Time to response with ravulizumab, a long-acting terminal complement inhibitor, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.

BACKGROUND AND PURPOSE: The efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG) were demonstrated in the CHAMPION MG study (NCT03920293). This analysis aimed to characterize the latency to onset of a clinically meaningful therapeutic effect for ravulizumab. METHODS: Post hoc analysis of data collected for up to 60 weeks from CHAMPION MG was performed to assess the timing of response to ravulizumab. Response was analyzed based on reductions of ≥2 and ≥3 points (minimal clinically important differences [MCIDs]) in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores, respectively, and on more rigorous reductions of ≥3 and ≥5 points, respectively. Time to first response was assessed using the Kaplan-Meier product-limit method. RESULTS: The median (95% confidence interval) time to first response was 2.1 (2.1-2.6) and 4.1 (2.3-10.0) weeks for reductions of ≥2 and ≥3 points in MG-ADL total score, respectively (n = 139), and 4.1 (2.1-10.0) and 18.3 (11.0-33.4) weeks for reductions of ≥3 and ≥5 points in QMG total score, respectively (n = 134). Cumulative response rates at Week 60 (data cut-off) were 88% and 82% for ≥2- and ≥3-point MG-ADL score reductions, respectively, and 86% and 59% for ≥3- and ≥5-point QMG score reductions, respectively. CONCLUSIONS: The median times to MCID with ravulizumab treatment in patients with AChR Ab+ gMG were ~2 weeks and ~4 weeks based on MCID MG-ADL and QMG total score reductions, respectively.

Safety and outcomes with efgartigimod use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice.

INTRODUCTION/AIMS: Multiple novel therapies have been approved for patients with myasthenia gravis. Our aim is to describe the early experience of efgartigimod use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG). METHODS: This multicenter retrospective study included AChR+ve gMG patients from five major neuromuscular centers who were treated with efgartigimod and had both pre- and post-efgartigimod myasthenia gravis activities of daily living (MG-ADL) scores. Information regarding MG history, concomitant treatment(s), MG-ADL and other MG-specific measures, laboratory data, and adverse events were recorded. RESULTS: A total of 37 patients (M:23, F:14) with a mean age of 65.56 (±14.74) y were included in this cohort. A total of 36/37 patients completed at least one cycle and 28 patients completed at least two cycles of efgartigimod. A total of 72% (26/36) of patients had a clinically meaningful reduction (≥2 point change) in MG-ADL after the completion of the first cycle of efgartigimod (mean pre-efgartigimod 8.02) (±3.09) versus post-efgartigimod 4.33 (±3.62). Twenty-five percent (9/36) achieved minimal symptom expression status after one cycle and 25% (7/28) after the second cycle. Treatment benefit was sustained after cycle 2. Three out of four patients with thymoma in this cohort had clinically significant reductions in MG-ADL scores. Immunoglobulin G (IgG) levels decreased by about 60% (n = 10). One patient had a relapse of Clostridium difficile infection resulting in the discontinuation of therapy. Four patients had mild side effects. DISCUSSION: Efgartigimod led to clinically meaningful improvement in MG-ADL in diverse AChR+ve gMG patients but treatment frequency to achieve optimal symptom control needs to be explored.

Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Patient preference for virtual versus in-person visits in neuromuscular clinical practice.

INTRODUCTION/AIMS: It is unknown if patients with neuromuscular diseases prefer in-person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in-person visits, and the factors influencing such preferences. METHODS: Telephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed. RESULTS: Five hundred and twenty surveys were completed. Twenty-six percent of respondents preferred virtual visits, while 50% preferred in-person visits. Sixty-four percent reported physical interaction as "very important." For receiving a new diagnosis, 55% preferred in-person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% who were concerned about evaluating vital signs. Eighty four percent reported virtual visits were sufficiently private. Sixty eight percent did not consider expenses a factor in their preference. Although 92% were comfortable with virtual communication technology, 55% preferred video communications, and 19% preferred phone calls. Visit preference was not significantly associated with gender, diagnosis, disease severity, or symptom management. Patients who were concerned about a lack of physical exam or assessment of vitals had significantly higher odds of selecting in-person visits than no preference. DISCUSSION: Although neither technology, privacy, nor finance burdened patients in our study, more patients preferred in-person visits than virtual visits and 40% were concerned about a lack of physical examination. Interactions that occur with in-person encounters had high importance for patients, reflecting differences in the perception of the patient-physician relationship between virtual and in-person visits.

