Publications by authors named "Zahir Amoura"

358 Publications

Sustained high expression of multiple APOBEC3 cytidine deaminases in systemic lupus erythematosus.

Sci Rep 2021 Apr 12;11(1):7893. Epub 2021 Apr 12.

Molecular Retrovirology Unit, UMR 3569, Institut Pasteur, CNRS, 28 rue du Dr. Roux, 75724, Paris cedex 15, France.

APOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.
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http://dx.doi.org/10.1038/s41598-021-87024-1DOI Listing
April 2021

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic).

Arthritis Res Ther 2021 03 3;23(1):70. Epub 2021 Mar 3.

MEDSENIC, SAS, a company with CNRS participation, Strasbourg, France.

Background: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE.

Methods: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS).

Results: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4).

Conclusions: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy.

Trial Registration: ClinicalTrials.gov, NCT01738360  registered 30 November 2012.
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http://dx.doi.org/10.1186/s13075-021-02454-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927234PMC
March 2021

Acute Tubular Injury and Renal Arterial Myocyte Vacuolization Following Crizotinib Administration.

Kidney Int Rep 2021 Feb 1;6(2):526-528. Epub 2020 Dec 1.

Department of Internal Medicine, Pitie-Salpetriere Hospital, Paris, France.

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http://dx.doi.org/10.1016/j.ekir.2020.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879097PMC
February 2021

The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

Université Paris Saclay, Université Paris-Sud, UVSQ, Villejuif, France.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.
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http://dx.doi.org/10.1093/ndt/gfab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928708PMC
February 2021

Outcomes of severe systemic rheumatic disease patients requiring extracorporeal membrane oxygenation.

Ann Intensive Care 2021 Feb 9;11(1):29. Epub 2021 Feb 9.

Service de Médecine Intensive-Réanimation, Hôpital La Pitié-Salpêtrière, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.

Background: Systemic rheumatic diseases (SRDs) are a group of inflammatory disorders that can require intensive care unit (ICU) admission because of multiorgan involvement with end-organ failure(s). Critically ill SRD patients requiring extracorporeal membrane oxygenation (ECMO) were studied to gain insight into their characteristics and outcomes.

Methods: This French monocenter, retrospective study included all SRD patients requiring venovenous (VV)- or venoarterial (VA)-ECMO admitted to a 26-bed ECMO-dedicated ICU from January 2006 to February 2020. The primary endpoint was in-hospital mortality.

Results: Ninety patients (male/female ratio: 0.5; mean age at admission: 41.6 ± 15.2 years) admitted to the ICU received VA/VV-ECMO, respectively, for an SRD-related flare (n = 69, n = 38/31) or infection (n = 21, n = 10/11). SRD was diagnosed in-ICU for 31 (34.4%) patients. In-ICU and in-hospital mortality rates were 48.9 and 51.1%, respectively. Nine patients were bridged to cardiac (n = 5) or lung transplantation (n = 4), or left ventricular assist device (n = 2). The Cox multivariable model retained the following independent predictors of in-hospital mortality: in-ICU SRD diagnosis, day-0 Simplified Acute Physiology Score (SAPS) II score ≥ 70 and arterial lactate ≥ 7.5 mmol/L for VA-ECMO-treated patients; diagnosis other than vasculitis, day-0 SAPS II score ≥ 70, ventilator-associated pneumonia and arterial lactate ≥ 7.5 mmol/L for VV-ECMO-treated patients.

Conclusions: ECMO support is a relevant rescue technique for critically ill SRD patients, with 49% survival at hospital discharge. Vasculitis was independently associated with favorable outcomes of VV-ECMO-treated patients. Further studies are needed to specify the role of ECMO for SRD patients.
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http://dx.doi.org/10.1186/s13613-021-00819-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871308PMC
February 2021

Clarkson's Disease Episode or Secondary Systemic Capillary Leak-Syndrome: That Is the Question!

