Publications by authors named "Amelia Evoli"

92 Publications

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

In sickness and in health: when myasthenia gravis is a conjugal matter.

Neurol Sci 2021 May 7;42(5):2099-2101. Epub 2021 Jan 7.

Institute of Neurology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Largo A. Gemelli, 8, 00168, Rome, Italy.

Objective: Genes and environment contribute to the multifactorial etiology of autoimmune diseases. Familial clusters of autoimmune diseases are often observed among first-degree relatives sharing the same genetic background and environmental exposure. Rarer is the occurrence of the same autoimmune diseases in non-consanguineous spouses. We hereinafter report two non-consanguineous spouses who developed one after the other AChR-positive myasthenia gravis.

Methods: This study has been approved by Catholic University Ethic Committee. The wife, previously affected by Graves-Basedow disease, was the first to be diagnosed with myasthenia gravis, basing on a generalized weakness and an anti-AChR-positive assay. The husband, who suffered from ulcerative colitis, 16 years after his wife diagnosis complained of a mild generalized weakness. Repetitive nerve stimulation test and anti-AChR assay were confirmed myasthenia gravis. In these spouses, myasthenia gravis was not associated with thymoma. Human leukocyte antigen (HLA) class II genotyping showed distinct associations, with the wife carrying the DRB1*03:01 DQB1*02:01 and the husband the DRB1*07 DQB102 alleles.

Results: The wife's haplotype is strongly associated with myasthenia gravis and thyroiditis whereas HLA DRB1*07 allele was found to be related both to late-onset myasthenia gravis and ulcerative colitis.

Conclusions: Compared with other autoimmune disorders, myasthenia gravis has a lower prevalence. The surveillance environmental exposure may greatly improve our knowledge of non-genetic drivers of autoimmunity.
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http://dx.doi.org/10.1007/s10072-020-04944-yDOI Listing
May 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

Controversies in Ocular Myasthenia Gravis.

Front Neurol 2020 30;11:605902. Epub 2020 Nov 30.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Myasthenia gravis (MG) with symptoms limited to eye muscles [ocular MG (OMG)] is a rare disease. OMG incidence varies according to ethnicity and age of onset. In recent years, both an increase in incidence rate, particularly in the elderly, and a lower risk for secondary generalization may have contributed to the growing disease prevalence in Western countries. OMG should be considered in patients with painless ptosis and extrinsic ophthalmoparesis. Though asymmetric muscle involvement and symptom fluctuations are typical, in some cases, OMG can mimic isolated cranial nerve paresis, internuclear ophthalmoplegia, and conjugate gaze palsy. Diagnostic confirmation can be challenging in patients negative for anti-acetylcholine receptor and anti-muscle-specific tyrosine kinase antibodies on standard radioimmunoassay. Early treatment is aimed at relieving symptoms and at preventing disease progression to generalized MG. Despite the absence of high-level evidence, there is general agreement on the efficacy of steroids at low to moderate dosage; immunosuppressants are considered when steroid high maintenance doses are required. The role of thymectomy in non-thymoma patients is controversial. Prolonged exposure to immunosuppressive therapy has a negative impact on the health-related quality of life in a proportion of these patients. OMG is currently excluded from most of the treatments recently developed in generalized MG.
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http://dx.doi.org/10.3389/fneur.2020.605902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734350PMC
November 2020

International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update.

Neurology 2021 01 3;96(3):114-122. Epub 2020 Nov 3.

From the Beth Israel Deaconess Medical Center/Harvard Medical School (P.N.), Boston, MA; Department of Neurology (D.B.S., J.M.), Duke University Medical Center, Durham, NC; Department of Neurology (G.W.), Univ. at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY; Department of Neurology (M.B.), University of Miami, Miller School of Medicine. Miami, FL; Gabriel Cea (G.C.), Departamento de Ciencias Neurologicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Dipartimento di Neuroscienze (A.E.), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy; Department of Clinical Medicine (N.E.G.), University of Bergen, Norway; Isabel Illa (I.I.), Department of Neurology, Hospital Santa Creu i Sant Pau. Universitat Autònoma de Barcelona, Barcelona, ERN EURO-NMD and CIBERER U762, Spain; Departments of Pediatrics and Neurology (N.L.K.), Northwestern Feinberg School of Medicine, Chicago, IL; Neurology (A.M.), University of Tübingen Medical Centre, Tübingen, Germany; Department of Neurology (H.M.), International University of Health and Welfare, Narita, Japan; Department of Clinical Neurological Sciences (M.N.), Western University, London, ON, Canada; Department of Clinical Neurology (J.P.), John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, UK; Department of Neurology (D.R.), University of California, Davis, Davis, CA; and Department of Neurology (J.V.), Leiden University Medical Centre, Leiden, the Netherlands.