Therapeutic Plasma Exchange Versus FcRn Inhibition in Autoimmune Disease.

Therapeutic plasma exchange (TPE or PLEX) is used in a broad range of autoimmune diseases, with the goal of removing autoantibodies from the circulation. A newer approach for the selective removal of immunoglobulin G (IgG) antibodies is the use of therapeutic molecules targeting the neonatal Fc receptor (FcRn). FcRn regulates IgG recycling, and its inhibition results in a marked decrease in circulating autoantibodies of the IgG subtype. The difference between FcRn inhibition and PLEX is often questioned. With anti-FcRn monoclonal antibodies (mAbs) and fragments only recently entering this space, limited data are available regarding long-term efficacy and safety. However, the biology of FcRn is well understood, and mounting evidence regarding the efficacy, safety, and potential differences among compounds in development is available, allowing us to compare against nonselective plasma protein depletion methods such as PLEX. FcRn inhibitors may have distinct advantages and disadvantages over PLEX in certain scenarios. Use of PLEX is preferred over FcRn inhibition where removal of antibodies other than IgG or when concomitant repletion of missing plasma proteins is needed for therapeutic benefit. Also, FcRn targeting has not yet been studied for use in acute flares or crisis states of IgG-mediated diseases. Compared with PLEX, FcRn inhibition is associated with less invasive access requirements, more specific removal of IgG versus other immunoglobulins without a broad impact on circulating proteins, and any impacts on other therapeutic drug levels are restricted to other mAbs. In addition, the degree of IgG reduction is similar with FcRn inhibitors compared with that afforded by PLEX. Here we describe the scientific literature regarding the use of PLEX and FcRn inhibitors in autoimmune diseases and provide an expert discussion around the potential benefits of these options in varying clinical conditions and scenarios.

Clinical meaningfulness and psychometric robustness of the MG Symptoms PRO scales in clinical trials in adults with myasthenia gravis.

Objectives: The objective of this research was to generate psychometric evidence supporting the myasthenia gravis (MG) symptoms patient-reported outcome (PRO) scales as a fit-for-purpose measure of severity of core symptoms of MG and provide information allowing their meaningful interpretation using data from a phase 3 study in MG. Methods: Data from the MycarinG study, a phase 3 study of rozanolixizumab in patients with generalized MG who experience moderate to severe symptoms (ClinicalTrials.gov Identifier: NCT03971422) were analyzed with both classical test theory (CTT) and Rasch measurement theory (RMT). Meaningful within-individual change and group-level meaningful change were estimated for three MG Symptoms PRO scales using anchor- and distribution-based methods. Anchor-based methods used patient global impression of severity (PGIS) and change (PGIC) in MG symptoms as anchors. Results: Good measurement properties of the MG Symptoms PRO scales were shown in the sample of 200 participants: good to excellent reliability (test-retest and internal consistency reliability) and validity (associations between items and scores within the MG Symptoms PRO scales and between the MG Symptoms PRO scores and other clinical outcomes-MG ADL, QMG score, MGC score, and MGFA classes-were as expected); and the items showed good coverage of the continuum and fit to the Rasch model. Triangulation of the anchor- and distribution-based method results led to the definition of clinically meaningful within-patient improvement in scores for Muscle Weakness Fatigability (-16.67), Physical Fatigue (-20.00), and Bulbar Muscle Weakness (-20.00), with associated ranges. Benchmarks are also proposed for the interpretation of group-level results. Conclusion: The strong psychometric performance of the MG Symptoms PRO scales and the information generated to guide its interpretation supports its use in clinical trials for demonstrating the clinical benefits of new treatments targeting core symptoms of MG (muscle weakness fatigability, physical fatigue, bulbar muscle weakness, respiratory muscle weakness, and ocular muscle weakness).

Effect of a Novel Adaptive Handle Design on the Ergonomic Performance of Periodontal Curettes in Dental Hygienists with and without Musculoskeletal Disorders: A Pilot Clinical Study.