Chest 2021 Jan;159(1):441

Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de Médecine Interne 2, Centre de Référence National Lupus et SAPL et Autres Maladies Auto-immunes et Systémiques Rares, Paris, France.

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http://dx.doi.org/10.1016/j.chest.2020.07.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831696PMC
January 2021

Impact of aging on phenotype and prognosis in IgA vasculitis.

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

Université Paris Descartes, Paris, France.

Objectives: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while the disease is more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV.

Methods: We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: <36; 36≤age < 52; 52≤age < 63 and ≥63 years. Comparison of presentation and outcome were performed according to age of disease onset.

Results: Mean age at diagnosis was 50.1 ± 18 years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (p< 0.0001) and gastrointestinal involvement (p= 0.001). In contrast, the oldest patients had more severe purpura with necrotic lesions (p= 0.001) and more frequent renal involvement (p< 0.0001), with more frequent hematuria, renal failure, higher urine protein excretion and more frequent tubulointerstitial lesions. Patients were treated similarly in all groups of age, and clinical response and relapse rates were similar between groups. In the 127 treated patients with follow-up data for >6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1-38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (p= 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase age.

Conclusion: Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.
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http://dx.doi.org/10.1093/rheumatology/keaa921DOI Listing
January 2021

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

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

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

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

Absence of Anti-Glomerular Basement Membrane Antibodies in 200 Patients With Systemic Lupus Erythematosus With or Without Lupus Nephritis: Results of the GOODLUPUS Study.

Front Immunol 2020 14;11:597863. Epub 2020 Dec 14.

Département de médecine interne, Centre Hospitalier Universitaire de Reims, Reims, France.

Introduction: Anti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.

Objective: The main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or without proliferative renal damage and compared to a healthy control group.

Methodology: This retrospective study was performed on SLE patients' sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).

Results: The cohort was composed of 100 SLE patients with proliferative LN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found "ambivalent" (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.

Conclusion: Anti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.
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http://dx.doi.org/10.3389/fimmu.2020.597863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768036PMC
December 2020

COVID-19-associated collapsing glomerulopathy: a report of two cases and literature review.

Intern Med J 2020 12;50(12):1551-1558

Service de Medecine Interne 2, Institut E3M, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Paris, France.

Nephrotic range proteinuria has been reported during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). However, the pathological mechanisms underlying this manifestation are unknown. In this article, we present two cases of collapsing glomerulopathy (CG) associated with acute tubular necrosis during the course of COVID-19, and review the literature for similar reports. In our two cases, as in the 14 cases reported so far, the patients were of African ancestry. The 14 patients assessed had an APOL1 high-risk genotype. At the end of the reported period, two patients had died and five patients were still requiring dialysis. The 16 cases detailed in the present report strongly argue in favour of a causal link between SARS-CoV-2 infection and the occurrence of CG in patients homozygous for APOL1 high-risk genotype for which the term COVID-associated nephropathy (COVIDAN) can be put forward.
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http://dx.doi.org/10.1111/imj.15041DOI Listing
December 2020

Cutaneous Kikuchi disease-like inflammatory pattern without lymph node involvement is associated with systemic disease and severe features in lupus erythematous: A case-control study.

Lupus 2021 Mar 8;30(3):473-477. Epub 2020 Dec 8.

Sorbonne Université, Medecine, Service de dermatologie et allergologie, APHP, Hôpital Tenon, Paris, France.

Introduction: Kikuchi-Fujimoto disease (KFD) is a self-limited histiocytic necrotizing lymphadenitis sometimes affecting the skin. "Kikuchi disease-like inflammatory pattern" (KLIP) has been described in cutaneous lesions as similar pathological features in patients without lymph node involvement and as a potential clue for the diagnosis of lupus. We aimed to describe KLIP-associated clinical and immunological features in lupus patients with a retrospective case-control study.