Objective: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature.

Methods: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity.

Results: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment.

Conclusion: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.
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http://dx.doi.org/10.1212/WNL.0000000000011124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884987PMC
January 2021

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

BMJ Open 2020 09 18;10(9):e037909. Epub 2020 Sep 18.

Institute of General Pathology, Catholic University, Fondazione Policlinico Universitario "A. Gemelli"-I.R.C.C.S, Rome, Italy.

Objectives: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families.

Design: Retrospective cohort study.

Setting: Clinics across North America.

Participants: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis.

Methods: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed.

Results: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members.

Discussion: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.
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http://dx.doi.org/10.1136/bmjopen-2020-037909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511637PMC
September 2020

Minimal manifestation status and prednisone withdrawal in the MGTX trial.

Neurology 2020 08 1;95(6):e755-e766. Epub 2020 Jul 1.

From the Departments of Neurology (I.L.) and Biostatistics (H.-C.K., I.B.A., G.R.C., T.M., G.M.), University of Alabama at Birmingham; Department of Neurology (H.J.K.), George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Neurology (J.S.), Greater Manchester Neuroscience Center, Salford, Greater Manchester, UK; Institute of Pathology (P.S.), University Medical Center Göttingen; Division of Neurology (J.O.), University of British Columbia, Vancouver, Canada; Department of Neurology (G.C.), University of Chile, Santiago; Division of Neurology (J.M.H.), Department of Medicine, University of Cape Town, South Africa; Department of Neurology (A.E.), Catholic University, Rome, Italy; Department of Neurology (W.N.), Johannes Gutenberg University, Mainz, Germany; Department of Neurology (E.C.), University of Rochester Medical Center, NY; Department of Neurosciences (G.A.), Mental Health and Sensory Organs, Sapienza University of Rome, Italy; Division of Neurology (R.W.), Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Department of Neurology (J.O.K.), Royal Melbourne Hospital, Victoria, Australia; Department of Neurology (S.R.B.), University of Southern California, Los Angeles; Department of Neurology (C.H.C.), McGill University, Montreal, Canada; Department of Neurology (A.C.B.), Medical College of Wisconsin, Milwaukee; Department of Neurology (A.A.A.), Harvard Medical School, Boston, MA; Nerve and Muscle Center of Texas (A.I.S.), Houston; Department of Neurology (B.K.), Case Western Reserve University, Cleveland, OH; Walton Centre for Neurology and Neurosurgery (B.R.F.L.), Liverpool; Nuffield Department of Clinical Neurosciences (C.B., A.V.), Oxford University, UK; Unit of Neurology (E.D.-T.), University of Brasilia, Brazil; Department of Neurology (H.Y.), Kanazawa University, Japan; Department of Neurology (M.W.-C.), Federal University, Rio de Janeiro, Brazil; Department of Neurology (M.T.P.), University of Florida, Jacksonville; Department of Neurology (M.H.R.), Augusta University, GA; Department of Neurology (A.K.-P.), Medical University of Warsaw, Poland; Department of Neurology (R.M.P.), Indiana School of Medicine, Indianapolis; Department of Neurology (C.E.J.), University of Texas Health Science Center, San Antonio; Department of Neurology (J.J.G.V.), Leiden University Medical Center, the Netherlands; Department of Neurology (J.M.M.), Duke University Medical Center, Durham, NC; Department of Neurology (J.T.K.), Ohio State University Wexner Medical Center, Columbus; Department of Neurology (L.C.W.), Universidade Federal do Parana, Curitiba, Brazil; Department of Neurology (M.B.), University of Miami, FL; Department of Neurology (R.J.B.), University of Kansas Medical Center, Kansas City; Department of Neurological Sciences (R.T.), University of Vermont College of Medicine, Burlington; Department of Neurology (T.M.), University of California Irvine Medical Center, Orange; Division of Extramural Research (R.C.), NIH, National Institute of Neurological Disorders and Stroke, Bethesda, MD; Section of General Thoracic Surgery (J.R.S.), Columbia University Medical Center, New York; and Department of Neurology (G.I.W.), University at Buffalo Jacobs School of Medicine and Biomedical Sciences, NY.

