Publications by authors named "Yves Allenbach"

98 Publications

The seasonality of Dermatomyositis associated with anti-MDA5 antibody: An argument for a respiratory viral trigger.

Autoimmun Rev 2021 Feb 18:102788. Epub 2021 Feb 18.

Sorbonne Universities, APHP, Pitié Salpêtrière Hospital, Department of Clinical Immunology and Internal Medicine Paris, France; INSERM, Myology Research Centre, UMRS 974, Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2021.102788DOI Listing
February 2021

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

Therapie 2021 Jan 28. Epub 2021 Jan 28.

AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France.

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients.

Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2.

Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs).

Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.therap.2021.01.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842207PMC
January 2021

Antiphospholipid antibodies and thrombotic events in COVID-19 patients hospitalized in medicine ward.

Autoimmun Rev 2021 Feb 13;20(2):102729. Epub 2020 Dec 13.

Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Centre National de Référence Maladies AUtoimmunes et systémiques rares Maladies Autoinflammatoires Rares et des Myopathies Inflamatoires, F-75013 Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2020.102729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834187PMC
February 2021

Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases.

Eur Radiol 2020 Nov 21. Epub 2020 Nov 21.

NMR Laboratory, Neuromuscular Investigation Center, Institute of Myology, Paris, France.

Objectives: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression.

Methods: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment.

Results: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM.

Conclusions: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement.

Key Points: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-020-07487-0DOI Listing
November 2020

Performance of serum apolipoprotein-A1 as a sentinel of Covid-19.

PLoS One 2020 20;15(11):e0242306. Epub 2020 Nov 20.

Department of Internal Medicine and Clinical Immunology, Sorbonne Université, AP-HP Pitié-Salpêtrière, Paris, France.

Background: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19.

Methods: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population.

Results: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04).

Conclusion: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679025PMC
December 2020

Immune-mediated necrotizing myopathy: clinical features and pathogenesis.

Nat Rev Rheumatol 2020 12 22;16(12):689-701. Epub 2020 Oct 22.

Normandie University, UNIROUEN, Inserm U1234, Department of Immunology and Biotherapy, Rouen University Hospital, Rouen, France.

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41584-020-00515-9DOI Listing
December 2020

Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study.

Pharmaceuticals (Basel) 2020 Oct 17;13(10). Epub 2020 Oct 17.

Department of Internal Medicine, Robert Ballanger Hospital, 93600 Aulnay-Sous-Bois, France.

Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO ≤ 96% despite O-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3-0.81), -value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135-0.51, = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis ( < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph13100317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603074PMC
October 2020

Development of a multivariate prediction model of intensive care unit transfer or death: A French prospective cohort study of hospitalized COVID-19 patients.

PLoS One 2020 19;15(10):e0240711. Epub 2020 Oct 19.

Department of Internal Medicine and Clinical Immunology, Centre National de Références Maladies Autoimmunes et Systémiques Rares Maladies Autoinflammatoires Rares et des Myopathies Inflammatoires, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne University, Paris, France.

Prognostic factors of coronavirus disease 2019 (COVID-19) patients among European population are lacking. Our objective was to identify early prognostic factors upon admission to optimize the management of COVID-19 patients hospitalized in a medical ward. This French single-center prospective cohort study evaluated 152 patients with positive severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase-polymerase chain reaction assay, hospitalized in the Internal Medicine and Clinical Immunology Department, at Pitié-Salpêtrière's Hospital, in Paris, France, a tertiary care university hospital. Predictive factors of intensive care unit (ICU) transfer or death at day 14 (D14), of being discharge alive and severe status at D14 (remaining with ventilation, or death) were evaluated in multivariable logistic regression models; models' performances, including discrimination and calibration, were assessed (C-index, calibration curve, R2, Brier score). A validation was performed on an external sample of 132 patients hospitalized in a French hospital close to Paris, in Aulnay-sous-Bois, Île-de-France. The probability of ICU transfer or death was 32% (47/147) (95% CI 25-40). Older age (OR 2.61, 95% CI 0.96-7.10), poorer respiratory presentation (OR 4.04 per 1-point increment on World Health Organization (WHO) clinical scale, 95% CI 1.76-9.25), higher CRP-level (OR 1.63 per 100mg/L increment, 95% CI 0.98-2.71) and lower lymphocytes count (OR 0.36 per 1000/mm3 increment, 95% CI 0.13-0.99) were associated with an increased risk of ICU requirement or death. A 9-point ordinal scale scoring system defined low (score 0-2), moderate (score 3-5), and high (score 6-8) risk patients, with predicted respectively 2%, 25% and 81% risk of ICU transfer or death at D14. Therefore, in this prospective cohort study of laboratory-confirmed COVID-19 patients hospitalized in a medical ward in France, a simplified scoring system at admission predicted the outcome at D14.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571674PMC
November 2020

