Publications by authors named "Valentina Damato"

29 Publications

  • Page 1 of 1

Heterogeneity in myasthenia gravis: considerations for disease management.

Expert Rev Clin Immunol 2021 May 27. Epub 2021 May 27.

Neuroscience Department, Università Cattolica del Sacro Cuore, Largo F. Vito, 1 - 00168, Rome, Italy.

Introduction: Myasthenia gravis is a rare disease of the neuromuscular junction and a prototype of B cell driven immunopathology. Pathogenic antibodies target post-synaptic transmembrane proteins, most commonly the nicotinic acetylcholine receptor and the muscle-specific tyrosine kinase, inducing end-plate alterations and neuromuscular transmission impairment. Several clinical subtypes are distinct on the basis of associated antibodies, age at symptom onset, thymus pathology, genetic factors and weakness distribution. These subtypes have distinct pathogenesis that can account for different responses to treatment. Conventional therapy is based on the use of symptomatic agents, steroids, immunosuppressants and thymectomy. Of late, biologics have emerged as effective therapeutic options.

Areas Covered: In this review we will discuss the management of myasthenia gravis in relation to its phenotypic and biological heterogeneity, in the light of recent advances in the disease immunopathology, new diagnostic tools and results of clinical trials.

Expert Opinion: Clinical management is shaped on serological subtype, and patient age at onset, lifestyle and comorbidities, balancing therapeutic needs and safety. Although reliable biomarkers predictive of clinical and biologic outcome are still lacking, recent developments promise a more effective and safe treatment. Disease subtyping according to serological testing and immunopathology is crucial to the appropriateness of clinical management.
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http://dx.doi.org/10.1080/1744666X.2021.1936500DOI Listing
May 2021

Response to: "MuSK-positive myasthenia may be triggered not only by SARS-CoV-2".

Eur J Neurol 2021 Mar 17. Epub 2021 Mar 17.

Neurology Unit, Galliera Hospital, Genoa, Italy.

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http://dx.doi.org/10.1111/ene.14827DOI Listing
March 2021

Human Leukocyte Antigen Class II associations in late-onset Myasthenia Gravis.

Ann Clin Transl Neurol 2021 03 5;8(3):656-665. Epub 2021 Feb 5.

Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy.

Objective: Genetic factors predisposing to late-onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome-wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup.

Methods: This study consecutively enrolled anti-acetylcholine receptor antibody-positive, non-thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA-DRB1 and -DQB1 genotyping and serum titin antibody testing were performed in this population.

Results: A total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50-92) were included. We found a positive association with HLA-DRB1*07 (P = 1.1 × 10 ), HLA-DRB1*14 (P = 0.0251) and HLA-DQB1*02 (P = 0.0095). HLA-DRB1*03, HLA-DRB1*11, and HLA-DQB1*03 were protective alleles (P = 7.9 × 10 , P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA-DRB1*07-DQB1*02 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80-5.99; P = 6.01 × 10 ). The mean age at onset was 73.4 years in DRB1*07 homozygotes, 69.7 years in heterozygotes, and 66.6 in non-carriers (P = 0.0488). DRB1*07 carriers and non-carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics.

Interpretation: In our study, we identified the HLA DRB1*07-DQB1*02 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.
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http://dx.doi.org/10.1002/acn3.51309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951107PMC
March 2021

Benefit and danger from immunotherapy in myasthenia gravis.

Neurol Sci 2021 Apr 5;42(4):1367-1375. Epub 2021 Feb 5.

Department of Neurosciences, Catholic University, Rome, Italy.

In the last years, significant advances have improved the knowledge of myasthenia gravis (MG) immunopathogenesis and have enabled to realize new molecules with a selective action targeting compounds of the immunological system. This review discusses emerging treatments for MG, including complement inhibitors, neonatal Fc receptor targeting agents, and B cell interfering drugs, focusing on benefit and danger. In the second section of the review, several related adverse events of immunotherapy, including MGonset, are debated.
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http://dx.doi.org/10.1007/s10072-021-05077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861968PMC
April 2021

Myasthenia gravis associated with anti-MuSK antibodies developed after SARS-CoV-2 infection.

Eur J Neurol 2021 Jan 9. Epub 2021 Jan 9.