(1) Background: Musculoskeletal disorders (MSDs), discomfort, fatigue, pain, and other acute and chronic work-related injuries are common among dental clinicians. Hand instruments constitute a primary risk factor for these conditions. The overall goal of this study was to compare in dental hygienists with healthy hands, and in those with MSDs, the effect of three different handle designs on instrumentation-related muscle work, comfort, fatigue, and quality of tactile feedback. (2) Methods: Clinicians tested three periodontal curettes: one with a novel adaptive silicone handle, another with a rigid resin handle, and the third with a rigid silicone handle. Ten hygienists-five with MSDs and five without-each scaled three typodonts using the three different curettes. Statistical analysis was performed using a General Linear Model (GLIM) and Tukey's post hoc test, and a significance level of p < 0.05 was implemented. (3) Results: On average, mean comfort and fatigue across all instruments were significantly worse in testers with MSDs, who also expended significantly more work to complete the same task. In all testers, a novel adaptive handle design was associated with significantly reduced total muscle work and post-instrumentation fatigue, as well as better comfort than conventional rigid handle designs. (4) Conclusions: An adaptive curette handle design demonstrated significantly better ergonomic outcomes than conventional rigid curette handle designs. Hygienists with MSDs expend significantly more muscle work during dental instrumentation.

Effect of a Novel Ergonomic Sheath on Dental Device-Related Muscle Work, Fatigue and Comfort-A Pilot Clinical Study.

Background: Dental instrumentation with hand-held devices is associated with discomfort, fatigue and musculoskeletal diseases or repetitive stress injuries. The goal of this in vivo study was to determine the effect of an ergonomic handle sheath on muscle work, comfort and fatigue associated with (a) piezoelectric scaling by hygienists with and without musculoskeletal disorders (MSDs), and (b) dental cavity preparation by healthy dentists using a dental micromotor. Materials and Methods: Two groups of ten hygienists each tested the piezoelectric scaler. Hygienists in Group 1 had no MSDs, while those in Group 2 had been diagnosed with MSDs. Additionally, ten dentists with no MSDs used a dental micromotor to prepare four standardized cavities. Time-based work in four muscles, comfort and fatigue were recorded in the presence and absence of an add-on soft, insulating handle sheath. Data were analyzed using a repeated measures analysis of variance model with Tukey's post-hoc test. Results: Comfort, fatigue and muscle work were significantly better for both devices when the sheath was used. While hygienists with MSDs used more muscle work to complete the set scaling task, and the sheath-related reduction in work was somewhat greater, these MSD-related differences did not quite reach significance. Conclusions: The results of this pilot study show that the ergonomic performance of an ultrasonic scaler and a dental micromotor may be improved by the use of an ergonomic handle sheath.

US Clinical Practice Experience with Eculizumab in Myasthenia Gravis: Acute Clinical Events and Healthcare Resource Utilization.

BACKGROUND AND OBJECTIVE: The terminal complement inhibitor eculizumab is approved in the USA for the treatment of patients with acetylcholine receptor antibody-positive generalized myasthenia gravis (MG). The ELEVATE study aimed to examine clinical-practice outcome data on eculizumab effectiveness in US adults with MG (generalized or ocular). This paper reports the findings on MG exacerbations and crises and associated healthcare resource utilization, and the use of rescue therapy. METHODS: A retrospective chart review was conducted of US adults with MG who initiated eculizumab. Outcomes assessed for up to 2 years before and after eculizumab initiation included percentages and rates per patient per year (PPPY) of exacerbations and crises (the latter defined as intubation/impending intubation), healthcare resource utilization, and rescue therapy administration. RESULTS: A total of 119 patients diagnosed with MG were enrolled in the study; 92 patients had ≥ 3 months of data both before and during eculizumab therapy and were included in the analyses. The mean rate of MG exacerbations decreased from 0.385 PPPY before eculizumab initiation to 0.152 PPPY during eculizumab treatment (p = 0.0034); the mean rate of MG crises decreased from 0.411 to 0.056 PPPY (p = 0.0018). Rates of healthcare resource utilization and rescue therapy use also decreased significantly during eculizumab treatment. CONCLUSIONS: This retrospective chart review analysis provides evidence for a beneficial impact of eculizumab treatment on the incidence of MG exacerbations and crises and associated healthcare resource utilization in clinical practice, and on rescue therapy use. These data further support the therapeutic benefits of eculizumab in patients with MG.

Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study.

OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject's legally authorized representative during enrollment. RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.

United States clinical practice experience with eculizumab in myasthenia gravis: symptoms, function, and immunosuppressant therapy use.

BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy. DISCUSSION: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab.

A Multidisciplinary Assessment of ChatGPT's Knowledge of Amyloidosis: Observational Study.

BACKGROUND: Amyloidosis, a rare multisystem condition, often requires complex, multidisciplinary care. Its low prevalence underscores the importance of efforts to ensure the availability of high-quality patient education materials for better outcomes. ChatGPT (OpenAI) is a large language model powered by artificial intelligence that offers a potential avenue for disseminating accurate, reliable, and accessible educational resources for both patients and providers. Its user-friendly interface, engaging conversational responses, and the capability for users to ask follow-up questions make it a promising future tool in delivering accurate and tailored information to patients. OBJECTIVE: We performed a multidisciplinary assessment of the accuracy, reproducibility, and readability of ChatGPT in answering questions related to amyloidosis. METHODS: In total, 98 amyloidosis questions related to cardiology, gastroenterology, and neurology were curated from medical societies, institutions, and amyloidosis Facebook support groups and inputted into ChatGPT-3.5 and ChatGPT-4. Cardiology- and gastroenterology-related responses were independently graded by a board-certified cardiologist and gastroenterologist, respectively, who specialize in amyloidosis. These 2 reviewers (RG and DCK) also graded general questions for which disagreements were resolved with discussion. Neurology-related responses were graded by a board-certified neurologist (AAH) who specializes in amyloidosis. Reviewers used the following grading scale: (1) comprehensive, (2) correct but inadequate, (3) some correct and some incorrect, and (4) completely incorrect. Questions were stratified by categories for further analysis. Reproducibility was assessed by inputting each question twice into each model. The readability of ChatGPT-4 responses was also evaluated using the Textstat library in Python (Python Software Foundation) and the Textstat readability package in R software (R Foundation for Statistical Computing). RESULTS: ChatGPT-4 (n=98) provided 93 (95%) responses with accurate information, and 82 (84%) were comprehensive. ChatGPT-3.5 (n=83) provided 74 (89%) responses with accurate information, and 66 (79%) were comprehensive. When examined by question category, ChatGTP-4 and ChatGPT-3.5 provided 53 (95%) and 48 (86%) comprehensive responses, respectively, to "general questions" (n=56). When examined by subject, ChatGPT-4 and ChatGPT-3.5 performed best in response to cardiology questions (n=12) with both models producing 10 (83%) comprehensive responses. For gastroenterology (n=15), ChatGPT-4 received comprehensive grades for 9 (60%) responses, and ChatGPT-3.5 provided 8 (53%) responses. Overall, 96 of 98 (98%) responses for ChatGPT-4 and 73 of 83 (88%) for ChatGPT-3.5 were reproducible. The readability of ChatGPT-4's responses ranged from 10th to beyond graduate US grade levels with an average of 15.5 (SD 1.9). CONCLUSIONS: Large language models are a promising tool for accurate and reliable health information for patients living with amyloidosis. However, ChatGPT's responses exceeded the American Medical Association's recommended fifth- to sixth-grade reading level. Future studies focusing on improving response accuracy and readability are warranted. Prior to widespread implementation, the technology's limitations and ethical implications must be further explored to ensure patient safety and equitable implementation.