Cytokine profile as a prognostic tool in coronavirus disease 2019. Comment on "Urgent avenues in the treatment of COVID-19: Targeting downstream inflammation to prevent catastrophic syndrome" by Quartuccio et al. Joint Bone Spine. 2020;87:191-93.

Joint Bone Spine 2021 01 17;88(1):105074. Epub 2020 Sep 17.

Centre National de Références Maladies Autoimmunes et systémiques rares Maladies Autoinflammatoires Rares et des Myopathies Inflammatoires, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, 75013 Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbspin.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497797PMC
January 2021

Relationship between change in physical activity and in clinical status in patients with idiopathic inflammatory myopathy: A prospective cohort study.

Semin Arthritis Rheum 2020 10 30;50(5):1140-1149. Epub 2020 Jun 30.

Department of Internal Medicine and Clinical Immunology and Inflammation-Immunopathology-Biotherapy Department (I2B), Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris 6, Paris, France; Institute of Myology, Neuromuscular Investigation Center, Pitié-Salpêtrière University Hospital, Paris, France.

Objective: This study aimed to investigate the relationship between changes in clinical status on daily life physical activity (PA) in patients with idiopathic inflammatory myopathy (IIM).

Methods: Patients with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) or overlap myositis (OM) who presented either a new-onset or relapsing IIM, stable disease on maintenance therapy or were undergoing immunosuppressant tapering were included. Patients were evaluated at inclusion (V0), and at two follow-up visits (V1, 94±12 days from V0; V2, 96±17 days from V1). The American College of Rheumatology/European League against Rheumatism (ACR/EULAR) response criteria was recorded. PA assessed using 14-days raw accelerometry data gathered using a wrist-worn accelerometer after each visit (mean daily Euclidean norm minus 1 g (ENMO) was computed).

Results: Fifty-five patients (16 OM, 27 IMNM and 12 DM) were included. At baseline, 67% of patients had an ENMO Z-score less than 1. At inclusion, ENMO mainly correlated with health assessment questionnaire score (HAQ, ρ=-0.51, p<0.01), manual muscle testing 8 (MMT8, ρ=0.42, p<0.01), creatinine level (ρ=0.41, p<0.01), and SF-36 physical functioning score (ρ=0.38, p<0.002). At follow-up, ENMO changes mainly correlated with changes in MMT8, HAQ, SF-36 fatigue, and depression score (all ρ>0.43, all p<0.001). Level of agreement between ACR/EULAR response criteria and changes in PA was 15, 45, and 90% for minimal (n = 13), moderate (n = 20), and major (n = 10) improvements, respectively.

Conclusion: Baseline PA levels and change in PA correlated with muscle strength and function, yet changes in PA were also influenced by psychological status. Only patients with major improvements on the ACR/EULAR criteria had significant increase in PA. Accelerometer may serve as an objective tool to define a clinically relevant real-life outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semarthrit.2020.06.014DOI Listing
October 2020

Clinical Pharmacology and Interplay of Immune Checkpoint Agents: A Yin-Yang Balance.

Annu Rev Pharmacol Toxicol 2021 01 1;61:85-112. Epub 2020 Sep 1.

Sorbonne Université, INSERM, CIC-1901 Paris-Est, CLIP² Galilée, UNICO-GRECO Cardio-oncology Program, and Department of Pharmacology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, F-75013 Paris, France; email:

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-pharmtox-022820-093805DOI Listing
January 2021

Response to: Comment on "Systematic retrospective study on 64 patients anti-Mi2 dermatomyositis: A classic skin rash with a necrotizing myositis and high risk of malignancy".