Neurology Unit, Galliera Hospital, Genoa, Italy.

Introduction: Since the onset of the novel coronavirus pandemic, several neurological complications secondary to SARS-CoV-2 infection have been reported, affecting central nervous system, peripheral nervous system and neuromuscular junction.

Case Report: We present the case of a 77-year-old man who developed bulbar myasthenia gravis (MG) eight weeks after SARS-CoV-2 infection. The search for serum antibodies against the acetylcholine receptor, the muscle-specific tyrosine kinase (MuSK), and the low-density lipoprotein receptor-related protein 4 antibodies, performed by radioimmunoassay (RIA), resulted negative, while anti-MuSK antibodies were detected by cell-based assay (CBA). The patient was treated with pyridostigmine (60 mg four times a day) with unsatisfactory clinical response, followed by immunosuppressive therapy (azathioprine 1.5 mg/kg/day) with improvement of MG symptoms after two months of treatment.

Discussion: Several viral diseases have been described as associated with the onset of MG, although the underlying mechanisms are not yet fully understood. Similarly, a growing number of scientific reports suggest a correlation between SARS-CoV-2 infection and autoimmune diseases. The interest of our case lies in the timing of the MG onset (after two months from infection), together with the unusual late onset of anti-MuSK MG. These elements suggest that coronavirus infection may act as a trigger of the disease. We confirm the importance of CBA in the serological diagnosis of RIA-negative MG.
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http://dx.doi.org/10.1111/ene.14721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014563PMC
January 2021

Acetylcholine receptor antibody positivity rate in ocular myasthenia gravis: a matter of age?

J Neurol 2021 May 2;268(5):1803-1807. Epub 2021 Jan 2.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, 00168, Rome, Italy.

Background: Anti-acetylcholine receptor antibodies (AChR Abs) are detected in 85% of myasthenia gravis (MG) patients, at higher rates in patients with late-onset disease. AChR Ab frequency is generally thought to be much lower in ocular MG (OMG), although recent studies reported positivity rates higher than 70%. We hypothesized that the improved AChR Ab diagnostic yield in OMG could be related to an increased frequency of late-onset disease, as observed in generalized MG.

Methods: We compared OMG patients, with disease onset before or after 1998, for the age of onset, sex, presence of thymoma, immunosuppressive therapy rate, AChR Ab positivity, and follow-up duration. All patients had a follow-up ≥ 2 years. AChR Abs were tested by radioimmunoassay.

Results: The study included 133 patients. Disease onset occurred before 1998 in 54/133 cases (41%). Age of onset, the proportion of late-onset patients, and AChR Ab positivity rate were significantly increased in the more recent population. Thymoma frequency was similar in the two series. On multivariate analysis, the only variable predicting AChR Ab positivity was the age at onset ≥ 50 years (OR = 6.50, 95% CI = 2.70-15.63, p < 0.0001).

Conclusions: Our results confirm that current AChR Ab positivity in OMG may be higher than generally thought. In our population, this finding was associated with an increased frequency of late-onset cases.
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http://dx.doi.org/10.1007/s00415-020-10342-3DOI Listing
May 2021

The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders.

Mov Disord 2018 09 14;33(9):1376-1389. Epub 2018 Sep 14.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

An increasing number of movement disorders are associated with autoantibodies. Many of these autoantibodies target the extracellular domain of neuronal surface proteins and associate with highly specific phenotypes, suggesting they have pathogenic potential. Below, we describe the phenotypes associated with some of these commoner autoantibody-mediated movement disorders, and outline increasingly well-established mechanisms of autoantibody pathogenicity which include antigen downregulation and complement fixation. Despite these advances, and the increasingly robust evidence for improved clinical outcomes with early escalation of immunotherapies, the underlying cellular immunology of these conditions has received little attention. Therefore, here, we outline the likely roles of T cells and B cells in the generation of autoantibodies, and reflect on how these may guide both current immunotherapy regimes and our future understanding of precision medicine in the field. In addition, we summarise potential mechanisms by which these peripherally-driven immune responses may reach the central nervous system. We integrate this with the immunologically-relevant clinical observations of preceding infections, tumours and human leucocyte antigen-associations to provide an overview of the therapeutically-relevant underlying adaptive immunology in the autoantibody-mediated movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221172PMC
September 2018

Serological and experimental studies in different forms of myasthenia gravis.