Methods: Thirteen cases of KLIP were included as well as thirty-nine age- and sex-matched control lupus patients without KLIP. At the time of KLIP diagnosis, 4/13 patients (31%) had isolated cutaneous lupus erythematosus (CLE) and 9/13 had (69%) systemic lupus erythematosus (SLE) including 6 (46%) with severe haematological, lung, cardiac or renal disease. KLIP features were observed in skin biopsies of different clinical presentations.

Results: Compared with our control group, KLIP patients more frequently had SLE 9/13 (69%) versus 8/39 (21%) (OR 12.9; IC95% [2.86-58.2]; p = 0.0004) and more frequently severe SLE. Two out of four CLE exhibiting KLIP lesions (50%) developed severe SLE with cardiac or renal involvement after 12 and 24 months, respectively.Treatment with thalidomide 100 mg/day allowed rapid and complete clearance of cutaneous lesions in 6/6 KLIP patients. The need to use thalidomide tended to be more frequent in KLIP patients than in controls.

Conclusion: Our study suggests that KLIP features in lupus skin lesions are associated with SLE and severe systemic features. Despite a limited number of isolated CLE patients with KLIP features in the skin, this observation may warrant closer follow-up on patients with a higher risk of developing SLE.
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http://dx.doi.org/10.1177/0961203320978519DOI Listing
March 2021

IgA dominates the early neutralizing antibody response to SARS-CoV-2.

Sci Transl Med 2021 01 7;13(577). Epub 2020 Dec 7.

Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 boulevard de l'Hôpital, 75013 Paris, France.

Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM, and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably 1 month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post-symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against reinfection and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.
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http://dx.doi.org/10.1126/scitranslmed.abd2223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857408PMC
January 2021

Response to: 'Antirheumatic drugs, B cell depletion and critical COVID-19: correspondence on 'Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine by Mathian ' by Notz .

Ann Rheum Dis 2020 Nov 25. Epub 2020 Nov 25.

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

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http://dx.doi.org/10.1136/annrheumdis-2020-218795DOI Listing
November 2020

Prevalence and severity of malnutrition in hospitalized COVID-19 patients.

Clin Nutr ESPEN 2020 12 18;40:214-219. Epub 2020 Sep 18.

Assistance Publique-Hôpitaux de Paris (AP-HP), Nutrition Department, Pitié-Salpêtrière University Hospital, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, 47-83 Boulevard de l'Hôpital, 75013, Paris, France.

Background & Aims: Nutritional knowledge in patients with SARS-Cov2 infection (COVID-19) is limited. Our objectives were: i) to assess malnutrition in hospitalized COVID-19 patients, ii) to investigate the links between malnutrition and disease severity at admission, iii) to study the impact of malnutrition on clinical outcomes such as transfer to an intensive care unit (ICU) or death.

Methods: Consecutive patients hospitalized in a medicine ward at a university hospital were included from March 21st to April 24th 2020 (n = 114, 60.5% males, age: 59.9 ± 15.9 years). Nutritional status was defined using Global Leadership Initiative on Malnutrition (GLIM) criteria. Clinical, radiological and biological characteristics of COVID-19 patients were compared according to the presence of malnutrition. Logistic regression was used to assess associations between nutritional parameters and unfavourable outcomes such as transfer to intensive care unit (ICU) or death.

Results: The overall prevalence of malnutrition was 42.1% (moderate: 23.7%, severe: 18.4%). The prevalence of malnutrition reached 66.7% in patients admitted from ICU. No significant association was found between nutritional status and clinical signs of COVID-19. Lower albumin levels were associated with a higher risk of transfer to ICU (for 10 g/l of albumin, OR [95%CI]: 0.31 [0.1; 0.7]; p < 0.01) and this association was independent of age and CRP levels.

Conclusions: COVID-19 in medical units dedicated to non-intensive care is associated with a high prevalence of malnutrition, especially for patients transferred from ICU. These data emphasize the importance of early nutritional screening in these patients to adapt management accordingly.
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http://dx.doi.org/10.1016/j.clnesp.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500887PMC
December 2020

Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus.

Rheumatology (Oxford) 2020 Nov 11. Epub 2020 Nov 11.