J Am Acad Dermatol 2020 Dec 3;83(6):e461-e462. Epub 2020 Aug 3.

Sorbonnes Universités Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de médecine Interne et d'immunologie clinique, Paris, France; Institut National de la Santé et de la Recherche Médicale, UMR974, Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.07.110DOI Listing
December 2020

Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.

Autoimmun Rev 2020 Aug 11;19(8):102586. Epub 2020 Jun 11.

Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Regional Pharmacovigilance Centre, Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. Electronic address:

Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.

Patients Methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC (lower end of the IC 95% credibility interval) >0 is deemed significant.

Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).

Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2020.102586DOI Listing
August 2020

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

Neurology 2020 07 2;95(1):e70-e78. Epub 2020 Jun 2.

From the Departments of Clinical Immunology and Internal Medicine (Y.A., S.T., G.L., B.H., N.C., K.M., O.B.), Immunobiology (M.M.), and Biostatistics, Public Health, and Medical Information (B.G.), Pitié-Salpêtrière Hospital, APHP, Sorbonne Universities; Myology Research Centre (Y.A., O.B.), INSERM, UMRS 974, Paris; Department of Pneumology (Y.U., H.N.), APHP, Avicenne Hospital, INSERM U1272, Université Sorbonne Paris Nord, Bobigny; Department of Internal Medicine (L.G., A. Marquet), Lyon Sud Hospital, Lyon Sud University, Paris; Reference Centre for Rare Autoimmune Diseases (A. Meyer) and Medical Intensive Care Unit, Hautepierre Hospital (V. Castelain), Hôpitaux Universitaires de Strasbourg, Strasbourg University; Division of Pneumology (R.B.), Bichat Hospital, AP-HP, Paris-Diderot University, Paris; Department of Pneumology (F.G., P.P.), Centre Hospitalier Universitaire, Angers University; Department of Internal Medicine Infectieuses (C.D.), CHU de Martinique, Fort de France; Departments of Internal Medicine and Clinical Immunology (S.A.) and Internal Medicine and Systemic Diseases (H.D.), François-Mitterrand University Hospital, University of Bourgogne-Franche-Comté, Dijon; Internal Medicine Department (B.T., A.B.), Cochin Hospital, AP-HP, René Descartes University, Paris; Department of Internal Medicine (C.G., N.L.), Henri Mondor Hospital, Paris Est Créteil University, Créteil, France; Department of Neurology (N.V.), Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Internal Medicine (E.D.), Hôpital Bretonneau Tours, Tours University; Internal Medicine Department (A.S.), Hôpital Robert-Debré, Reims University; Departments of Rheumatology (T.M.) and Internal Medicine (L.D.S.M.), Bretagne Occidentale University, Centre Hospitalo-Universitaire de Brest; Department of Internal Medicine (S.H.), CHU de Besançon; Department of Internal Medicine (C.B.-D.), Centre Hospitalier Général de Niort; Department of Internal Medicine (N.T.), Nice University, CHU Nice; Department of Internal Medicine (P.C.), Institut Mutualiste Montsouris, Paris; Department of Internal Medicine (M.G.), Jean Verdier Hospital, Paris Seine-Saint-Denis University, Bondy; Department of Internal Medicine (A. Mekinian), Saint Antoine Hospital, APHP, Sorbonne Universities, Paris; Department of Pneumology CHU (J.C.M.), Poitiers University; Department of Pneumology (A.T.), Hôpital Saint-Louis, APHP, Sorbonne Paris Cité, University Paris-Diderot, Paris; Department of Respiratory Medicine (V. Cottin), National Reference Center for Rare Pulmonary Diseases, Hospices Civils de Lyon, Claude Bernard University Lyon 1, Lyon University; Department of Pneumology (D.I.-B.), European George Pompidou Hospital, APHP, Paris V University; Department of Pneumology (S.P.-H.), Sainte-Camille Hospital, Bry-sur-Marne; Department of Pneumology (C.B.), Foch Hospital, Saint Quentin en Yveline University, Suresnes; and Department of Immunology (N.F.), Lyon-Sud Hospital, Hospices Civils-de-Lyon, Pierre-Bénite, France.