Ann N Y Acad Sci 2018 02 29;1413(1):143-153. Epub 2018 Jan 29.

Neuroimmunology Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.

Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10-20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor-related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed.
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http://dx.doi.org/10.1111/nyas.13592DOI Listing
February 2018

Myasthenia gravis with antibodies to MuSK: an update.

Ann N Y Acad Sci 2018 01 21;1412(1):82-89. Epub 2017 Dec 21.

Institute of General Pathology, Catholic University, Fondazione Policlinico Gemelli, Rome, Italy.

Myasthenia gravis with antibodies to the muscle-specific tyrosine kinase (MuSK MG) is a rare disease with distinctive pathogenic mechanisms and clinical features. An acute onset and predominant bulbar muscle weakness are very common and highly suggestive of the disease. On the other hand, a more indolent course, atypical ocular presentation, and signs of cholinergic hyperactivity may complicate the diagnosis. Though MuSK MG is still a severe disease, over the years we have observed a steady reduction in the rate of respiratory crisis and a significant improvement in the clinical outcome, both likely related to earlier diagnosis and timely treatment. Despite the improved management, MuSK MG patients tend to remain dependent on long-term immunosuppressive treatment and may develop permanent disabling weakness. In uncontrolled studies, B cell depletion with rituximab proved effective in most patients with refractory disease, inducing prolonged clinical responses associated with a sustained reduction of serum antibody levels. Promising results from experimental studies and case reports suggest that both 3,4-diaminopyridine and albuterol may be effective as symptomatic agents.
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http://dx.doi.org/10.1111/nyas.13518DOI Listing
January 2018

Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients.

J Neurol Neurosurg Psychiatry 2018 02 26;89(2):138-146. Epub 2017 Sep 26.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.

Objective: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies.

Methods: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections.

Results: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells.

Conclusions: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.
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http://dx.doi.org/10.1136/jnnp-2017-316583DOI Listing
February 2018

Pattern of ocular involvement in myasthenia gravis with MuSK antibodies.

J Neurol Neurosurg Psychiatry 2017 09 10;88(9):761-763. Epub 2017 Jun 10.

Institute of General Pathology, Catholic University, Fondazione Policlinico A. Gemelli, Rome, Italy.

Background: Myasthenia gravis (MG) with antibodies to the muscle-specific kinase (MuSK) has a characteristic phenotype. Ocular manifestations have not been systematically evaluated.

Objective: To investigate the features of extrinsic ocular muscle involvement in patients with MuSK-MG.

Methods: We retrospectively evaluated the prevalence, time of onset, clinical pattern and outcome of ocular symptoms in 82 patients with a clinical follow-up ≥2 years.

Results: Ocular manifestations were observed in 79 patients (96.4%) and were the presenting symptoms in 48 (58.5%). Intermittent diplopia with subtle ophthalmoparesis was the most common complaint, ptosis was generally symmetrical and conjugated gaze paresis occurred in 35% of the patients. Ocular manifestations responded well to prednisone and partially to symptomatic treatment. A few patients developed chronic symmetrical ophthalmoparesis, associated with persistent weakness in other muscle groups. All patients with ocular presentation progressed to generalised disease, though weakness spread to other muscle groups was considerably delayed in a few cases.

Conclusions: In MG with antibodies to MuSK, ocular manifestations were as frequent as in other disease subtypes. Symmetrical ophthalmoparesis with conjugated gaze limitation was rather common and associated with low functional disability. A proportion of these patients developed chronic eye muscle paresis.
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http://dx.doi.org/10.1136/jnnp-2017-315782DOI Listing
September 2017

Rituximab in Neuromyelitis Optica Spectrum Disorders-Reply: Why Not as First-Line Therapy.

JAMA Neurol 2017 04;74(4):482-483

Institute of Neurology, Fondazione Policlinico Universitario "A. Gemelli," Catholic University, Rome, Italy2Don Gnocchi ONLUS Foundation, Milan, Italy.

