FcRn Inhibitor Therapies in Neurologic Diseases.

In the last decade, the landscape of treating autoimmune diseases has evolved with the emergence and approval of novel targeted therapies. Several new biological agents offer selective and target-specific immunotherapy and therefore fewer side effects, such as neonatal Fc receptor (FcRn)-targeting therapy. Neonatal Fc receptor-targeted therapies are engineered to selectively target FcRn through various methods, such as Fc fragments or monoclonal anti-FcRn antibodies. These approaches enhance the breakdown of autoantibodies by blocking the immunoglobulin G recycling pathway. This mechanism reduces overall plasma immunoglobulin levels, including the levels of pathogenic autoantibodies, without affecting the other immunoglobulin class immunoglobulin A, immunoglobulin E, immunoglobulin M, and immunoglobulin D levels. Drugs that inhibit FcRn include efgartigimod, rozanolixizumab, batoclimab, and nipocalimab. These medications can be administered either intravenously or subcutaneously. Numerous clinical trials are currently underway to investigate their effectiveness, safety, and tolerability in various neurological conditions, including myasthenia gravis and other neurological disorders such as chronic inflammatory demyelinating polyneuropathy, myositis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein antibody disease. Positive results from clinical trials of efgartigimod and rozanolixizumab led to their approval for the treatment of generalized myasthenia gravis. Additional clinical trials are still ongoing. Neonatal Fc receptor inhibitor agents seem to be well tolerated. Reported adverse events include headache (most commonly observed with efgartigimod and rozanolixizumab), upper respiratory tract infection, urinary tract infection, diarrhea, pyrexia, and nausea. Additionally, some of these agents may cause transient hypoalbuminemia and hypercholesterolemia notably reported with batoclimab and nipocalimab. In this review, we discuss the available clinical data for FcRN inhibitor agents in treating different neurological autoimmune diseases.

Whole-body magnetic resonance neurography in patients with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Whole-body magnetic resonance neurography (MRN) is an imaging modality that shows peripheral nerve signal change in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We aimed to explore the diagnostic potential of whole-body MRN and its potential as a monitoring tool after immunotherapy in treatment-naïve CIDP patients. METHODS: Whole-body MRN using coronal 3-dimensional short tau inversion recovery (STIR) sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) techniques was performed in patients being investigated for CIDP and in healthy controls. Baseline clinical neuropathy scales and electrophysiologic parameters were collected, and MRN findings were compared before and after CIDP treatment. RESULTS: We found highly concordant symmetrical thickening and increased T2 signal intensities in the brachial/lumbosacral plexus, femoral, or sciatic nerves in five of the eight patients with a final diagnosis of CIDP and none of the healthy controls. There were no treatment-related imaging changes in five patients with CIDP who completed a follow-up study. Diffuse, symmetrical thickening, and increased T2 signal in root, plexus, and peripheral nerves were found in two patients ultimately excluded due to a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome in addition to signal changes in the muscles, bony lesions, organomegaly, and lymphadenopathy. DISCUSSION: Whole-body MRN imaging shows promise in detecting abnormalities in proximal nerve segments in patients with CIDP. Future studies evaluating the role of MRN in assessing treatment response should consider follow-up scans after treatment durations of more than 4 months.

Value of multi-modality small fiber assessments in a genotypically diverse cohort of transthyretin-related amyloidosis in the early stages of disease.

INTRODUCTION: Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers. METHODS: We compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients. RESULTS: Of 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm2, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT. CONCLUSIONS: In a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.

Epilepsy in neurofibromatosis type 1: Prevalence, phenotype, and genotype in adults.

PURPOSE: Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood. METHODS: Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model. RESULTS: Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI95%=6-18%) and point prevalence 7% (CI95%= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI95%=3-65) and specificity of 99% (CI95%=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI95%=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI95%=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI95%=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy. CONCLUSIONS: In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.

Safety and Efficacy of Nipocalimab in Patients With Generalized Myasthenia Gravis: Results From the Randomized Phase 2 Vivacity-MG Study