Objectives: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.

Methods: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data.

Results: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis.

Conclusion: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371381PMC
July 2020

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

Ann Rheum Dis 2021 01 23;80(1):36-48. Epub 2020 Apr 23.

Rheumatology, University Hospital of Bordeaux, Bordeaux, France.

Background: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.

Methods: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.

Results: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.

Conclusion: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2020-217139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788064PMC
January 2021

Edematous myositis: a clinical presentation first suggesting dermatomyositis diagnosis.

Brain Pathol 2020 09 15;30(5):867-876. Epub 2020 Jun 15.

Department of Internal Medicine and Clinical Immunology, National Reference Center of Neuromuscular disorders, APHP, Pitié-Salpêtrière University Hospital, Sorbonne University, University Pierre et Marie Curie, Paris, France.

Aims: Edema of the limbs is uncommon in idiopathic inflammatory myopathies (IIM). The few reported cases have been associated with severe and refractory dermatomyositis (DM), sometimes in association with cancers. We aimed to determine if edematous myositis is a homogeneous subtype based on clinical, serological and pathological features.

Methods: This is a retrospective observational study performed between 2008 and 2015 in the French national referral center for myositis. All adult patients with an inflammatory muscle biopsy and upper limbs edema were included as well as IIM cases without limb edema as controls. Clinical, biological and pathological features were collected.

Results: Seventeen edematous myositis were included and compared to 174 IIM without edema, including 50 DM controls. Edema was the first manifestation in 23% of patients. Muscle weakness was severe and symmetric, 71% of patients presented dysphagia and a restrictive ventilatory pattern was found in 40%. Fifty-two percent of patients had a typical DM skin rash and 23% had cancer within 3 years of diagnosing myositis. Fifty-three percent of patients presented a myositis specific antibody and only DM-specific antibodies were detected. Classic pathological DM features (perifascicular atrophy, perifascicular/perimysial perivascular inflammation) were uncommon but capillary C5b-9 deposition and MxA expression were seen in 79% and 73% of cases, respectively. A perimysial edema was found in 82% of cases. Seventeen percent of patients died (median follow up of 18 months). Edematous myositis demonstrated more marked capillary C5b-9 deposition compared to IIM controls. There was no clinical, biological or pathological difference with DM controls except for limb edema.

Conclusion: Our study underlines that limb edema could be a symptom of IIM and that edematous myositis are mostly DM. The vasculopathy seems to play a key role in its pathophysiology. Limb edema associated with muscle impairment should suggest the diagnosis of DM in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bpa.12844DOI Listing
September 2020

Evolving spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors results from the WHO's pharmacovigilance database.

J Autoimmun 2020 Jul 14;111:102454. Epub 2020 Apr 14.

Department of Internal Medicine and Clinical Immunlogy, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre national de référence maladies auto-immunes systémiques rares, Centre national de référence maladies auto-inflammatoires et amylose, INSERM UMR_S 959, Immunologie-Immunopathologie-Immunothérapie, i3, France. Electronic address:

Purpose: Drug-induced uveitis is a rare but sight-threatening condition. We seek to determine the spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors (ICI).

Methods: Retrospective pharmacovigilance study based on adverse drug reactions reported within VigiBase, the WHO international pharmacovigilance database. We included deduplicated individual case safety reports (ICSRs) reported as 'uveitis' at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities between 1967 and 04/28/2019. We performed a case/non-case analysis to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. We excluded drugs with potential indication bias.

Results: 1404 ICSRs corresponding to 37 drugs had a significant over-reporting signal with a median age of 57 [42-68] years and 45.7% of males. We identified five major groups of treatments: bisphosphonates (26.9%), non-antiviral anti-infectious drugs (25.4%), protein kinase inhibitors (15.5%), ICI (15.0%), and antiviral drugs (11.1%). Severe visual loss was reported in 12.1% of cases. ICI and protein kinase inhibitors were the most recently emerging signals. The time to onset between first infusion and uveitis was significantly different between groups ranging from 5 days [2-19] in the bisphosphonate group to 138.5 [47.25-263.75] in protein kinase inhibitors group (p < 0.0001). Anti-Programmed Cell death 1 represented more than 70% of ICI-induced uveitis. We identified Vogt-Koyanagi-Harada (VKH)-like syndrome as being associated with ICI use.

