Carlo Antozzi

Objective study was the quantification of controlled/inadequately controlled generalized myasthenia gravis (gMG) disease burden, health care resource utilization and costs in MG patients, followed-up at a reference center for MG in Italy. The study is a 2010 to 2020 retrospective analysis of gMG patients. Clinical and health economics variables were those observed during routine clinical care. Data were anonymized and treated in aggregated forms in compliance with GDPR. Only patients with gMG were included in the study. Out of 237 patients, 55.3% were males and 44.7% females with a median follow up duration of 4.7 years. Males were older, with a median age at onset of 58.3 years versus 45.7 years for females; an increased representation of late and very late onset patients was recorded. A shorter time from onset to diagnosis was observed in males. The incidence rate per year of exacerbations changed from 0.76 in the first year to 0.23 at the sixth year, with a similar trend for MG crisis; both exacerbations and crisis incidence were higher in inadequately controlled patients. Disease burden and health care resources utilizations were particularly evident in inadequately controlled patients, which showed a 138% increase of costs. Our data confirmed the observed epidemiological changes occurring in MG population and the high use of health care system resources in uncontrolled patients. The estimates obtained will provide a useful basis for assessing the impact of recently introduced targeted therapies on healthcare expenditure for MG.

Background: Patients with generalized myasthenia gravis (gMG) frequently have variable and fluctuating symptoms. Treatments providing long‐term, sustained disease control are essential for improving function and health‐related quality of life. Methods: In the phase 3 Vivacity‐MG3 study, nipocalimab improved clinical outcomes in adults with gMG when added to standard‐of‐care (SOC) therapy. These post hoc analyses further assessed the ability of nipocalimab to produce sustained responses over 24 weeks, using the following response categories for total score improvements in Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG), respectively: Meaningful Clinical Improvement (MCI; ≥ 2‐ and ≥ 3‐point), Substantial Improvement (SI; ≥ 3‐ and ≥ 4‐point), Considerable Improvement (CIP; ≥ 4‐ and ≥ 5), Composite Response (CR; MG‐ADL improvement ≥ 2‐points plus QMG improvement ≥ 3‐points), and Minimal Symptom Expression (MSE; MG‐ADL 0 or 1). Results: Significantly higher percentages of nipocalimab‐treated than placebo‐treated participants achieved MG‐ADL MCI, SI, and CIP, sustained for ≥ 12 consecutive weeks; achievement of these outcomes occurred as early as week 1 among nipocalimab‐treated participants. Similar results were observed for QMG MCI, SI, and CIP. Significantly higher percentages of nipocalimab‐treated participants achieved CR, sustained for ≥ 8 consecutive weeks versus placebo; the likelihood of achieving sustained CR for ≥ 8 weeks was higher with nipocalimab (odds ratio = 6.3). Nipocalimab‐treated participants were 4‐fold more likely to achieve MSE, sustained for ≥ 8 consecutive weeks versus placebo ( p = 0.022). MSE and CR were achieved earlier among nipocalimab‐treated participants. Conclusions: Nipocalimab treatment improves gMG symptoms earlier than placebo and provides meaningful and long‐term sustained disease control over 24 weeks among participants with gMG.

Background and Purpose: Myasthenia gravis (MG) is a complex autoimmune disorder affecting neuromuscular transmission, often leading to diagnostic and therapeutic challenges. Timely identification of “red flags” in diagnosis, therapeutic reassessment, and myasthenic crisis is crucial to optimizing patient outcomes. This Delphi‐based consensus is aimed at synthesizing expert recommendations for improving clinical practice in Italy. Methods: A scientific board of 19 MG specialists and an extended panel of 47 neuromuscular experts participated in a structured Delphi methodology. Over an 11‐month period, consensus was developed across four areas: diagnostic red flags, confirmatory instrumental examinations, therapeutic reassessment, and the continuum from exacerbation to impending myasthenic crisis or to crisis. The threshold for achieving consensus was set at ≥ 75% agreement. Results: Globally, 68 statements reached consensus. Key findings include the identification of “red flags” for suspecting MG, with fluctuating and fatigable muscle weakness serving as primary diagnostic indicators, often involving ocular, bulbar, and respiratory muscles. Instrumental tests, such as repetitive nerve stimulation and antibody assays, were deemed essential for diagnostic confirmation. Therapeutic reassessment in MG is warranted for unsatisfactory symptom control, clinically significant adverse events, new or worsening comorbidities, planning pregnancy, or neoplastic disease. Persistent fluctuations, exacerbations, or triggers like infections should prompt adjustments, aiming to optimize treatment while minimizing risks. High‐risk factors and triggers for myasthenic crises, including thymoma and infections, were identified, with arterial blood gas analysis highlighted as critical for crisis management. Conclusions: This consensus provides actionable recommendations to enhance the identification and management of MG, addressing diagnostic delays, therapy optimization, and crisis prevention. These findings aim to guide clinical practice and foster a systematic approach to managing this heterogeneous disorder.