Hospitalizations and Mortality From Myasthenia Gravis: Trends From 2 US National Datasets

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is a rare neuromuscular disorder where IgG antibodies damage the communication between nerves and muscles, leading to muscle weakness that can be severe and have a significant impact on patients' lives. MG exacerbations include myasthenic crisis with respiratory failure, the most serious manifestation of MG. Recent studies have found MG prevalence increasing, especially in older patients. This study examined trends in hospital admissions and in-hospital mortality for adult patients with MG and readmissions and postdischarge mortality in older (65 years or older) adults with MG. METHODS: Data from the Nationwide Inpatient Sample (NIS), an all-payer national database of hospital discharges, were used to characterize trends in hospitalizations and in-hospital mortality related to MG exacerbations and MG crisis among adult patients aged 18 years or older. The Medicare Limited Data Set, a deidentified, longitudinal research database with demographic, enrollment, and claims data was used to assess hospitalizations, length of stay (LOS), readmissions, and 30-day postdischarge mortality among fee-for-service Medicare beneficiaries aged 65 years or older. The study period was 2010-2019. Multinomial logit models and Poisson regression were used to test for significance of trends. RESULTS: Hospitalization rates for 19,715 unique adult patients and 56,822 admissions increased from 2010 to 2019 at an average annualized rate of 4.9% (MG noncrisis: 4.4%; MG crisis: 6.8%; all p < 0.001). Readmission rates were approximately 20% in each study year for both crisis and noncrisis hospitalizations; the in-hospital mortality rate averaged 1.8%. Among patients aged 65 years or older, annualized increases in hospitalizations were estimated at 5.2%, 4.2%, and 7.7% for all, noncrisis, and crisis hospitalizations, respectively (all p < 0.001). The average LOS was stable over the study period, ranging from 11.3 to 13.1 days, but was consistently longer for MG crisis admissions. Mortality among patients aged 65 years or older was higher compared with that in all patients, averaging 5.0% across each of the study years. DISCUSSION: Increasing hospitalization rates suggest a growing burden associated with MG, especially among older adults. While readmission and mortality rates have remained stable, the increasing hospitalization rates indicate that the raw numbers of readmissions-and deaths-are also increasing. Mortality rates are considerably higher in older patients hospitalized with MG.

Risk-Benefit Analysis of Novel Treatments for Patients with Generalized Myasthenia Gravis.

INTRODUCTION: This study used network meta-analysis (NMA) to inform and compare the number needed to treat (NNT), number needed to harm (NNH), and cost per improved outcome (CPIO) associated with more recently approved treatments for anti-acetylcholine receptor antibody-positive (anti-AChR Ab+) generalized myasthenia gravis (gMG). METHODS: Clinical trials of neonatal Fc receptor (FcRn) inhibitors, efgartigimod intravenous (IV) and rozanolixizumab, and complement inhibitors, ravulizumab and zilucoplan, versus placebo (with background conventional treatment) were included in the primary NMA to compare efficacy and safety outcomes. The outputs from the NMAs were used to estimate NNT and NNH of each treatment versus placebo. CPIO (2024 USD) was estimated for a ≥ 3- or ≥ 5-point reduction from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores. Sensitivity analyses were performed adding efgartigimod PH20 subcutaneous (SC) and eculizumab to the NMA. RESULTS: Efgartigimod IV had the lowest NNT versus placebo for achieving a ≥ 3- and ≥ 5-point reduction in QMG, as well as a ≥ 5-point reduction in MG-ADL, whereas rozanolixizumab had the lowest NNT for a ≥ 3-point reduction in MG-ADL. The NNH versus placebo was similar across comparator treatments. Efgartigimod IV had the lowest CPIO among all treatments for all assessed efficacy outcomes. Sensitivity analyses yielded results consistent with primary analysis and indicated that efgartigimod PH20 SC had comparable NNT and CPIO values to efgartigimod IV, whereas eculizumab had comparable NNT and higher CPIO values compared to other complement inhibitors. CONCLUSIONS: FcRn inhibitors and complement inhibitors assessed in this study all demonstrated clinical benefit in terms of NNT as well as an acceptable safety profile in terms of NNH. Within the limitations of this meta-analysis, efgartigimod was associated with a favorable benefit-risk profile as well as a better economic value compared to ravulizumab, rozanolixizumab, and zilucoplan as treatments for anti-AChR Ab+ gMG.

Efficacy and safety of rozanolixizumab in patients with muscle-specific tyrosine kinase autoantibody-positive generalised myasthenia gravis: a subgroup analysis of the randomised, double-blind, placebo-controlled, adaptive phase III MycarinG study.