Conclusions: The spectrum of drug-induced uveitis has changed with the evolution of pharmacopeia and the recent emergence of ICIs. VKH-like syndrome has been reported with ICI and protein kinase inhibitors therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaut.2020.102454DOI Listing
July 2020

Severe axial and pelvifemoral muscle damage in immune-mediated necrotizing myopathy evaluated by whole-body MRI.

Semin Arthritis Rheum 2020 12 29;50(6):1437-1440. Epub 2020 Feb 29.

Department of Internal Medicine and Clinical Immunology and Inflammation-Immunopathology-Biotherapy Department (I2B), Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris 6, Paris, France.

Background: Our objective was to define the pattern and severity of muscle damage in immune-mediated necrotizing myopathy (IMNM) and its relationship with clinical and serological features.

Methods: IMNM patients with a whole-body MRI (n=42) were included and compared to sporadic inclusion-body myositis (s-IBM) patients (n=60). Fat replacement was estimated using the Mercuri score in 55 muscles. Overall lesion load was defined as the sum of all abnormal Mercuri scores (reported in % maximal score) and lesion load quotient was defined as the overall lesion load divided by disease duration. Linear relationships between variables were assessed and multidimensional analysis was performed to define homogenous groups of patients.

Results: IMNM patients were aged 48.1±15.8 years and had a disease duration of 9.8±8.1 years. Most severely affected muscle groups were located in the pelvifemoral and lumbar region. Unsupervised analysis showed two subgroups of patients: one with mild lesion load (15±10%, n=32/42) and another with severe lesion load (60±10%, n=10/42: p<0.001) associated with a mean disease duration of 6.8±6.0 years and 19.5±5.7 years, respectively (p<0.0001). Correlational studies confirmed that disease duration was the most important predictor of muscle damage. Multivariate analyses demonstrated a more severe involvement in select muscle groups in females and seropositive patients. No difference was found in overall lesion load quotient of IMNM compared to IBM (p=0.07) but with a distinct muscle pattern.

Conclusion: IMNM is associated with severe axial and pelvifemoral muscle damage. Disease duration is an important predictor of muscle damage. IMNM and s-IBM patients have a comparable damage burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semarthrit.2020.02.009DOI Listing
December 2020

Anti-RNP antibodies delineate a subgroup of myositis: A systematic retrospective study on 46 patients.

Autoimmun Rev 2020 Mar 7;19(3):102465. Epub 2020 Jan 7.

Department of Internal Medicine and Clinical Immunology, Sorbonne Université, University Pierre et Marie et Curie, APHP, Hôpital Pitié-Salpêtrière, Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2020.102465DOI Listing
March 2020

Granulomatosis-associated myositis: High prevalence of sporadic inclusion body myositis.

Neurology 2020 03 27;94(9):e910-e920. Epub 2019 Dec 27.

From the Département d'Immunologie Clinique et Médecine Interne (Y.D.) and Département de Rhumatologie (J.-E.G., J.S., A.M.), Centre de Référence des Maladies Auto-immunes Rares, Département d'Immunobiologie (B.N.), Département de Pathologie (B.L.), Département de Neurologie, Centre de Référence des Maladies Neuro-musculaires (A.E.-L.), and Institut de Physiologie EA 3072, Service de Physiologie et d'Explorations Fonctionnelles (B.G., A.M.), Hôpitaux Universitaires de Strasbourg; Département de Médecine Interne et Immunologie Clinique (Y.A., O.B., B.H., K.M.), Centre de Référence des Maladies Neuro-Musculaires Paris Est, Assistance Publique-Hôpitaux de Paris (AP-HP), DHU I2B, Sorbonne Universités UPMC Univ Paris 06, Inserm, UMR 974, Centre de Recherche en Myologie, Hôpital Universitaire Pitié-Salpêtrière; Département de Neuropathologie (S.L.-L.), Centre de Référence des Maladies Neuro-Musculaires Paris Est, Hôpital Universitaire Pitié-Salpêtrière; Fédération de Médecine Translationnelle de Strasbourg (B.L., J.-E.G., B.G., J.S., A.M.), Université de Strasbourg; Département de Rhumatologie (D.W.), Hôpital Universitaire de Besançon, France; Département de Rhumatologie (C.V.F.), Hôpital Universitaire Sart-Tilman, Liège, Belgium; Departement de Rhumatologie (N.P.), Hôpital Universitaire de Bordeaux; Departement de Médicine Interne (E.M.), Hôpital Universitaire Louis Mourier, Colombes; Departement de Médicine Interne et Maladies Vasculaires (C.L.), Hôpital Universitaire d'Angers; Departement de Médicine Interne (O.H.), Hôpital Emile Muller, Mulhouse; Departement de Médicine Interne (J.M.), Hôpital Universitaire de Tours, France.