Centre National de Référence des Maladies Autoimmunes Systémiques Rares Est Sud-Ouest (RESO)-LUPUS, European Reference Networks (ERN) ReCONNET and RITA, Strasbourg.

Objective: The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients.

Methods: We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared.

Results: A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th-75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0-4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0-6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8-17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001).

Conclusion: LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.
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http://dx.doi.org/10.1093/rheumatology/keaa671DOI Listing
November 2020

The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim-Chester Disease.

Cancers (Basel) 2020 Nov 3;12(11). Epub 2020 Nov 3.

Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel.

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.
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http://dx.doi.org/10.3390/cancers12113240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693724PMC
November 2020

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients.

Clin Rheumatol 2020 Oct 24. Epub 2020 Oct 24.

Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France.

Objective: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer.

Methods: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study.

Results: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV.

Conclusion: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points • Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. • Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. • All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.
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http://dx.doi.org/10.1007/s10067-020-05455-zDOI Listing
October 2020

Factors associated with implantable cardioverter defibrillators appropriate therapy in cardiac sarcoidosis: a meta-analysis.

Sarcoidosis Vasc Diffuse Lung Dis 2020 15;37(1):17-23. Epub 2020 Mar 15.

Sorbonne Université, INSERM UMRS-1135, CIMI, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares, Hôpital Pitié-Salpêtrière, 75013-Paris, France.

Background: Patients with cardiac sarcoidosis (CS) are at increased risk of atrioventricular blocks, ventricular arrhythmias, and sudden cardiac death. Objectives We aimed to investigate the characteristics associated with appropriate therapy in implantable cardiac defibrillator (ICD) -implanted CS patients.

Methods: We performed a PubMed and Web of Science search for studies reporting patients with CS who underwent an ICD implantation. The primary criterion was an appropriate therapy.

Results: We screened 705 studies, of which 5 were included in the final analysis. We conducted a meta-analysis including 464 patients (mean age 55 years, 282 males (60%)). The mean follow-up was 3.5 years. Among the 464 patients, 180 received an appropriate therapy (39%). Patients who received an appropriate therapy were younger (-3.33, 95% confidence interval (CI) -6.42 to -0.23, p=0.004), were more likely to be male (OR 2.06, 95% CI 1.37-3.09, p=0.0005), had a lower left ventricular ejection fraction (LVEF) (-10.5, 95% CI -18.23 to -2.78, p=0.008), had a higher rate of complete heart block (OR 2.19, 95% CI 1.20 to 3.99, p=0.01), and more frequently had ventricular pacing (OR 6.44 95% CI 2.57 to 16.16, p<0.0001).

Conclusions: Appropriate ICD therapy during CS is associated with young age, male sex, low LVEF, history of complete heart block, and ventricular pacing. .
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http://dx.doi.org/10.36141/svdld.v37i1.8271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569536PMC
November 2020

Clinical phenotypes of extrapulmonary sarcoidosis: an analysis of a French, multi-ethnic, multicentre cohort.

Eur Respir J 2021 Apr 1;57(4). Epub 2021 Apr 1.

Service de Médecine Interne 2, Centre National de Référence Maladies Systémiques Rares, Lupus et Syndrome des Anticorps Antiphospholipides, Centre National de Référence Histiocytoses, Sorbonne Université, Assistance Publique Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France

Sarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups.The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis.A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes.This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category.
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http://dx.doi.org/10.1183/13993003.01160-2020DOI Listing
April 2021

High frequency of clonal hematopoiesis in Erdheim-Chester disease.

Blood 2021 Jan;137(4):485-492

Service de Médecine Interne 2, Centre National de Référence Histiocytoses, and.

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.
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http://dx.doi.org/10.1182/blood.2020005101DOI Listing
January 2021

Prevalence of hyposmia and hypogeusia in 390 COVID-19 hospitalized patients and outpatients: a cross-sectional study.