BACKGROUND AND OBJECTIVES: To evaluate in a phase 2 study the safety and efficacy of IV nipocalimab, a fully human, antineonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: Patients with gMG with inadequate response to stable standard-of-care (SOC) therapy were randomized 1:1:1:1:1 to receive either IV placebo every 2 weeks (Q2W) or one of 4 IV nipocalimab treatments: 5 mg/kg once every 4 weeks (Q4W), 30 mg/kg Q4W, 60 mg/kg Q2W each for 8 weeks, or a 60 mg/kg single dose, in addition to their background SOC therapy. Infusions (placebo or nipocalimab) were Q2W in all groups to maintain blinding. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs), including serious adverse events and adverse events of special interest. The primary efficacy endpoint was change from baseline to day 57 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores. Dose response of change at day 57 was analyzed with a linear trend test over the placebo, nipocalimab 5 mg/kg Q4W, nipocalimab 30 mg/kg Q4W, and nipocalimab 60 mg/kg Q2W groups. RESULTS: Sixty-eight patients (nipocalimab: n = 54; placebo, n = 14) were randomized; 64 patients (94.1%) were positive for antiacetylcholine receptor autoantibodies, and 4 patients (6%) were positive for antimuscle-specific tyrosine kinase autoantibodies. Fifty-seven patients (83.8%) completed treatment through day 57. The combined nipocalimab group compared with the placebo group demonstrated similar incidences of TEAEs (83.3% vs 78.6%, respectively) and infections (33.3% vs 21.4%, respectively). No deaths or discontinuations due to TEAEs and no TEAEs of special interest (grade ≥3 infection or hypoalbuminemia) were observed with nipocalimab treatment. A statistically significant dose response was observed for change from baseline in MG-ADL at day 57 (p = 0.031, test of linear trend). DISCUSSION: Nipocalimab was generally safe, well-tolerated, and showed evidence of dose-dependent reduction in MG-ADL scores at day 57 in this phase 2 study. These results support further evaluation of nipocalimab for the treatment of gMG. TRIAL REGISTRATION INFORMATION: Clinical Trials Registration: NCT03772587; first submitted December 10, 2018; EudraCT Number: 2018-002247-28; first submitted November 30, 2018; date of first patient dosed April 10, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, nipocalimab was well-tolerated, and it did not significantly improve MG-ADL at any individual dose but demonstrated a significant dose response for improved MG-ADL across doses.

Subcutaneous batoclimab in generalized myasthenia gravis: Results from a Phase 2a trial with an open-label extension.

OBJECTIVES: To assess the safety, tolerability, and key pharmacodynamic effects of subcutaneous batoclimab, a fully human anti-neonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis and anti-acetylcholine receptor antibodies. METHODS: A Phase 2a, proof-of-concept, randomized, double-blind, placebo-controlled trial is described. Eligible patients were randomized (1:1:1) to receive once-weekly subcutaneous injections of batoclimab 340 mg, batoclimab 680 mg, or matching placebo for 6 weeks. Subsequently, all patients could enter an open-label extension study where they received batoclimab 340 mg once every 2 weeks for 6 weeks. Primary endpoints were safety, tolerability, and change from baseline in total immunoglobulin G, immunoglobulin G subclasses, and anti-acetylcholine receptor antibodies at 6 weeks post-baseline. Secondary endpoints included changes from baseline to 6 weeks post-baseline for Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, Myasthenia Gravis Composite, and revised 15-item Myasthenia Gravis Quality of Life scores. RESULTS: Seventeen patients were randomized to batoclimab 680 mg (n = 6), batoclimab 340 mg (n = 5), or placebo (n = 6). Batoclimab was associated with significantly greater reductions in total immunoglobulin G and anti-acetylcholine receptor antibodies from baseline to 6 weeks post-baseline than placebo. Reductions in immunoglobulin G subclasses were generally consistent with total immunoglobulin G. While clinical measures showed directionally favorable improvements over time, the study was not powered to draw conclusions about therapeutic efficacy. No safety issues were identified. INTERPRETATION: The safety profile, pharmacodynamics, and preliminary clinical benefits observed in this study support further investigation of subcutaneous batoclimab injections as a potential patient-administered therapy for seropositive generalized myasthenia gravis.