Background: Muscle-specific tyrosine kinase (MuSK) autoantibody-positive (Ab+) generalised myasthenia gravis (gMG) is a rare and frequently severe subtype of gMG. Objectives: To assess the efficacy and safety of rozanolixizumab in the subgroup of patients with MuSK Ab+ gMG in the MycarinG study. Design: A randomised, double-blind, placebo-controlled phase III study. Methods: Patients with acetylcholine receptor (AChR) Ab+ or MuSK Ab+ gMG (aged ⩾18 years, Myasthenia Gravis Foundation of America Disease Class II-IVa, Myasthenia Gravis Activities of Daily Living [MG-|ADL] score ⩾3.0 [non-ocular symptoms], Quantitative Myasthenia Gravis score ⩾11.0) were randomly assigned (1:1:1) to receive once-weekly subcutaneous infusions of rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo for 6 weeks, followed by an 8-week observation period. Randomisation was stratified by AChR and MuSK autoantibody status. The primary study endpoint was change from baseline to Day 43 in MG-ADL score. Treatment-emergent adverse events (TEAEs) were also assessed. Results: Overall, 200 patients were randomised, of whom 21 had MuSK Ab+ gMG and received rozanolixizumab 7 mg/kg (n = 5), 10 mg/kg (n = 8) or placebo (n = 8). In patients with MuSK Ab+ gMG, reductions from baseline to Day 43 in MG-ADL scores were observed: rozanolixizumab 7 mg/kg least squares mean (LSM) change (standard error), -7.28 (1.94); 10 mg/kg, -4.16 (1.78); and placebo, 2.28 (1.95). Rozanolixizumab 7 mg/kg LSM difference from placebo was -9.56 (97.5% confidence interval: -15.25, -3.87); 10 mg/kg, -6.45 (-11.03, -1.86). TEAEs were experienced by four (80.0%), five (62.5%) and three (37.5%) patients with MuSK Ab+ gMG receiving rozanolixizumab 7 mg/kg, 10 mg/kg and placebo, respectively. No patients experienced serious TEAEs. No deaths occurred. Conclusion: This subgroup analysis of adult patients with MuSK Ab+ gMG enrolled in the MycarinG study supports the use of rozanolixizumab as an effective treatment option for patients with gMG who have MuSK autoantibodies. Trial registration: ClinicalTrials.gov: NCT03971422 (https://clinicaltrials.gov/study/NCT03971422); EU Clinical Trials Register: EudraCT 2019-000968-18 (https://www.clinicaltrials|register.eu/ctr-search/trial/2019-000968-18/GB).

Rozanolixizumab improved symptoms in people with anti-muscle-specific tyrosine kinase antibody-positive generalised myasthenia gravis in the MycarinG clinical study Myasthenia gravis is a rare, chronic autoimmune disease affecting the communication between nerves and muscles. People with the disease experience fluctuating muscle weakness and fatigue, leading to problems with mobility, speaking, swallowing and breathing. The disease is called generalised when muscles other than those that move the eyes and eyelids are affected. It is caused by antibodies that attack a person's own cells. Most people with the disease have antibodies against acetylcholine receptors (AChRs). However, some have antibodies against the muscle-specific tyrosine kinase (MuSK) protein and can experience more severe symptoms compared with people who have anti-AChR antibodies. Standard treatments for myasthenia gravis do not always work for people with anti-MuSK antibodies. The MycarinG study looked at whether rozanolixizumab was better than a placebo at treating the symptoms of adults with generalised myasthenia gravis and anti-AChR or anti-MuSK antibodies. Assessments measured disease severity and myasthenia gravis symptoms, such as physical fatigue, and how they affected daily activities. The study also looked at whether people receiving rozanolixizumab had any side effects. Here, we look at the group of people with anti-MuSK antibodies who took part in the MycarinG study. In total, 21 of the 200 people in the study had anti-MuSK antibodies. The symptoms of myasthenia gravis improved more in people with anti-MuSK antibodies who received rozanolixizumab than in those who received placebo. Common side effects with rozanolixizumab included headache, diarrhoea and feeling sick. No serious side effects were seen, and no patients died. The results show that rozanolixizumab is an effective treatment for people with generalised myasthenia gravis who have anti-MuSK antibodies. The results in this group of people are consistent with those seen in all people who took part in the study (with either antibody type).