Objective: To refine the predictive significance of muscle granuloma in patients with myositis.

Methods: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM).

Results: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis.

Conclusion: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008863DOI Listing
March 2020

[Dermatomyositis: new antibody, new classification].

Med Sci (Paris) 2019 Nov 20;35 Hors série n° 2:18-23. Epub 2019 Dec 20.

Service de médecine interne et immunologie clinique, APHP Pitié-Salpêtrière, Paris, France.

Dermatomyositis are rare chronic auto-immune diseases characterized by cutaneous involvement. Diagnosis could be made in childhood or in aldult. There are some different clinical and histological presentation associated with different myositis specific antibody. There are five dermatomyositis specific autoantibodies, anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5, and anti-SAE. Anti-Mi2 are associated with "classical form" of DM with cutaneous and muscular involvement. Anti-Tif1γ and anti-NXP2 are found in juvenile and adult dermatomyositis, and are associated with recurrent diseases with cutaneous involvement at the forefront. In adults, they are associated with cancer. Anti-MDA5 antibodies are associated with a systemic involvement and an interstitial lung disease. Finally, anti-SAE have been found only in adults, with a classic form.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1051/medsci/2019178DOI Listing
November 2019

239th ENMC International Workshop: Classification of dermatomyositis, Amsterdam, the Netherlands, 14-16 December 2018.

Neuromuscul Disord 2020 01 25;30(1):70-92. Epub 2019 Oct 25.

Department of Internal Medicine and Clinical Immunology, Pitié Salpetrière Hospital, AP-HP Sorbonne University, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2019.10.005DOI Listing
January 2020

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

Rheumatology (Oxford) 2020 08;59(8):1927-1937

Paediatric Hematology-Immunology and Rheumatology Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Necker-Enfants Malades, AP-HP, Paris.

Objectives: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2).

Methods: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes.

Results: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported.

Conclusion: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kez525DOI Listing
August 2020

Infliximab as effective treatment for aseptic neutrophilic myositis.

Neurology 2019 12 29;93(23):1009-1011. Epub 2019 Oct 29.

From the Sorbonne Université (P.G.-J., O.B., Y.A.), INSERM UMRS_974, Center of Research in Myology, AP-HP, Department of Internal Medicine and Clinical Immunology, DHU I2B, Pitié-Salpêtrière Hospital; Université Paris Descartes (S.G.), Service de Dermatologie, Hôpital Cochin-Centre Tarnier, APHP; Department of Neurology and Myology (S.L.-L.), Pitié-Salpêtrière Hospital; and Department of Dermatology (S.B.), Pitié-Salpêtrière Hospital, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008584DOI Listing
December 2019

Reply: Treatment of anti-MDA5 autoantibody-positive juvenile dermatomyositis using tofacitinib.

Brain 2019 11;142(11):e60

Department of Internal Medicine and Clinical Immunology, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris 6, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz294DOI Listing
November 2019

Inclusion body myositis: accumulation of evidence for its autoimmune origin.

Brain 2019 09;142(9):2549-2551

Sorbonne Université, Paris, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz229DOI Listing
September 2019

Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology

Circulation 2019 07;140(2):80-91

Division of Cardiovascular Medicine, Clinical Pharmacology, Cardio-Oncology Program, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN.

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779326PMC
July 2019