Objective: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).

Methods: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.

Results: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.

Conclusions: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.

Clinicaltrialsgov Identifier: NCT00294658.

Classification Of Evidence: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
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http://dx.doi.org/10.1212/WNL.0000000000010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455358PMC
August 2020

An Italian Neurology Outpatient Clinic Facing SARS-CoV-2 Pandemic: Data From 2,167 Patients.

Front Neurol 2020 29;11:564. Epub 2020 May 29.

Dipartimento Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Neurological sequelae of SARS-CoV-2 infection have already been reported, but there is insufficient data about the impact of the pandemic on the management of the patients with chronic neurological diseases. We aim to analyze the effect of COVID-19 pandemic and social restriction rules on these fragile patients. Patients with chronic neurologic diseases routinely followed at the outpatient clinic of Gemelli University Hospital, Rome, were assessed for symptoms suggestive of SARS-CoV-2 infection in the pandemic period, consequences of social restrictions, and neurological disease features, concomitant medical conditions, current medical and disease-specific treatments. Data source: a dedicated telephone survey designed to encompass questions on COVID-19 symptoms and on pandemic effects in chronic neurologic conditions. Overall, 2,167 individuals were analyzed: 63 patients reported contact with COVID-19 positive cases, 41 performed the swab, and 2 symptomatic patients tested positive for COVID-19 (0.09%). One hundred fifty-eight individuals (7%) needed urgent neurological care, deferred due to the pandemic; 641 patients (30%) suspended hospital treatments, physiotherapy or other support interventions; 405 individuals (19%) reported a subjective worsening of neurological symptoms. In our population, the presence of neurological chronic diseases did not increase the prevalence of COVID-19 infection. Nevertheless, the burden of neurological disorders has been worsened by the lockdown.
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http://dx.doi.org/10.3389/fneur.2020.00564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273723PMC
May 2020

Long-Lasting Rituximab-Induced Reduction of Specific-But Not Total-IgG4 in MuSK-Positive Myasthenia Gravis.

Front Immunol 2020 5;11:613. Epub 2020 May 5.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.

The use of rituximab (RTX), an anti-CD20 monoclonal antibody (Ab), in refractory myasthenia gravis (MG) is associated with a better response in patients with Abs to the muscle-specific tyrosine kinase (MuSK) than in other MG subgroups. Anti-MuSK Abs are mostly IgG4 with proven pathogenicity and positive correlation with clinical severity. The rapid and sustained response to RTX may be related to MuSK Ab production by short-lived Ab-secreting cells derived from specific CD20 B cells. Here, we investigated the long-term effects of RTX in nine refractory MuSK-MG patients with a follow-up ranging from 17 months to 13 years. In patients' sera, we titrated MuSK-specific IgG (MuSK-IgG) and MuSK-IgG4, along with total IgG and IgG4 levels. Optimal response to RTX was defined as the achievement and maintenance of the status of minimal manifestations (MM)-or-better together with ≥ 50% steroid reduction, withdrawal of immunosuppressants, and no need for plasma-exchange or intravenous immunoglobulin. After a course of RTX, eight patients improved, with optimal response in six, while only one patient did not respond. At baseline, MuSK-IgG and MuSK-IgG4 serum titers were positive in all patients, ranging from 2.15 to 49.5 nmol/L and from 0.33 to 46.2 nmol/L, respectively. MuSK Abs mostly consisted of IgG4 (range 63.80-98.86%). RTX administration was followed by a marked reduction of MuSK Abs at 2-7 months and at 12-30 months ( < 0.02 for MuSK-IgG and < 0.01 for MuSK-IgG4). In patients with a longer follow-up, MuSK Ab titers remained suppressed, paralleling clinical response. In the patient who achieved long-term complete remission, MuSK-IgG4 was no longer detectable within 2 years, while MuSK-IgG remained positive at very low titers up to 10 years after RTX. In the patient who did not respond, MuSK-IgG and MuSK-IgG4 remained unchanged. In this patient series, total IgG and IgG4 transiently decreased ( < 0.05) at 2-7 months after RTX. The different trends of reduction between MuSK-IgG4 and total IgG4 after RTX support the view that short-lived Ab-secreting cells are the main producers of MuSK Abs. The ratio between short-lived Ab-secreting cells and long-lived plasma cells may influence the response to RTX, and B-cell severe depletion may reduce self-maintaining autoimmune reactivity.
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http://dx.doi.org/10.3389/fimmu.2020.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214629PMC
March 2021

SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.

Neurol Neuroimmunol Neuroinflamm 2020 01 12;7(1). Epub 2019 Dec 12.

From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic University, Rome, Italy.

Objective: To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).

Methods: The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.

Results: In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.

Conclusions: Stimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.
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http://dx.doi.org/10.1212/NXI.0000000000000645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935836PMC
January 2020

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Neurol Sci 2019 Oct 3;40(10):2017-2030. Epub 2019 Jun 3.

Department of Neurology, Ospedale Santa Chiara, Trento, Italy.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.
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http://dx.doi.org/10.1007/s10072-019-03930-3DOI Listing
October 2019

Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis.

Neurology 2019 06 22;92(23):e2661-e2673. Epub 2019 May 22.

From the Department of Neurology (J.F.H.), University of North Carolina, Chapel Hill; Krembil Neuroscience Centre (V.B.), University Health Network, Toronto, Canada; Department of Neurology (T.M.B.), University of Virginia, Charlottesville; Department of Neuroimmunology and Neuromuscular Diseases (R.M.), Fondazione Istituto Neurologico Carlo Besta, Milan, Italy; Department of Neurology (B.M.), Wroclaw Medical University; Department of Neurology (A.S.), Jagiellonian University Medical College, Cracow, Poland; Department of Neurology (S.B.), University of Southern California, Keck School of Medicine, Los Angeles County Medical Center; Department of Neurology (F.J.R.D.R.G.), La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonoma University of Madrid, Spain; Neuroimmunology Unit, Department Clinical Neuroscience (F.P.), Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden; USC Neurologia (M.R.), USS Malattie Autoimmuni-Centro Sclerosi Multipla, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy; Neurology Department (P.V.D.), University Hospitals Leuven; Laboratory of Neurobiology (P.V.D.), Department of Neuroscience, KU Leuven and Center for Brain & Disease Research, VIB, Leuven, Belgium; Department of Neurology (T.V.), University of South Florida, Morsani College of Medicine, Tampa; Institute of Neurology (A.E.), Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy; Neurology Department (M.F.), The Ohio State University, Columbus; Department of Neurology (T.M.), University of California, Irvine; Department of Molecular and Cellular Medicine (E.S.W.), Texas A&M University Health Science Center, College Station; argenx BVBA (T.D., P.U., K.V., A.G., H.d.H., N.L.), Zwijnaarde, Belgium; and Department of Neurology (J.J.G.M.V.), Leiden University Medical Center (LUMC), the Netherlands.

Objective: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.

Methods: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.

Results: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.

Conclusions: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.

Classification Of Evidence: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
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http://dx.doi.org/10.1212/WNL.0000000000007600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556100PMC
June 2019

Myasthenia gravis.

Nat Rev Dis Primers 2019 05 2;5(1):30. Epub 2019 May 2.

Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.
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http://dx.doi.org/10.1038/s41572-019-0079-yDOI Listing
May 2019

An update on thymectomy in myasthenia gravis.

Expert Rev Neurother 2019 09 5;19(9):823-833. Epub 2019 Apr 5.

Fondazione Policlinico Gemelli , IRCCS , Roma , Italy.