Background Myasthenia Gravis, traditionally known as a purely motor disease, has been recently associated also with non-motor symptoms, including psychological and cognitive symptoms. However, the presence of cognitive impairment in Myasthenia Gravis remains unclear due to limited and heterogeneous findings. This systematic review and meta-analysis aims to clarify the relationship between Myasthenia Gravis and cognitive performances. Methods Following PRISMA guidelines, we systematically searched PubMed, Web of Science, and SCOPUS for original researches published between January 2000 and December 2024 assessing cognitive functioning in people with MG compared to healthy controls. Pooled standardized mean differences and 95% confidence intervals were calculated for each cognitive domain using random-effects meta-analysis. Results Six studies comprising 242 Myasthenia Gravis patients and 166 healthy controls met inclusion criteria. Compared to healthy controls, people with Myasthenia Gravis showed significantly lower performance in processing speed (Symbol Digit Modalities Test), phonemic and animal verbal fluency, visuo-spatial memory (visual reproduction), and verbal learning (California Verbal Learning Test). Heterogeneity was low to moderate across most outcomes. Conclusions This meta-analysis supports the presence of selective cognitive impairments in individuals with Myasthenia Gravis. These findings underscore the need for a multidimensional approach to care in Myasthenia Gravis, that includes cognitive and psychological health.

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies targeting the neuromuscular junction. MG, characterized clinically by fluctuating muscle weakness and fatigability, is traditionally treated primarily with corticosteroids and nonspecific immunosuppressive drugs. Despite their documented efficacy in a proportion of patients, current standard-of-care treatments are associated with moderate-to-severe side effects that underline the need for new targeted therapies. Nipocalimab, a fully human monoclonal antibody, binds to the neonatal Fc receptor (FcRn) with high affinity and specificity, causing selective reduction of circulating IgG and pathogenic IgG autoantibodies. The phase 3 study Vivacity-MG3 confirmed nipocalimab as an efficacious and safe treatment providing sustained disease control in seropositive patients with generalized MG (gMG). The efficacy and safety of nipocalimab in gMG from the phase 2 study Vivacity-MG (NCT03772587) and the phase 3 study Vivacity-MG3 (NCT04951622). Clinical studies have demonstrated that nipocalimab provided rapid and sustained reduction of total IgG and pathogenic IgG autoantibodies together with sustained disease control over 6 months in a broad population of seropositive patients with gMG, with an acceptable safety profile. The long-term impact of nipocalimab on the course of gMG needs to be further investigated in real-world settings.

Efgartigimod (EFG), a biological drug targeting the IgG recycling neonatal Fc receptor (FcRn), leads to clinical improvements in patients affected by myasthenia gravis (MG), a prototypic autoantibody (Ab)-mediated autoimmune disease affecting neuromuscular junction. Because FcRn is a multifunctional protein expressed in different immune system cells, including B cells, we investigated whether FcRn blockade by EFG may have further immunologic effects, other than IgG reduction, in patients with MG. Anti-acetylcholine receptor Ab-positive (AChR-MG) patients were treated with EFG according to the GENERATIVE protocol. Clinical evaluation, IgG and autoAb quantification, and circulating T-cell and B-cell subpopulation analyses by flow cytometry were performed at different time points. The expression of regulatory plasma cell-related candidate genes (CD38, lymphocyte-activation gene 3 [LAG3], IL-12a, Ebi3) was assessed by real-time PCR in peripheral blood mononuclear cells (PBMCs) from patients on treatment and in PBMCs either untreated or in vitro treated with an EFG-mimicking anti-FcRn monoclonal Ab (mAb) or with EFG (Vyvgart). A significantly increased percentage of CD19+/CD27+ memory B cells and CD27+/CD138+ plasma cells was observed at the end of EFG treatment cycle 1 and cycle 2 in patients with AChR-MG. Plasma cell increase, maintained up to cycle 3, significantly correlated with Quantitative Myasthenia Gravis score improvement. Moreover, PBMCs from EFG-treated patients showed overexpression of CD38, LAG3, and IL-12a genes, suggesting EFG's ability to induce non-pathogenic regulatory plasma cells. This ability was confirmed in vitro, because anti-FcRn mAb-treated and EFG-treated PBMCs displayed an up-regulation of CD38 and LAG3 compared with untreated cells. Our findings indicate an unknown immunoregulatory action of EFG in patients with AChR-MG, by unraveling a drug effect on B-cell differentiation, and suggest the induction of regulatory plasma cells as a further mechanism, beyond IgG reduction, associated with clinical improvement. A deep understanding of the immunologic effects of EFG can help to optimize its usage over time in individual patients and disclose biomarkers suitable for monitoring the long-term patient-specific response.