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http://dx.doi.org/10.1001/jamaneurol.2016.5936DOI Listing
April 2017

Remission of myasthenia gravis with MuSK antibodies during ruxolitinib treatment.

Muscle Nerve 2017 Mar 25;55(3):E12-E13. Epub 2016 Nov 25.

General Pathology, Catholic University, Rome, Italy.

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http://dx.doi.org/10.1002/mus.25458DOI Listing
March 2017

Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders: A Systematic Review and Meta-analysis.

JAMA Neurol 2016 Nov;73(11):1342-1348

Institute of Neurology, Department of Neuroscience, Fondazione "A. Gemelli," Catholic University, Rome, Italy2Don Gnocchi ONLUS Foundation, Milan, Italy.

Importance: Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune astrocytopathies characterized by predominant involvement of the optic nerves and spinal cord. In most patients, an IgG autoantibody binding to astrocytic aquaporin 4, the principal water channel of the central nervous system, is detected. Rituximab, a chimeric monoclonal antibody specific for the CD20 B-lymphocyte surface antigen, has been increasingly adopted as a first-line off-label treatment for patients with NMOSDs.

Objective: To perform a systematic review and a meta-analysis of the efficacy and safety of rituximab use in NMOSDs, considering the potential predictive factors related to patient response to rituximab in this disease.

Evidence Review: English-language studies published between January 1, 2000, and July 31, 2015, were searched in the MEDLINE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases. Patient characteristics, outcome measures, treatment regimens, and recorded adverse effects were extracted.

Findings: Forty-six studies were included in the systematic review. Twenty-five studies that included 2 or more patients with NMOSDs treated with rituximab were included in the meta-analysis. Differences in the annualized relapse rate ratio and Expanded Disability Status Scale score before and after rituximab therapy were the main efficacy measures. Safety outcomes included the proportion of deaths, withdrawals because of toxic effects, and adverse effects.

Results: Among 46 studies involving 438 patients (381 female and 56 male [sex was not specified in 1 patient]; mean age at the outset of treatment, 32 years [age range, 2-77 years]), rituximab therapy resulted in a mean (SE) 0.79 (0.15) (95% CI, -1.08 to -0.49) reduction in the mean annualized relapse rate ratio and a mean (SE) 0.64 (0.27) (95% CI, -1.18 to -0.10) reduction in the mean Expanded Disability Status Scale score. A significant correlation was observed between disease duration and the Expanded Disability Status Scale score. Adverse effects were recorded in 114 of 438 (26%) patients treated with rituximab. Specifically, 45 patients (10.3%) experienced infusion-related adverse effects, 40 patients (9.1%) had an infection, 20 patients (4.6%) developed persistent leukopenia, 2 patients (0.5%) were diagnosed as having posterior reversible encephalopathy, and 7 patients (1.6%) died.

Conclusions And Relevance: This systematic review and meta-analysis provides evidence that rituximab therapy reduces the frequency of NMOSD relapses and neurological disability in patients with NMOSDs. However, the safety profile suggests caution in prescribing rituximab as a first-line therapy.
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http://dx.doi.org/10.1001/jamaneurol.2016.1637DOI Listing
November 2016

Disease specific enrichment of circulating let-7 family microRNA in MuSK+ myasthenia gravis.

J Neuroimmunol 2016 Mar 7;292:21-6. Epub 2016 Jan 7.

Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden. Electronic address:

Myasthenia gravis (MG) patients with antibodies against the muscle specific tyrosine kinase (MuSK+) have predominantly involvement of cranio-bulbar muscles and do not display thymus pathology, as do acetylcholine receptor antibody seropositive (AChR+) MG patients. In search of novel biomarkers for MuSK+ MG, we evaluated circulating serum microRNAs. Four analyzed microRNAs were specifically elevated in MuSK+ MG patient serum samples: let-7a-5p, let-7f-5p, miR-151a-3p and miR-423-5p. The circulating microRNA profile in MuSK+ MG differs from the profile previously observed in the serum of AChR+ MG, thus indicating the etiological difference between these two entities. We propose that the identified microRNAs could serve as potential serum biomarkers for MuSK+ MG.
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http://dx.doi.org/10.1016/j.jneuroim.2016.01.003DOI Listing
March 2016

3,4-Diaminopyridine may improve myasthenia gravis with MuSK antibodies.