Guillain-Barré Syndrome.

OBJECTIVE: This article summarizes the clinical features, diagnostic criteria, differential diagnosis, pathogenesis, and prognosis of Guillain-Barré syndrome (GBS), with insights into the current and future diagnostic and therapeutic interventions for this neuromuscular syndrome. LATEST DEVELOPMENTS: GBS is an acute, inflammatory, immune-mediated polyradiculoneuropathy that encompasses many clinical variants and divergent pathogenic mechanisms that lead to axonal, demyelinating, or mixed findings on electrodiagnostic studies. The type of antecedent infection, the development of pathogenic cross-reactive antibodies via molecular mimicry, and the location of the target gangliosides affect the subtype and severity of the illness. The data from the International GBS Outcome Study have highlighted regional variances, provided new and internationally validated prognosis tools that are beneficial for counseling, and introduced a platform for discussion of GBS-related open questions. New research has been undertaken, including research on novel diagnostic and therapeutic biomarkers, which may lead to new therapies. ESSENTIAL POINTS: GBS is among the most frequent life-threatening neuromuscular emergencies in the world. At least 20% of patients with GBS have a poor prognosis and significant residual deficits despite receiving available treatments. Research is ongoing to further understand the pathogenesis of the disorder, find new biomarkers, and develop more effective and specific treatments.

Measuring Overall Severity of Myasthenia Gravis (MG): Evidence for the Added Value of the MG Symptoms PRO.

INTRODUCTION: Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. METHODS: The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. RESULTS: The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. CONCLUSION: The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03052751.

Myasthenia gravis (MG) is a chronic disease affecting the communication between nerves and muscles. People with MG experience muscle weakness that worsens after activity and improves after rest. MG can affect different groups of body muscles (e.g., around the eyes, in the limbs, and face or throat).We show that the various symptoms of MG can be used to summarize the overall severity of the disease: people with mild and moderate MG often report only the fast onset of weakness in their limb muscles and mild physical fatigue, while those with more severe MG report more severe fatigue and also difficulties associated with weakness in facial and throat muscles (leading to difficulty with swallowing or speaking) and in respiratory muscles (making breathing difficult). This ordering of MG manifestations will help create more accurate methods to assess the severity of MG that can be used to evaluate new treatments or to monitor patients in the clinic.We also suggest that weakness of muscles around the eyes (leading to eyelid drooping or double vision) may represent a unique aspect of MG, and may not provide as much information to summarize the severity of MG as other symptoms. However, this needs further investigation as our study did not include participants who had weakness in eye muscles as their only symptom.We also document the ability of the MG Symptoms Patient-Reported Outcome questionnaire, a new questionnaire completed by patients, to provide useful information for measuring the severity of MG.

A Novel Ergonomic Curette Design Reduces Dental Prophylaxis-Induced Muscle Work and Fatigue.

BACKGROUND: To compare fatigue, comfort, and muscle work associated with the use of two periodontal curettes during scaling: one with a novel adaptive design, the other with a conventional non-adaptive design. METHODS: Twelve hygienists scaled a typodont using two Universal Barnhart 5/6 curettes: (1) a prototype featuring an adaptive silicone-covered handle (Curette A), and (2) a stainless-steel curette (Curette B). Surface Electromyography (sEMG) traced muscle work. Hand positions, fatigue, comfort, pinch, and grasp strength were recorded. Paired t-tests and a repeated measures ANOVA with covariates were tested for differences. The significance level was set at p < 0.05. RESULTS: Curette A performed significantly better in all categories. Pinch and grasp strength and fatigue were significantly reduced post-instrumentation for Curette B. Curette A required significantly less (i) total muscle work and (ii) work in individual muscles. Comfort, correct grasp, and blade adaptation were significantly better using Curette A. CONCLUSIONS: A curette featuring a novel adaptive handle design demonstrated significantly improved ergonomic performance. Additional clinical studies are needed to solidify our understanding of the potential short- and long-term benefits of the novel curette handle design. PRACTICAL IMPLICATIONS: A novel adaptive curette handle design that enables the clinician to adapt the instrument across the index finger may reduce musculoskeletal burden and fatigue, as well as improve comfort during periodontal instrumentation.