Fasted C-Peptide Distribution and Associated Clinical Factors in Adults With Longstanding Type 1 Diabetes: Analysis of the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Although insulin production is reportedly retained in many people with longstanding type 1 diabetes (T1D), the magnitude and relevance of connecting peptide (C-peptide) production are uncertain. In this study, we aimed to define fasted C-peptide distributions and associated clinical factors. METHODS: In a cross-sectional analysis of the Canadian Study of Longevity, fasted serum and urinary C-peptide was measured in 74 patients with longstanding T1D (duration ≥50 years) and 75 age- and sex-matched controls. Extensive phenotyping for complications was performed and patient-reported variables were included. C-peptide distributions were analyzed, and multivariable logistic regression was used to assess the variable association in participants with T1D. RESULTS: The 74 participants with T1D had a mean age of 66±8 years, a disease duration of 54 (interquartile range 52 to 58) years, and a glycated hemoglobin (A1C) of 7.4%±0.8% (56.8±9.15 mmol/mol). The 75 controls had a mean age of 65±8 years and an A1C of 5.7%±0.4% (38.4±4.05 mmol/mol). Participants with T1D had lower fasted serum C-peptide than controls (0.013±0.022 vs 1.595±1.099 nmol/L, p<0.001). Of the participants with T1D, C-peptide was detectable in 30 of 73 (41%) serum samples, 32 of 74 (43%) urine samples, and 48 of 74 (65%) for either serum or urine. The variables independently associated with detectable serum or urinary C-peptide were lower total daily insulin requirement (odds ratio 2.351 [for 1 lower unit/kg], p=0.013) and lower hypoglycemia worry score (odds ratio 1.059 [for 1 point lower on the worry subscore of the Hypoglycemia Fear Survey], p=0.030). CONCLUSIONS: Although detectable C-peptide in longstanding diabetes was common, the magnitude of concentration was extremely low when compared with age- and sex-matched controls. Despite minimal detectability, its presence is validated by lower insulin requirements and strongly associated with lower hypoglycemia worry.

Clinical characteristics and treatment outcomes in patients with double-seronegative myasthenia gravis.

BACKGROUND AND PURPOSE: Double-seronegative myasthenia gravis (dSNMG) is defined as myasthenia gravis (MG) without detectable or low affinity antibodies to acetylcholine receptor (AChR) and muscle-specific kinase (MuSK). There are limited data on detailed clinical features and outcomes after treatment in dSNMG patients. The aim was to describe the clinical characteristics and outcomes in dSNMG patients based on MG scales. METHODS: A retrospective study was performed of patients diagnosed with MG who had negative AChR or MuSK antibodies and they were compared with an AChR-positive MG cohort. Correlations were made with data from the first and last clinic visits, between demographics, clinical characteristics, treatment and disease severity, based on the Myasthenia Gravis Foundation of America category, Myasthenia Gravis Impairment Index (MGII), Patient Acceptable Symptom State and simple single question (SSQ). RESULTS: Eighty patients met the inclusion criteria for dSNMG. The baseline MGII and SSQ scores in the dSNMG cohort showed no significant differences from the AChR group (p = 0.94 and p = 0.46). The dSNMG cohort MGII and SSQ scores improved significantly at the last clinical evaluation (p = 0.001 and p = 0.047). The MGII improvement in the AChR cohort was significantly better (p = 0.003). CONCLUSIONS: The initial severity of dSNMG based on clinical scores is similar to antibody-positive MG patients. There is significant clinical improvement in dSNMG patients after therapy, measured in the last clinical evaluation. This supports an immune pathophysiology of many dSNMG patients.

Effect of efgartigimod on muscle group subdomains in participants with generalized myasthenia gravis: post hoc analyses of the phase 3 pivotal ADAPT study.

BACKGROUND AND PURPOSE: Generalized myasthenia gravis (gMG) is a rare, chronic, neuromuscular autoimmune disease mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Patients with gMG experience debilitating muscle weakness, resulting in impaired mobility, speech, swallowing, vision and respiratory function. Efgartigimod is a human IgG1 antibody Fc fragment engineered for increased binding affinity to neonatal Fc receptor. The neonatal Fc receptor blockade by efgartigimod competitively inhibits endogenous IgG binding, leading to decreased IgG recycling and increased degradation resulting in lower IgG concentration. METHODS: The safety and efficacy of efgartigimod were evaluated in the ADAPT study. Key efficacy outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Efgartigimod demonstrated significant improvement in both the MG-ADL and QMG scores. This post hoc analysis aimed to determine whether all subdomains of MG-ADL and QMG improved with efgartigimod treatment. Individual items of MG-ADL and QMG were grouped into four subdomains: bulbar, ocular, limb/gross motor and respiratory. Change from baseline over 10 weeks in each subdomain was calculated for each group. RESULTS: Greater improvements from baseline were seen across MG-ADL subdomains in participants treated with efgartigimod compared with placebo. These improvements were typically observed 1 to 2 weeks after the first infusion and correlated with reductions in IgG. Similar results were observed across most QMG subdomains. CONCLUSIONS: These post hoc analyses of MG-ADL and QMG subdomain data from ADAPT suggest that efgartigimod is beneficial in improving muscle function and strength across all muscle groups, leading to the observed efficacy in participants with gMG.

