Epilepsy is one of the most common neurological disorders. Studies have demonstrated that genetic factors have a strong role in etiology of epilepsy. Mutations in genes encoding ion channels, neurotransmitters and other proteins involved in the neuronal biology have been recognized in different types of this disease. Moreover, some chromosomal aberration including ring chromosomes will result in epilepsy. In this review, we intend to highlight the role of molecular genetic in etiology of epilepsy syndromes, inspect the most recent classification of International League against Epilepsy and discuss the role of genetic counseling and genetic testing in management of epilepsy syndromes. Furthermore, we emphasize on collaboration of neurologists and geneticists to improve diagnosis and management.
Myositis-specific autoantibodies (MSAs) are typically considered mutually exclusive, and multiple positivities using the reference standard, Immunoprecipitation, are increasingly rare. However, other techniques, such as Enzyme-Linked Immunosorbent Assay (ELISA) and Line Blot Immunoassay (LIA), are commonly employed in clinical practice. These assays are cheaper, faster and require less clinical expertise to perform; however, they are associated with rates of multiple positivity and an increased probability of false positivity.
Objectives:
This study aims to evaluate the real-life prevalence and the clinical meaning of multiple seropositivity for MSA and Myositis Associated Antibodies (MAAs) in the Classification Criteria of Anti-Synthetase Syndrome (CLASS) cohort.
Methods:
The CLASS Project represents a collaborative, multi-center initiative to develop and validate classification criteria for Anti-synthetase Syndrome (ASSD). This retrospective and prospective study involved 101 centers globally, enrolling 2003 ASSD patients and 2175 controls (ASSD mimickers) from June 2020 to March 2022. Data for the study were collected and managed using Research Electronic Data Capture. From our database, we extracted clinical features and Antinuclear Antibody (ANA) patterns in patients exhibiting positivity for MSA and/or Myositis Associated Antibodies (MAA), excluding anti-Ro52kD (Figure 1).
Results:
Seropositivity for MSA/MAA was confirmed in 2832 patients (67.8%). Multiple positivities for MSA/MAAs (excluding anti-Ro52kD) were identified in 305/2589 cases (11.8%). Notably, 176/2589 patients (6.8%) exhibited positivity for at least two MSAs. Multiple seropositivity was reported by 69/101 centres, with a single centre contributing to 25.2% of total positive results. ELISA confirmed multiple seropositivity in 134/585 subjects (33.7%), IP in 99/412 (24%), and LIA in 720/1646 (43.7%, p=<0.0001). Unknown or other methods were recorded in 377 seropositive patients, of which 119 (31.6%) had multiple positivity. Anti-PmScl and anti-Mi2 exhibited significantly less association with the expected ANA pattern when present in combination than alone (p=0.005 and 0.001, respectively). No differences were noted for the other autoantibodies. We stratified multiple seropositive patients according to the reported autoantibodies, obtaining seven groups (Figure 1). Interstitial Lung Disease (ILD) and arthritis were more common in combinations including ASA, whereas myositis was more prevalent in combinations including NA-MSA (Figure 2). Beyond the triad of ASSD, combinations including ASA showed the highest proportion of Mechanic's Hands (MH) (MH, p=0.007 vs. MAA+NA-ASA), and those with NA-MSA exhibited the highest proportion of Gottron's Papules (GP) or Heliotropic Rash (HR) (GP or HR, p=0.0004 vs. MAA+ASA). Associations including MAA had the highest proportion of scleroderma skin involvement and Raynaud's Phenomenon (RP) (RP, p=0.0002 and 0.04, respectively, vs. multiple ASA positivity). We defined the presence of Scleroderma features by the presence of RP and skin fibrosis or puffy fingers; ASSD features by the presence of ILD, MH, arthritis, or myositis and Dermatomyositis as myositis and GP or HR. With this strict definition, 11.8% of the 305 multiple seropositive patients, specifically 7.9% of those with multiple MSAs, exhibit a clinical picture coherent with the reported autoantibodies.
Conclusion:
The utilization of LIA exposes individuals to a recognized risk of false positivity. However, in the CLASS cohort, a substantial contribution of patients was from a single centre. It was noted that there was an absence of an association between anti-PmScl and anti-Mi2 with the anticipated ANA pattern, whether present individually or in combination. Our study demonstrates that MSAs correlated with known clinical associations even in instances of combined positivity. Notably, 7.9% of cases with multiple MSAs exhibited a clinical presentation coherent with all the seropositivity. Our analysis demonstrates the potential existence of overlap syndromes that may be under-recognized in clinical practice.
REFERENCES:
NIL.
Acknowledgements:
We are grateful to all members of the CLASS project
Disclosure of Interests:
Aravinthan Loganathan: None declared, Gianluca Sambataro Boheringer Ingelheim, Akira Yoshida: None declared, Eduardo Dourado: None declared, Giovanni Zanframundo: None declared, Francisca Bozan: None declared, Daphne Rivero Gallegos: None declared, Iazsmin Bauer-Ventura: None declared, Yasuhiko Yamano: None declared, Sangmee Bae: None declared, Darosa Lim: None declared, Sara Faghihi-Kashani: None declared, Francesco Bonella: None declared, Tamera J. Corte: None declared, Tracy Doyle Bayer, David Fiorentino: None declared, Miguel Ángel González-Gay: None declared, Marie Hudson: None declared, Masataka Kuwana Asahi Kasei Parma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, Kissei, Mochida, Nippon Shinyaku, and Ono Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Chugai, GSK, Kissei, and Mochida; Research grants: Boehringer-Ingelheim, MBL, and Ono Pharmaceuticals, Ingrid E. Lundberg: None declared, Andrew Mammen: None declared, Neil McHugh: None declared, Fredrick Miller: None declared, Carlomaurizio Montecucco: None declared, Chester V Oddis: None declared, Jorge Rojas-Serrano: None declared, Jens Schmidt: None declared, Carlo Alberto Scirè: None declared, Albert Selva-O'Callaghan: None declared, Victoria Werth: None declared, Rohit Aggarwal Actigraph, Alexion, ANI Pharmaceuticals, Argenx, AstraZeneca, Boehringer-Ingelheim, Bristol Myers-Squibb, CabalettaBio, Capella Bioscience, Corbus, CSL Behring, EMD Serono, Galapagos, Horizon Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Novartis, Nuvig Therapeutics, Octapharma, Pfizer, Regeneron, Roivant, Sanofi, Teva, Artsome, Capstanx, Manta, Boehringer Ingelheim, Bristol Myers-Squibb, EMD Serono, Janssen, Mallinckrodt, Pfizer, Q32, Lorenzo Cavagna Boheringer Ingelheim.
Although administration of G-CSF to healthy donors for mobilization and collection of peripheral blood stem cell (PBSC) is common in adult volunteers, there are limited data on short-and especially long-term efficacy in healthy pediatric donors, notably due to ethical issues. The purpose of this study was to assess the short- and long-term adverse effects of using G-CSF in pediatric sibling donors.
Objective Anti‐synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data‐driven classification criteria for ASSD. Methods We utilized a large, international, multi‐center “ Classification Criteria for Anti‐synthetase Syndrome ” (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort. Results Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo‐1 and non‐Jo‐1 anti‐synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti‐Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD. Conclusion We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data‐driven classification criteria for ASSD. image
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