Neurology 2016 Mar 12;86(11):1070-1. Epub 2016 Feb 12.

From the Institute of Neurology, Catholic University, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000002466DOI Listing
March 2016

Myasthenia gravis with presynaptic neurophysiological signs: Two case reports and literature review.

Neuromuscul Disord 2015 Aug 5;25(8):646-50. Epub 2015 May 5.

Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.

The distinction between myasthenia gravis and Lambert-Eaton myasthenic syndrome is based on clinical, neurophysiological and immunological features. We hereby report two cases with a clinical diagnosis of myasthenia gravis and neurophysiological features consistent with a pre-synaptic neuromuscular transmission defect. Both patients had increased anti-acetylcholine receptor antibody titres and showed a good response to cholinesterase inhibitors, along with a >100% facilitation of the compound muscle action potential on electrophysiological studies. We provide a review of English literature studies on co-existing features of myasthenia gravis and Lambert-Eaton myasthenic syndrome, and discuss diagnostic controversies.
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http://dx.doi.org/10.1016/j.nmd.2015.04.012DOI Listing
August 2015

Poly-autoimmunity in patients with myasthenia gravis: A single-center experience.

Autoimmunity 2015 14;48(6):412-7. Epub 2015 Apr 14.

a Institute of Neurology, Catholic University , Rome , Italy .

We evaluated the co-occurrence of autoimmune diseases (ADs) in a large population of myasthenia gravis (MG) patients from a single center. Our survey included 984 patients, 904 with anti-acetylcholine receptor antibodies and 80 with anti-muscle specific kinase antibodies. The anti-acetylcholine receptor positive population included patients with early-onset (age at onset ≤ 50 years), late-onset and thymoma-associated disease. Follow-up ranged 2-40 years. Two-hundred and fourteen ADs were diagnosed in 185 patients; 26 of them had two or more ADs in association with MG. Thyroid disorders were the most common and, together with vitiligo and thrombocytopenia, occurred in all disease subsets. Otherwise, there was a broad variability with partial overlap among patient groups. The highest rate of ADs was observed in early-onset patients, while clusters, i.e. 2 or more ADs other than MG in the same individual, were more common among thymoma cases. Thirty-four diseases were diagnosed at the same time, 88 occurred before and 92 after the onset of MG. On multivariate analysis, immunosuppressive treatment was the only independent variable which negatively influenced the risk of developing other ADs in our cohort.
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http://dx.doi.org/10.3109/08916934.2015.1031890DOI Listing
May 2016

Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4.

Mult Scler 2015 May 25;21(6):791-4. Epub 2015 Feb 25.

Institute of Neurology, Catholic University, Rome, Italy.

Background: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic.

Results: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient's cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity.

Conclusions And Relevance: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD.
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http://dx.doi.org/10.1177/1352458515572241DOI Listing
May 2015

Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis.

J Neurol 2015 May 12;262(5):1115-9. Epub 2014 Oct 12.

Don Carlo Gnocchi ONLUS Foundation, Milan, Italy,

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction caused by circulating antibodies specific for the post-synaptic acetylcholine receptor or, in a minority of cases, for the muscle-specific tyrosine-kinase and the low-density lipoprotein receptor-related protein 4. A wide range of symptomatic and immunosuppressive treatments is currently available for MG patients with variable outcome. However, most immunosuppressive treatments are characterized by delayed onset of action and in some cases are not sufficient to induce stable remission of the disease. Rituximab (RTX) is a chimaeric monoclonal antibody specific for the CD20 B-cell surface antigen. Recent studies have provided evidence that RTX may be an effective treatment for patients with myasthenia gravis (MG) who are refractory to standardized immunosuppressive therapy. We performed a systematic review and a meta-analysis of the efficacy and safety of RTX in myasthenia gravis considering the potential predictive factors related to patients' response to RTX in this disease.
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http://dx.doi.org/10.1007/s00415-014-7532-3DOI Listing
May 2015

Distinct lymphocytes subsets in IgM-related neuropathy: clinical-immunological correlations.

Neurol Sci 2015 Feb 6;36(2):303-8. Epub 2014 Sep 6.