An evaluation of rozanolixizumab-noli for the treatment of anti-AChR and anti-MuSK antibody-positive generalized myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is an auto-immune disease characterized by fluctuating symptoms of muscle weakness and fatigue. Corticosteroids and corticosteroid-sparing broad-spectrum immunosuppression play a great role in the treatment of myasthenia gravis. However, debilitating side effects and long time to treatment effect highlight the need for development of novel target-specific medications. Rozanolixizumab is a highly specific neonatal Fc receptor (FcRn) inhibitor that acts on immunoglobulin G (IgG) homeostasis. Results from the MycarinG Phase III randomized controlled trial demonstrated significant efficacy of rozanolixizumab in generalized MG in terms of primary outcome and all secondary endpoints, tolerability, and safety compared to placebo. AREAS COVERED: We included different trials on myasthenia gravis and rozanolixizumab which include Phase II (NCT03052751) and Phase III MycarinG (NCT03971422) studies. EXPERT OPINION: Clinical trials have demonstrated that rozanolixizumab has strong efficacy with a 78% reduction in pathogenic IgG like plasma exchange (PLEX) and has therapeutic benefits comparable with PLEX and IVIG. It has less treatment adverse events and is easily accessible through subcutaneous infusion. The safety and effectiveness of rozanolixizumab need to be assessed further in the real-world context in post-marketing studies. If current trial information holds true, rozanolixizumab may become a medication of choice for MG in succeeding years.

Symptom and Treatment Satisfaction in Members of the US and Canadian GBS/CIDP Foundations with a Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy.

INTRODUCTION: Current guidelines for defining good outcomes in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) are predominately defined by experts. At present, we do not have a patient-anchored definition of what constitutes a "good" outcome. Our study aimed to assess the symptom burden of people living with CIDP, as well as satisfaction with treatments and clinical outcomes. METHODS: We conducted an online-survey in CIDP patients registered with the US and Canadian GBS/CIDP foundations. Respondents answered general demographic and clinical questions, as well as satisfaction with current symptom burden and treatments, plus validated outcome measures. RESULTS: A total of 318 individuals with self-reported CIDP completed the online survey, of whom 128 (40%) considered their current disease burden as satisfactory while 190 (60%) did not. Of 305 patients who answered the treatment satisfaction question, 222(74%) were satisfied with their treatments. Patients who were satisfied with their current symptoms had, on average, better scores in quality of life and disease severity scales, although regression modeling showed that only ability to walk, stable symptoms, and health utility scores were associated with symptom satisfaction. Treatment satisfaction was associated with stable symptoms, use of IVIG, and use of one versus no medication. CONCLUSIONS: A high proportion of members of the US and Canadian GBS/CIDP Foundations reporting a diagnosis of CIDP were unsatisfied with current symptoms, despite a high level of overall satisfaction with treatments. There is an unmet need for improving long-term outcomes in people with a diagnosis of CIDP, and for studying patient-centered long-term treatment goals.

Quantitative sonographic assessment of muscle thickness and fasciculations distribution is a sensitive tool for neuromuscular disorders.

INTRODUCTION: Loss of muscle thickness can be demonstrated in a wide spectrum of neuromuscular disorders, while fasciculations are more frequent in amyotrophic lateral sclerosis (ALS). In the current study, we aimed to determine the sensitivity and specificity of quantitative sonographic assessment of muscle thickness and the presence of fasciculations for diagnosing various neuromuscular disorders. METHODS: The thickness and the presence of fasciculations in eight muscles were determined by sonography in patients with myopathy (22), polyneuropathy (36), ALS (91), and spinal muscular atrophy (SMA) (31) and compared to normative values determined in 65 heathy control subjects. RESULTS: Reduced muscle thickness in at least one relaxed muscle showed 92-100% sensitivity for diagnosing a neuromuscular disease, with a specificity of 85% for differentiating patients from heathy controls (AUC = 0.90). Subtracting distal from proximal muscle thickness may differentiate between myopathy and polyneuropathy. Fasciculations in ≥1 proximal muscle showed good diagnostic accuracy (AUC = 0.87) for diagnosing ALS. DISCUSSION: Sonographic assessment of muscle thickness is a sensitive tool for diagnosing a wide spectrum of neuromuscular diseases, and may facilitate diagnosis even in patients with normal strength on neurological examination, while the presence of fasciculations in proximal muscles may facilitate ALS diagnosis.