: Myasthenia gravis (MG) is one of the best treatable autoimmune diseases. However, in most patients, treatment is necessarily long-term and related side effects are a serious burden. Thymectomy has a special place in the disease management as a non-pharmacological disease-modifying therapy. For several decades, its role has only been supported by observational studies. Despite the recently achieved class I evidence, many questions remain unaddressed. : This review discusses the pathogenic role of the thymus and evidence and controversies concerning therapeutic thymectomy. It also describes minimally invasive techniques that have largely replaced open surgery and the available evidence in MG patients. : Thymectomy plays a primary role in MG management, though its use is still controversial in some disease subtypes. Patient selection for surgery and adequate pre-operative MG control are critical. Thymectomy must ensure the exeresis of the whole thymus together with peri-thymic fat tissue. Minimally invasive techniques have many advantages over open approaches, provided they are as extensive as trans-sternal thymectomy. The investigation of thymectomy-related biomarkers will contribute to enhance the knowledge of its impact on the specific immune response.
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http://dx.doi.org/10.1080/14737175.2019.1600404DOI Listing
September 2019

Italian recommendations for the diagnosis and treatment of myasthenia gravis.

Neurol Sci 2019 Jun 18;40(6):1111-1124. Epub 2019 Feb 18.

Unit of Neurology and Neuromuscular Diseases, University of Messina, Messina, Italy.

Myasthenia gravis is a well-treatable disease, in which a prompt diagnosis and an adequate management can achieve satisfactory control of symptoms in the great majority of patients. Improved knowledge of the disease pathogenesis has led to recognition of patient subgroups, according to associated antibodies, age at onset and thymus pathology, and to a more personalized treatment. When myasthenia gravis is suspected on clinical grounds, diagnostic confirmation relies mainly on the detection of specific antibodies. Neurophysiological studies and, to a lesser extent, clinical response to cholinesterase inhibitors support the diagnosis in seronegative patients. In these cases, the differentiation from congenital myasthenia can be challenging. Treatment planning must consider weakness extension and severity, disease subtype, thymus pathology, together with patient characteristics and comorbidities. Since most subjects with myasthenia gravis require long-term immunosuppressive therapy, surveillance of expected and potential adverse events is critical. For patients refractory to conventional immunosuppression, the use of biologic agents is highly promising. These recommendations are addressed to non-experts on neuromuscular transmission disorders. The diagnostic procedures and therapeutic approaches hereafter described are largely accessible in Italy.
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http://dx.doi.org/10.1007/s10072-019-03746-1DOI Listing
June 2019

Cognitive dysfunction in mice with passively induced MuSK antibody seropositive myasthenia gravis.

J Neurol Sci 2019 Apr 4;399:15-21. Epub 2019 Feb 4.

Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.

Recent reports on cognitive dysfunction, in addition to skeletal muscle fatigue, in muscle-specific tyrosine kinase antibody seropositive (MuSK+) myasthenia gravis (MG) patients led us to study cognition in mice with MuSK+ passive transfer MG (PTMG). Twelve 7-week-old female wild-type C57BL/6J mice were passively immunized with IgG from MuSK+ MG patients and 12 control mice received intraperitoneal saline injections. Mice were evaluated with clinical, neurophysiological and behavioral tests (Barnes maze (BM) and novel object recognition (NOR)), and the muscles were immunostained to evaluate the neuromuscular junction in the end of the study. Two-thirds of the immunized mice developed clinically distinct MuSK+ PTMG. MuSK+ PTMG mice spent less time exploring the novel object in the NOR test (MuSK+ mice 36.4% ± 14.0 vs controls 52.4% ± 13.0, p = .02), unrelated to the muscle weakness and regardless of rodents' innate preference of novelty. In the BM test, control mice were more eager to use the direct strategy than the MuSK+ mice (MuSK+ 17.3% vs controls 29.5%, p = .02). Our findings shed new light on cognition dysfunction in human MuSK+ MG patients and indicate that recognition memory in the perirhinal cortex could be affected in MuSK+ MG.
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http://dx.doi.org/10.1016/j.jns.2019.02.001DOI Listing
April 2019

Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial.

Lancet Neurol 2019 03 25;18(3):259-268. Epub 2019 Jan 25.

Department of Neurology, University of Florida, Jacksonville, FL, USA.

Background: The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.

Methods: We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.

Findings: Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.

Interpretation: At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.

Funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke.
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http://dx.doi.org/10.1016/S1474-4422(18)30392-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774753PMC
March 2019

Italian recommendations for diagnosis and management of congenital myasthenic syndromes.

Neurol Sci 2019 Mar 15;40(3):457-468. Epub 2018 Dec 15.

Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, 20133, Milan, Italy.

Congenital myasthenic syndromes (CMS) are genetic disorders due to mutations in genes encoding proteins involved in the neuromuscular junction structure and function. CMS usually present in young children, but perinatal and adult onset has been reported. Clinical presentation is highly heterogeneous, ranging from mild symptoms to severe manifestations, sometimes with life-threatening respiratory episodes, especially in the first decade of life. Although considered rare, CMS are probably underestimated due to diagnostic difficulties. Because of the several therapeutic opportunities, CMS should be always considered in the differential diagnosis of neuromuscular disorders. The Italian Network on CMS proposes here recommendations for proper CMS diagnosis and management, aiming to guide clinicians in their practical approach to CMS patients.
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http://dx.doi.org/10.1007/s10072-018-3682-xDOI Listing
March 2019

Serological Immunoglobulin-Free Light Chain Profile in Myasthenia Gravis Patients.

J Immunol Res 2018 25;2018:9646209. Epub 2018 Mar 25.

Dipartimento di Medicina di Laboratorio, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Serological levels of free immunoglobulin light chains (FLCs), produced in excess of heavy chains during synthesis of immunoglobulins by plasma cells, can be considered a direct marker of B cell activity in different systemic inflammatory-autoimmune conditions and may represent a useful predictor of rituximab (RTX) therapeutic efficacy, as reported for rheumatoid arthritis and systemic lupus erythematosus. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction with antibodies (abs) targeting the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK), inducing muscle weakness and excessive fatigability. As MG course may be remarkably variable, we evaluated the possible use of FLCs as biomarkers of disease activity.

Subjects And Methods: We assessed FLC levels in 34 sera from 17 AChR-MG and from 13 MuSK-MG patients, in comparison with 20 sera from patients with systemic autoimmune rheumatic diseases and 18 from healthy blood donors, along with titers of specific auto-abs and IgG subclass distribution.

Results: We found a statistically significant increase in free chains in both AChR- and MuSK-MG patients, while free chain levels were increased only in AChR-MG. We also observed a significant reduction of both free and chains in 1/4 MuSK-MG patients along with specific abs titer, two months after RTX treatment.

Conclusions: From our data, FLCs appear to be a sensitive marker of B cell activation in MG. Further investigations are necessary to exploit their potential as reliable biomarkers of disease activity.
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http://dx.doi.org/10.1155/2018/9646209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889870PMC
September 2018

Rituximab in myasthenia gravis: a "to be or not to be" inhibitor of T cell function.

Ann N Y Acad Sci 2018 02 25;1413(1):41-48. Epub 2018 Jan 25.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.

In recent years, rituximab (RTX), a monoclonal antibody that binds the B lymphocyte membrane protein CD20, has been increasingly used for the treatment of autoimmune diseases, with the rationale of destroying pathogenic B lymphocytes and decreasing autoantibody formation. Surprisingly, RTX has also proven effective in predominantly T cell-mediated diseases, raising the question whether additional mechanisms may play roles in determining the therapeutic response. Here, we review the current literature on the effects of RTX in autoimmune diseases, with special emphasis on myasthenia gravis (MG). To elicit a complete and effective immune response, B and T lymphocytes cooperate in a loop in which they affect each other. Disruption of this cross talk has profound effects on the immune system. RTX is likely to affect the whole spectrum of B cell function, including antigen presentation, cytokine production, and T cell stimulation. In addition, as a small subset of T lymphocytes expresses CD20, its direct targeting by RTX may contribute to the therapeutic effect. Owing to its distinctive immune characteristics, MG proved to be a useful model to investigate the multifaceted implications of B cell depletion.
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http://dx.doi.org/10.1111/nyas.13562DOI 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

Diagnostics of autoimmune encephalitis associated with antibodies against neuronal surface antigens.

Neurol Sci 2017 Oct;38(Suppl 2):225-229

Ospedale S.Antonio AULSS Euganea, Padua, Italy.

This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3032-4DOI Listing
October 2017

Diagnostics of paraneoplastic neurological syndromes.

Neurol Sci 2017 Oct;38(Suppl 2):237-242

Ospedale S. Antonio AULSS Euganea, Padua, Italy.