Fondazione Don Gnocchi ONLUS, Milan, Italy.

IgM-related neuropathy generally presents as a late-onset demyelinating polyneuropathy with predominant sensory loss and ataxia. However, we recently reported the clinical, neurophysiological and pathological findings from our cohort and identified in about a third of patients an atypical phenotype. We analyzed by flow cytometry the different lymphocytes subsets in the peripheral blood of patients affected by IgM-related neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance and healthy subjects, to investigate whether different immunological patterns may differentiate the classical phenotype from atypical forms. IFN-gamma producing CD4+ and CD8+ T lymphocytes, as well as CD4+ and CD8+ T cells expressing T-bet (T-helper type 1, Th1) were increased in CIDP patients. The percentage of circulating CD4+ and CD8+ T cells producing IL-10 as well as the percentage of CD19+ cells expressing Blimp-1 were higher in patients with IgM-neuropathy. We did not find any significant differences in the different lymphocytes subsets in the IgM-related neuropathy between patients with classical and atypical phenotype. Th1 cells are increased in CIDP patients while a T helper type 2-phenotype seems to prevail in patients with IgM-neuropathy. Further studies involving a larger patient population are needed to evaluate if different lymphocytes subset may be involved in different clinical phenotypes of IgM-related neuropathy.
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http://dx.doi.org/10.1007/s10072-014-1935-xDOI Listing
February 2015

Lower motor neuron involvement in longitudinally extensive transverse myelitis with and without aquaporin-4 antibodies.

Clin Neurophysiol 2014 Sep 27;125(9):1925-6. Epub 2014 Jan 27.

Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2013.12.116DOI Listing
September 2014

Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis.

J Neuroimmunol 2013 Dec 12;265(1-2):124-7. Epub 2013 Oct 12.

Institute of Neurology, Catholic University, Rome, Italy. Electronic address:

In this study we evaluated the percentages of CD3(-)CD56(bright), CD3(-)CD56(dim), CD3(-)CD56(bright)perforin(+) and CD3(-)CD56(dim)perforin(+) Natural Killer (NK) cells in peripheral blood from untreated secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) patients and age and sex matched healthy subjects. Both PPMS patients and SPMS patients showed increased percentages of circulating CD3(-)CD56(dim)perforin(+) NK cells than healthy subjects. The increased percentage of CD3(-)CD56(dim) NK cells expressing perforin in patients affected by the progressive forms of MS suggests a possible role of this NK cell subpopulation in the pathogenesis of the disease.
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http://dx.doi.org/10.1016/j.jneuroim.2013.10.004DOI Listing
December 2013

Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma.

J Neuroimmunol 2013 Oct 3;263(1-2):155-8. Epub 2013 Aug 3.

Institute of Neurology, Department of Neuroscience, Catholic University, Rome, Italy. Electronic address:

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.
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http://dx.doi.org/10.1016/j.jneuroim.2013.07.015DOI Listing
October 2013

Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies.

J Neurol 2013 Sep 21;260(9):2396-402. Epub 2013 Jun 21.

Institute of Neurology, Department of Geriatrics Neurosciences and Orthopedics, Catholic University, L. go Gemelli, 8 00168 Rome, Italy.

Longitudinally extensive transverse myelitis (LETM) is a characteristic feature of Neuromyelitis Optica (NMO), but it can also occur in several other inflammatory diseases of the central nervous system (CNS). An IgG autoantibody that binds to aquaporin-4 (AQP4), the predominant water channel of the CNS, is a reliable biomarker of the NMO spectrum disorders, and if detected predicts the recurrence of the myelitis. In this study, we compared the clinical and neuroimaging characteristics of AQP4-IgG+ and AQP4-IgG- LETM patients. Thirty-seven first-ever LETM patients were retrospectively evaluated and divided into two groups according to the presence of AQP4 autoantibodies. AQP4-IgG was detected in the serum and in the cerebrospinal fluid of sixteen patients. The female to male ratio was higher in AQP4-IgG+ patients. Intractable nausea and vomiting and paroxysmal tonic spasms often accompanied the LETM in AQP4-IgG+ patients. T2-weighted spinal cord MRI revealed that inflammatory lesions extending into the brainstem and involving the central grey matter occurred more frequently in AQP4-IgG+ LETM patients. Hypointense lesions on T1-weighted spinal cord MRI were detected more frequently in the seropositive group, and their presence correlated with attack severity. In conclusion, this study provides clinical and spinal cord neuroimaging clues that can help distinguishing AQP4-IgG+ LETM patients.
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http://dx.doi.org/10.1007/s00415-013-6997-9DOI Listing
September 2013

Anorexia heralding the onset of neuromyelitis optica.

