will describe (1) sera and peritoneal fluid cytokines and immune markers; (2) autoantibodies; and (3) immunomodulatory treatments in endometriosis with infertility.

Methods: The literature research was conducted in MEDLINE, Embase, and Cochrane Library with the following keywords: "endometriosis", "unexplained miscarriage", "implantation failure", "recurrent implantation failure » and « IVF-ICSI », « biomarkers of autoimmunity", "TNF-α", "TNF-α antagonists", "infliximab", "adalimumab", "etanercept", "immunomodulatory treatment", "steroids", "intralipids", "intravenous immunoglobulins", "G-CSF", "pentoxyfylline".

Results: Several studies analyzed the levels of pro-inflammatory cytokines in sera and peritoneal fluid of endometriosis-associated infertility, in particular TNF-α. Various autoantibodies have been found in peritoneal fluid and sera of infertile endometriosis women even in the absence of clinically defined autoimmune disease, as antinuclear, anti-SSA, and antiphospholipid autoantibodies. In few uncontrolled studies, steroids and TNF-α antagonists could increase the pregnancy rates in endometriosis-associated infertility, but well-designed trials are lacking.

Conclusion: Endometriosis is characterized by increased levels of cytokines and autoantibodies. This suggests the role of inflammation and immune cell deregulation in infertility associated with endometriosis. The strategies of immunomodulation to regulate these immune deregulations are poorly studied, and well-designed studies are necessary.
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http://dx.doi.org/10.1111/aji.13384DOI Listing
March 2021

Low dose IL-2 in patients with steroid-dependent dysimmune manifestations associated with myelodysplastic syndromes: a three-case report.

Rheumatology (Oxford) 2021 07;60(7):3404-3408

Service de Médecine Interne, IUCT Oncopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse.

Objectives: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context.

Methods: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight.

Results: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease.

Conclusion: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.
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http://dx.doi.org/10.1093/rheumatology/keaa696DOI Listing
July 2021

Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.

J Clin Immunol 2021 01 31;41(1):163-170. Epub 2020 Oct 31.

AP-HP, HUPC, Unité de Gynécologie Endocrinienne, Centre de Référence sur les angiœdèmes à kinines (CRéAk), Hôpital Port Royal, Université de Paris, Paris, France.

Purpose: Most types of hereditary angioedema (HAE) are worsened by endogenous or exogenous estrogens. Conversely, androgens can improve HAE with abnormal C1-Inhibitor (C1-INH) by increasing C1-INH concentrations. Menopause is associated with an extinction of ovarian estrogenic and androgenic secretion. There is currently insufficient information on postmenopausal women with HAE. The objective of this study was to describe the activity of HAE in postmenopausal women.

Methods: This was a French retrospective, multicenter study in postmenopausal women with HAE with or without C1-INH deficiency/dysfunction. The patients were classified before and after menopause with a previously validated HAE disease severity score.

Results: We included 65 women from 13 centers in France. The mean age was 62.7± 9.2 years, and the mean time between menopause and inclusion was 12.5± 9.1 years. HAE was associated with C1-INH deficiencyin 88% (n = 57) of the patients, a mutation of factor 12 in 8% (n = 5), a mutation in plasminogen gene in one, and unknown HAE for two. The HAE course was not different after menopause in 46.1% (n = 30), improved in 38.5% (n = 25), and worsened in 15.4% (n = 10). Improvement was correlated with estrogen sensitivity of angioedema before menopause (p = 0.06 for improvement vs no effect or worsening). In addition, we observed that only ten women received treatment (transdermal or oral estradiol+ progestogen) for their menopause symptoms. Among them, only 3 experienced worsening of symptoms (2 on transdermal and 1 on oral estradiol).

Conclusion: Following menopause, most women with HAE remain stable but some worsen. Improvement was mainly observed in patients with previous estrogen sensitivity. More research is required in menopausal women with HAE to better understand how to manage climacteric symptoms.
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http://dx.doi.org/10.1007/s10875-020-00902-7DOI Listing
January 2021

Primary Sjögren's syndrome: central and peripheral nervous system involvements.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):103-109. Epub 2020 Oct 22.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU i3), Paris, France.

Primary Sjögren's syndrome (pSS) is a common systemic autoimmune disease characterised by exocrinopathy resulting in dryness of the mouth and eyes, unexplained fatigue and diffuse pain. Neurological involvement is uncommon in pSS, involving the central nervous system in 2-5% of cases and more frequently the peripheral nervous system in 5-15% of cases. The diagnosis of pSS is to be considered when confronted with symptoms such as mouth and eye dryness, fatigue and pain, the most frequent of pSS symptoms. Objective measures of oral and eye dryness may help assert the diagnosis of pSS, as well as ACR/EULAR criteria. Differential diagnoses have to be excluded in patients exhibiting neurological symptoms, such as cryoglobulinaemic vasculitis or multiple sclerosis, before considering a neurological involvement specific to pSS. The treatment of these neurological manifestations takes into account different parameters, such as the presence of cryoglobulinaemic vasculitis, the severity of the symptoms, a rapidly progressing evolution and the failure of previous symptomatic treatments.
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October 2020

[Pelvic actinomycosis].

Rev Prat 2020 05;70(5):523

AP-HP Sorbonne Université, service de médecine interne, hôpital Saint-Antoine, Paris, France.

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May 2020

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

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

UPMC, Université Paris 6, Paris, France.

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

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

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

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

Tocilizumab versus Rituximab in Patients with Moderate to Severe Steroid-resistant Graves' Orbitopathy.

Ocul Immunol Inflamm 2020 Sep 23:1-6. Epub 2020 Sep 23.

AP-HP, Hôpital Saint Antoine, Service De Médecine Interne Et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Sorbonne Universités, Paris, France.

To describe the efficacy of tocilizumab in patients with Graves' orbitopathy resistant or dependent to steroids and compare to rituximab treated patients. Graves's orbitopathy response was considered as decrease of at least 2 points of the CAS. Twenty-one patients were included, 7 patients were treated with tocilizumab and 14 with rituximab. The primary was achieved in all 7 patients (100%) on tocilizumab and 9 out of 14 patients on (64%) rituximab ( = .17). Mean change in CAS was consistent with a decrease of 3.3 ± 0.5 points in patients on tocilizumab versus 2.5 ± 1.9 in patients on rituximab ( = .07). One patient on tocilizumab (14%) and 4 patients (29%) on rituximab experienced significant relapse during the follow-up. The difference in relapse-free survival was not significant in patients on tocilizumab (10.8 ± 4 months) compared with rituximab (17.88 ± 3.66). We showed a significant improvement in the CAS, visual acuity, diplopia, and proptosis with both tocilizumab and rituximab.
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http://dx.doi.org/10.1080/09273948.2020.1808688DOI Listing
September 2020
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