FcRN receptor antagonists in the management of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies specifically directed against proteins located within the postsynaptic membrane of the neuromuscular junction. These pathogenic autoantibodies can be reduced by therapies such as plasma exchange, IVIG infusions and other immunosuppressive agents. However, there are significant side effects associated with most of these therapies. Since there is a better understanding of the molecular structure and the biological properties of the neonatal Fc receptors (FcRn), it possesses an attractive profile in treating myasthenia gravis. FcRn receptors prevent the catabolism of IgG by impeding their lysosomal degradation and facilitating their extracellular release at physiological pH, consequently extending the IgG half-life. Thus, the catabolism of IgG can be enhanced by blocking the FcRn, leading to outcomes similar to those achieved through plasma exchange with no significant safety concerns. The available studies suggest that FcRn holds promise as a versatile therapeutic intervention, capable of delivering beneficial outcomes in patients with distinct characteristics and varying degrees of MG severity. Efgartigimod is already approved for the treatment of generalized MG, rozanolixizumab is under review by health authorities, and phase 3 trials of nipocalimab and batoclimab are underway. Here, we will review the available data on FcRn therapeutic agents in the management of MG.

Reliability of confocal corneal microscopy for measurement of dendritic cell density in suspected small fiber neuropathy.

INTRODUCTION/AIMS: Dendritic cells (DCs) and their contacts with corneal nerves are described in animal models of nerve damage. Dendritic cell density (DCD) is a potential marker of immune activity in suspected small-fiber neuropathy (SFN). Here, we aim to evaluate the intra- and inter-rater reliability of DCD measurements in suspected SFN. METHODS: This retrospective study collected DCD from confocal microscopy images from the corneal sub-basal epithelium of the eye from 48 patients (mean age 49.6 ± 12.1 y, 61% female). Two examiners, each blinded to the other's examinations and measurements, assessed DCD to evaluate inter-rater reliability. For intra-rater reliability, the first examiner performed a second measurement after 14 days. DCs were classified into two cell morphological subtypes: mature and immature. RESULTS: Test-retest reliability for total DCD showed excellent agreement, with an intraclass correlation coefficient of 0.96 and inter-rater reliability intraclass correlation coefficient of 0.77. The immature cell subtype showed excellent intra-rater reliability but lower inter-rater reliability. DISCUSSION: We found that DCD measurements in the corneal sub-basal epithelium are sufficiently reliable for consideration in clinical studies of patients with suspected SFN.

Time to achieve a patient acceptable symptom state in myasthenia gravis.

Introduction: The patient acceptable symptom state (PASS) is a reliable way to characterize a patient's satisfaction with their disease state in a "Yes"/"No" dichotomous manner. There is limited data on the time required to reach an acceptable state in Myasthenia Gravis (MG). We aimed to determine the time to reach a first PASS "Yes" response in patients at MG diagnosis and a PASS "No" status, and also to determine the influence of various factors on this time. Methods: We performed a retrospective study of patients diagnosed with myasthenia gravis who had an initial PASS "No" response and defined the time to reach a first PASS "Yes" by Kaplan-Meier analysis. Correlations were made between demographics, clinical characteristics, treatment and disease severity, using the Myasthenia Gravis Impairment Index (MGII) and Simple Single Question (SSQ). Results: In 86 patients meeting inclusion criteria, the median time to PASS "Yes" was 15 months (95% CI 11-18). Of 67 MG patients who achieved PASS "Yes," 61 (91%), achieved it by 25 months after diagnosis. Patients who required only prednisone therapy achieved PASS "Yes" in a shorter time with a median of 5.5 months (p = 0.01). Very-late-onset MG patients reached PASS "Yes" status in a shorter time (HR = 1.99, 95% CI 0.26-2.63; p = 0.001). Discussion: Most patients reached PASS "Yes" by 25 months after diagnosis. MG patients who only required prednisone and those with very-late-onset MG reach PASS "Yes" in shorter intervals.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Systematic Comparison of Muscle Ultrasound Thickness in Polyneuropathies and Other Neuromuscular Diseases.

BACKGROUND: We have aimed to assess whether muscle thickness ultrasound (US) shows differences between patients with chronic inflammatory demyelinating polyneuropathy (CIDP), chronic axonal polyneuropathy (CAP), and other neuromuscular (NM) diseases compared to controls and to each other. METHODS: We performed a cross-sectional study from September 2021 to June 2022. All subjects underwent quantitative sonographic evaluation of muscle thickness in eight relaxed muscles and four contracted muscles. Differences were assessed using multivariable linear regression, correcting for age and body mass index (BMI). RESULTS: The study cohort consisted of 65 healthy controls, and 95 patients: 31 with CIDP, 34 with CAP, and 30 with other NM diseases. Both relaxed and contracted muscle thickness in all patient groups were lower than in the healthy controls, after controlling for age and body mass index (BMI). Regression confirmed that the differences persisted between patient groups and healthy controls. Differences between patient groups were not apparent. CONCLUSION: The current study shows that muscle ultrasound thickness is not specific in NM disorders, but shows a global reduction in thickness compared with healthy controls after corrections for age and BMI.