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Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course.

ABSTRACT: Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.

SUBMITTER: Cavagna L

PROVIDER: S-EPMC6912490 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course.

Cavagna Lorenzo L Trallero-Araguás Ernesto E Meloni Federica F Cavazzana Ilaria I Rojas-Serrano Jorge J Feist Eugen E Zanframundo Giovanni G Morandi Valentina V Meyer Alain A Pereira da Silva Jose Antonio JA Matos Costa Carlo Jorge CJ Molberg Oyvind O Andersson Helena H Codullo Veronica V Mosca Marta M Barsotti Simone S Neri Rossella R Scirè Carlo C Govoni Marcello M Furini Federica F Lopez-Longo Francisco Javier FJ Martinez-Barrio Julia J Schneider Udo U Lorenz Hanns-Martin HM Doria Andrea A Ghirardello Anna A Ortego-Centeno Norberto N Confalonieri Marco M Tomietto Paola P Pipitone Nicolò N Rodriguez Cambron Ana Belen AB Blázquez Cañamero María Ángeles MÁ Voll Reinhard Edmund RE Wendel Sarah S Scarpato Salvatore S Maurier Francois F Limonta Massimiliano M Colombelli Paolo P Giannini Margherita M Geny Bernard B Arrigoni Eugenio E Bravi Elena E Migliorini Paola P Mathieu Alessandro A Piga Matteo M Drott Ulrich U Delbrueck Christiane C Bauhammer Jutta J Cagnotto Giovanni G Vancheri Carlo C Sambataro Gianluca G De Langhe Ellen E Sainaghi Pier Paolo PP Monti Cristina C Gigli Berzolari Francesca F Romano Mariaeva M Bonella Francesco F Specker Christof C Schwarting Andreas A Villa Blanco Ignacio I Selmi Carlo C Ceribelli Angela A Nuno Laura L Mera-Varela Antonio A Perez Gomez Nair N Fusaro Enrico E Parisi Simone S Sinigaglia Luigi L Del Papa Nicoletta N Benucci Maurizio M Cimmino Marco Amedeo MA Riccieri Valeria V Conti Fabrizio F Sebastiani Gian Domenico GD Iuliano Annamaria A Emmi Giacomo G Cammelli Daniele D Sebastiani Marco M Manfredi Andreina A Bachiller-Corral Javier J Sifuentes Giraldo Walter Alberto WA Paolazzi Giuseppe G Saketkoo Lesley Ann LA Giorgi Roberto R Salaffi Fausto F Cifrian Jose J Caporali Roberto R Locatelli Francesco F Marchioni Enrico E Pesci Alberto A Dei Giulia G Pozzi Maria Rosa MR Claudia Lomater L Distler Jorg J Knitza Johannes J Schett George G Iannone Florenzo F Fornaro Marco M Franceschini Franco F Quartuccio Luca L Gerli Roberto R Bartoloni Elena E Bellando Randone Silvia S Zampogna Giuseppe G Gonzalez Perez Montserrat I MI Mejia Mayra M Vicente Esther E Triantafyllias Konstantinos K Lopez-Mejias Raquel R Matucci-Cerinic Marco M Selva-O'Callaghan Albert A Castañeda Santos S Montecucco Carlomaurizio C Gonzalez-Gay Miguel Angel MA

Journal of clinical medicine 20191118 11

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of o ...[more]

PMID: 31752231

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Project description:ImportanceAntisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients' serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies.ObjectiveTo elucidate the clinical features of myositis in patients with antisynthetase syndrome.Design, setting, and participantsIn this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016.ExposuresSix different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped.Main outcomes and measuresThe main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied.ResultsOf 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1-the anti-OJ antibody-was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis.Conclusions and relevanceAlthough clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies.

Project description:Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

Project description:BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.MethodsWe have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.ResultsWe collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.ConclusionsMPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

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Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course.

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Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course.

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