Intern Med 2013 15;52(4):489-91. Epub 2013 Feb 15.

Department of Neurosciences, Institute of Neurology, Catholic University, Italy.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. An autoantibody (NMO-IgG) targeting the aquaporin-4 water channel distinguishes NMO from other inflammatory disorders of the CNS. Recent studies have demonstrated that the area postrema and other circumventricular organs (CVOs) can be targeted in NMO.We herein report the case of a 12-year-old girl who experienced anorexia six months before the onset of NMO. Anorexia caused by hypothalamic or CVO dysfunction may herald the onset of NMO.
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http://dx.doi.org/10.2169/internalmedicine.52.8992DOI Listing
August 2013

Tissue-infiltrating lymphocytes analysis reveals large modifications of the duodenal "immunological niche" in coeliac disease after gluten-free diet.

Clin Transl Gastroenterol 2012 Dec 13;3:e28. Epub 2012 Dec 13.

Institute of Internal Medicine, Catholic University, Rome, Italy.

Objectives: The role of T lymphocytes in the pathogenesis of Celiac disease (CD) is well established. However, the mechanisms of T-cell involvement remain elusive. Little is known on the distribution of T subpopulations: T-regulatory (Treg), Th17, CD103, and CD62L cells at disease onset and after gluten-free diet (GFD). We investigated the involvement of several T subpopulations in the pathogenesis of CD.

Methods: We studied T cells both in the peripheral blood (PB) and the tissue-infiltrating lymphocytes (TILs) from the mucosa of 14 CD patients at presentation and after a GFD, vs. 12 controls.

Results: Our results extend the involvement of Treg, Th1, and Th17 cells in active CD inflammation both in the PB and at the TILs. At baseline, Tregs, Th1, and Th17 cells are significantly higher in active CD patients in TILs and PB. They decreased after diet. Moreover, CD62L+ TILs were increased at diagnosis as compared with GFD patients.

Conclusions: Our data show significant modifications of the above-mentioned subpopulations both in the PB and TILs. The increase of suppressive Tregs in active CD both in the PB and TILs is intriguing. T lymphocytes are known to have a crucial role in the pathogenesis of CD. We have shown that gluten trigger results in systemic recruitment of T lymphocytes, the unbalance between pro-inflammatory and anti-inflammatory populations and the increase of CD62L+ T cells in TILs. Our results delineate a more complete picture of T-cell subsets in active vs. GFD disease. Our data of T-cell subpopulations, combined with known data on cytokine production, support the concept that duodenal micro-environment acts as an immunological niche and this recognition may have an important role in the diagnosis, prognosis and therapeutical approach of CD.
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http://dx.doi.org/10.1038/ctg.2012.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535075PMC
December 2012

Type 1 immune response in progressive multiple sclerosis.

J Neuroimmunol 2012 Aug 20;249(1-2):112-6. Epub 2012 May 20.

Department of Neurology, Catholic University of Sacred Heart Rome, Rome, Italy.

The aim of the study was to evaluate the type-1 immune response by analyzing T-bet expression in circulating T and B cells in Primary Progressive (PP) and Secondary Progressive (SP) Multiple Sclerosis (MS) patients. We found higher percentages of circulating CD4+T-bet+ and CD8+T-bet+ T cells in SPMS and PPMS than in remitting-relapsing MS patients and controls. Moreover, in SPMS, we observed a positive correlation between the percentages of circulating CD4+T-bet+ or CD8+T-bet+ T cells and disease severity. The increased percentages of Th1 and Tc1 cells suggest that MS progressive forms, unlike RRMS, are characterized by a permanent peripheral type-1 immune activation.
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http://dx.doi.org/10.1016/j.jneuroim.2012.04.019DOI Listing
August 2012