Eur J Clin Microbiol Infect Dis 2021 Apr 8;40(4):691-697. Epub 2020 Oct 8.

Groupe Hospitalier Universitaire APHP, Sorbonne Université, site Pitié-Salpêtrière, Paris, France.

Anecdotal evidence rapidly accumulated during March 2020 from sites around the world that sudden hyposmia and hypogeusia are significant symptoms associated with the SARS-CoV-2 pandemic. Our objective was to describe the prevalence of hyposmia and hypogeusia and compare it in hospitalized and non-hospitalized COVID-19 patients to evaluate an association of these symptoms with disease severity. We performed a cross-sectional survey during 5 consecutive days in March 2020, within a tertiary referral center, associated outpatient clinic, and two primary care outpatient facilities in Paris. All SARS-CoV-2-positive patients hospitalized during the study period and able to be interviewed (n = 198), hospital outpatients seen during the previous month (n = 129), and all COVID-19-highly suspect patients in two primary health centers (n = 63) were included. Hospitalized patients were significantly more often male (64 vs 40%) and older (66 vs 43 years old in median) and had significantly more comorbidities than outpatients. Hyposmia and hypogeusia were reported by 33% of patients and occurred significantly less frequently in hospitalized patients (12% and 13%, respectively) than in the health centers' outpatients (33% and 43%, respectively) and in the hospital outpatients (65% and 60%, respectively). Hyposmia and hypogeusia appeared more frequently after other COVID-19 symptoms. Patients with hyposmia and/or hypogeusia were significantly younger and had significantly less respiratory severity criteria than patients without these symptoms. Olfactory and gustatory dysfunction occurs frequently in COVID-19, especially in young, non-severe patients. These symptoms might be a useful tool for initial diagnostic work-up in patients with suspected COVID-19.
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http://dx.doi.org/10.1007/s10096-020-04056-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543958PMC
April 2021

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

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

AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, 27 rue du Faubourg Saint-Jacques, 75014, 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

Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.

N Engl J Med 2020 09;383(12):1117-1128

From the Division of Rheumatology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Great Neck, NY (R.F.); the Division of Nephrology, Ohio State University, Columbus (B.H.R.); Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, and Service de Rhumatologie, Cliniques Universitaires Saint-Luc - both in Brussels (F.H.); Organización Médica de Investigación, Buenos Aires (A.M.); the Department of Internal Medicine, Section of Nephrology, Leiden University Medical Center, Leiden, the Netherlands (Y.K.O.T.); the Division of Nephrology, Division of Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami (G.C.); Sorbonne Université, INSERM Unité 1135 (Z.A.), and Assistance Publique-Hôpitaux de Paris Sorbonne Université, Service de Médecine Interne 2, Institut Endocrinologie, Maladies Métaboliques et Médecine Interne, Centre de Référence National du Lupus et Syndrome des Antiphospholipides, Hôpital Pitié-Salpêtrière (Z.A.) - both in Paris; the Department of Nephrology, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou (X.Y.), and the Department of Medicine, Tuen Mun Hospital, Hong Kong (C.C.M.) - both in China; Escola Bahiana de Medicina e Saúde Pública, Salvador, Brazil (M.B.S.); the Division of Rheumatology, New York University School of Medicine, New York (A.S.); GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom (Y.G., B.J.); Parexel, Durham, NC (C.K.); and GlaxoSmithKline, Collegeville, PA (S.W.B., C.B., D.A.R.).

Background: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown.

Methods: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m, and no use of rescue therapy). The time to a renal-related event or death was assessed.

Results: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.

Conclusions: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).
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http://dx.doi.org/10.1056/NEJMoa2001180DOI Listing
September 2020

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

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

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

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

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

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

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

Response to: 'Implications of SARS-CoV-2 infection for patients with rheumatic disease' by Lin .

Ann Rheum Dis 2020 Sep 7. Epub 2020 Sep 7.

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

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http://dx.doi.org/10.1136/annrheumdis-2020-218404DOI Listing
September 2020