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3031-5DOI Listing
October 2017

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

Immune checkpoint inhibitor therapy: A double-edged sword?

Neurology 2017 09 18;89(11):1101-1102. Epub 2017 Aug 18.

From the Department of Neurology (H.J.K.), Research Institute and Hospital of National Cancer Center, Goyang, Korea; and Institute of Neurology (A.E.), Catholic University, Policlinico Gemelli, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000004369DOI Listing
September 2017

Myasthenia gravis: new developments in research and treatment.

Authors:
Amelia Evoli

Curr Opin Neurol 2017 10;30(5):464-470

Institute of Neurology, Catholic University, Fondazione Policlinico Gemelli, Roma, Italy.

Purpose Of Review: Myasthenia gravis, a rare disorder of the neuromuscular transmission, is increasingly acknowledged as a syndrome more than as a single disease. This review summarizes recent advances in pathophysiology which confirm the disease heterogeneity, and may help find disease-targeted and patient-targeted therapies.

Recent Findings: Antibodies to the acetylcholine receptor, the muscle-specific tyrosine kinase and the lipoprotein receptor protein 4, characterize disease subtypes with distinct clinical traits and immune-pathogenic mechanisms. Genome-wide approaches have identified susceptibility loci within genes that participate in the immune response. Regulatory T and B cells appear to be defective in myasthenia gravis. In patients with acetylcholine receptor antibodies, thymectomy associated with prednisone proved more effective than prednisone alone in a multicenter randomized trial. New therapeutic options target B cells, B-cell growth factors and complement inhibition, and are currently reserved for patients with refractory disease.

Summary: In the recent past, there has been an active search for new antigens in myasthenia gravis, whereas clinical and experimental studies have provided new insights of crucial pathways in immune regulation, which might become the targets of future therapeutic interventions.
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http://dx.doi.org/10.1097/WCO.0000000000000473DOI Listing
October 2017

IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 5;4(4):e357. Epub 2017 Jun 5.

Nuffield Department of Clinical Neurosciences (S.H., P.W., M.W., M.I.L., L.J., J.C., D.H.-J., A.V.), University of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., R.R.), Neurology Unit, Pisa, Italy; Division of Neurology (J.M.H.), University of Cape Town, South Africa; Oslo University Hospital (A.M.), Norway; and Department of Neuroscience (A.E.), Catholic University, Rome, Italy.

Objective: To increase the detection of MuSK-Abs using a CBA and test their pathogenicity.

Methods: Sera from 69 MuSK-RIA-positive patients with myasthenia gravis (MG) (Definite MuSK-MG), 169 patients negative for MuSK-RIA and AChR-RIA (seronegative MG, SNMG), 35 healthy individuals (healthy controls, HCs), and 16 NMDA receptor-Ab-positive (NMDAR-Ab) disease controls were tested for binding to MuSK on a CBA using different secondary antibodies.

Results: Initially, in addition to 18% of SNMG sera, 11% of HC and 19% of NMDAR-Ab sera showed positive binding to MuSK-transfected cells; this low specificity was due to anti-IgG(H+L) detection of IgM bound nonspecifically to MuSK. Using an IgG Fc gamma-specific secondary antibody, MuSK-Abs were detected by CBA in 68/69 (99%) of Definite MuSK-MG, 0/35 HCs, 0/16 NMDAR-Ab, and 14/169 (8%) of SNMG sera, providing increased sensitivity with high specificity. The RIA-negative, CBA-positive MuSK-IgG sera, but not IgM-MuSK-binding sera, reduced agrin-induced AChR clustering in C2C12 myotubes, qualitatively similar to RIA-positive MuSK-Abs.

Conclusions: An IgG-specific MuSK-CBA can reliably detect IgG MuSK-Abs and increase sensitivity. In the MuSK-CBA, IgG specificity is essential. The positive sera demonstrated pathogenic potential in the in vitro AChR-clustering assay, although less effective than Definite MuSK-MG sera, and the patients had less severe clinical disease. Use of IgG-specific secondary antibodies may improve the results of other antibody tests.

Classification Of Evidence: This study provides Class III evidence that an IgG-specific MuSK-CBA identifies patients with MG.
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http://dx.doi.org/10.1212/NXI.0000000000000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459793PMC
July 2017