Background: In the Phase 3 MycarinG study (NCT03971422), rozanolixizumab improved myasthenia gravis (MG)‐specific outcomes versus placebo in patients with generalised MG, including those measured by the five independent MG Symptoms patient‐reported outcome (PRO) scales: Muscle Weakness Fatigability (MWF), Physical Fatigue (PF) and Bulbar Muscle Weakness (BMW) as secondary endpoints and Ocular Muscle Weakness and Respiratory Muscle Weakness (exploratory endpoints). This research aimed to provide further insights into these improvements.Methods: Post hoc analyses evaluated correlation (Pearson coefficient) between MG Symptoms PRO and subdomain scores of MG Activities of Daily Living (MG‐ADL) and Quantitative MG (QMG) at baseline. Proportions of responders reaching clinically meaningful thresholds and analyses at the item level (observed mean change and Rasch modelling of predicted change from baseline) are reported for MWF, PF, and BMW with rozanolixizumab versus placebo at Day 43.Results: Correlation coefficients between MG Symptoms PRO and MG‐ADL were strong (≥ 0.7) for ocular and bulbar scores and moderate (0.5 to < 0.7) for other scores. Correlations with clinician‐assessed QMG scores were generally weak (< 0.5). For MWF, PF, and BMW, greater proportions of responders were observed with rozanolixizumab 7 mg/kg (46.9%, 31.3% and 26.6%, respectively) or 10 mg/kg (56.5%, 48.4% and 32.3%) versus placebo (28.1%, 26.6% and 10.9%). Item‐level analyses demonstrated rozanolixizumab benefit at a symptom‐specific level.Discussion: MG Symptoms PRO scales correlate well with concepts in MG‐ADL while assessing additional concepts, such as PF and MWF. Results from the MG Symptoms PRO in MycarinG reflected improvements from baseline in patient‐relevant symptoms, including fatigue, with rozanolixizumab.

Moyamoya angiopathy (MMA) is a cerebrovascular disease determining chronic progressive steno-occlusion of the supraclinoid internal carotid arteries and their main branches. The pathogenesis of MMA remains largely unknown. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system characterized by the progressive accumulation of focal demyelinating lesions, whose pathophysiology has been theorized but still incompletely understood. Beyond misdiagnoses due to mimicking features among the two disorders, MS coexisting with MMA have been previously, rarely, reported. Herein, we present two other cases of patients with MMA with a concomitant, previously missed, diagnosis of MS and discuss their overlapping features as a hint for a potentially shared pathophysiology. The finding of typical angiographic features enables MMA diagnosis, yet it does not allow us to rule out other potentially concomitant disorders affecting the CNS. The association may be easily missed if the clinical/neuroradiological picture is not carefully assessed. Cerebral spinal fluid analysis and spine neuroimaging should be suggested in all MMA patients with atypical MRI lesions.

Introduction The neonatal Fc receptor (FcRn) inhibitor Efgartigimod (EFG) has been approved for treatment of generalized Myasthenia Gravis (gMG) with anti-AChR antibodies. Information on the effect of EFG in non-AChR MG is limited. We investigated the efficacy of EFG in non-AChR gMG along a clinical follow-up of 2 years. Methods We treated 13 patients with gMG without anti-AChR antibodies: 5 MuSK+, 2 LRP4 + and 6 triple-negative (confirmed by live CBA). EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of 2 treatment cycles of 4 infusions at weekly intervals, followed by a Flexible period during which EFG was given in case of initial worsening) starting from November 2021. Outcomes were evaluated by means of the MG-ADL, QMG, MGC and MGQoL15r scales. Results The mean follow-up was 21 ± 5.3 months. Meaningful improvement was observed with the clinical scores adopted. The number of cycles/year was 3.92 ± 0.9. The interval between cycles was 10.1 ± 3.6 weeks. MG-ADL improvement of at least 5 points was recorded in 58% of cycles. 46% of patients required hospitalization during the two years before treament with EFG and 70% plasmaexchange/IVIG; during EFG none of the patients was hospitalized or required immunomodulation. No major side effects or infusion related reactions occurred. Conclusion EFG was effective in non-AChR gMG and modified significantly the course of the disease. Our experience strengthens the role of FcRn inhibition as a new therapeutic tool for MG without anti-AChR antibodies.