ABSTRACT
BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.
Subject(s)
Antibodies, Monoclonal, Humanized , Complement Inactivating Agents , Myasthenia Gravis , Humans , Adolescent , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacology , Myasthenia Gravis/drug therapy , Male , Female , Child , Complement Inactivating Agents/administration & dosage , Complement Inactivating Agents/pharmacology , Treatment Outcome , Quality of Life , Outcome Assessment, Health CareABSTRACT
An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.
Subject(s)
Myasthenia Gravis , Quality of Life , Humans , Activities of Daily Living , Myasthenia Gravis/drug therapy , Outcome Assessment, Health Care , Clinical Trials as TopicABSTRACT
OBJECTIVE: To design a physician and patient derived tool, the Adverse Event Unit (AEU), akin to currency (e.g. U.S. Dollar), to improve AE burden measurement independent of any particular disease or medication class. PATIENTS/METHODS: A Research Electronic Data Capture (REDCap) online survey was administered to United States physicians with board certification or board eligibility in general neurology, subspecialty neurology, primary care internal medicine or family medicine, subspecialty internal medicine, general pediatrics, and subspecialty pediatrics. Physicians assigned value to 73 AE categories chosen from the Common Terminology Criteria of Adverse Events (CTCAE) relevant to neurologic disorder treatments. An online forced choice survey was administered to non-physician, potential patients, through Amazon Mechanical Turk (MTurK) to weight the severity of the same AE categories. Physician and non-physician data was combined to assign value to the AEU. Surveys completed between 1/2017 and 3/2019. RESULTS: 363 physicians rated the 73 AE categories derived from CTCAE. 660 non-physicians completed forced choice experiments comparing AEs. The AEU provides 0-10, weighted values for the AE categories studied that differ from the ordinal 1-4 CTCAE scale. For example, CTCAE severe diabetes (category 4) is assigned an AEU score of 9. Although non-physician input changed physician assigned AEU values, there was general agreement among physicians and non-physicians about severity of AEs. CONCLUSION: The AEU has promise to be a useful, practical tool to add precision to AE burden measurement in the clinic and in comparative efficacy research with neurology patients. AEU utility will be assessed in planned comparative efficacy clinical trials.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/pathology , Drugs, Investigational/adverse effects , Nervous System Diseases/drug therapy , Patient Reported Outcome Measures , Physicians/statistics & numerical data , Adult , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Female , Humans , Male , Middle Aged , Nervous System Diseases/pathology , Surveys and QuestionnairesABSTRACT
INTRODUCTION/AIMS: Telemedicine may be particularly well-suited for myasthenia gravis (MG) due to the disorder's need for specialized care, its hallmark fluctuating muscle weakness, and the potential for increased risk of virus exposure among patients with MG during the coronavirus disease 2019 (COVID-19) pandemic during in-person clinical visits. A disease-specific telemedicine physical examination to reflect myasthenic weakness does not currently exist. METHODS: This paper outlines step-by-step guidance on the fundamentals of a telemedicine assessment for MG. The Myasthenia Gravis Core Exam (MG-CE) is introduced as a MG-specific, telemedicine, physical examination, which contains eight components (ptosis, diplopia, facial strength, bulbar strength, dysarthria, single breath count, arm strength, and sit to stand) and takes approximately 10 minutes to complete. RESULTS: Pre-visit preparation, remote ascertainment of patient-reported outcome scales and visit documentation are also addressed. DISCUSSION: Additional knowledge gaps in telemedicine specific to MG care are identified for future investigation.
Subject(s)
COVID-19/prevention & control , Myasthenia Gravis/diagnosis , Patient Education as Topic/methods , Physical Examination/methods , Physicians , Telemedicine/methods , Female , Humans , Male , Myasthenia Gravis/therapy , Patient Education as Topic/standards , Physical Examination/standards , Physicians/standards , Telemedicine/standardsABSTRACT
INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.
Subject(s)
Myasthenia Gravis/genetics , Myasthenia Gravis/therapy , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cholinergic/genetics , Thymectomy , Adolescent , Adult , Age of Onset , Aged , Child , Cohort Studies , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Male , Middle Aged , Prednisone/therapeutic use , Retrospective Studies , Rituximab/therapeutic use , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG). METHODS: This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs. RESULTS: Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome.
Subject(s)
Autoantibodies/metabolism , Immunologic Factors/therapeutic use , Myasthenia Gravis/drug therapy , Myasthenia Gravis/immunology , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Rituximab/therapeutic use , Adult , Anti-Inflammatory Agents/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prednisone/therapeutic use , Prospective Studies , Severity of Illness Index , Single-Blind Method , Treatment OutcomeABSTRACT
INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.
Subject(s)
Amyloid Neuropathies, Familial/drug therapy , Diagnostic Techniques, Neurological , Neurologists , Oligonucleotides/therapeutic use , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Amyloid Neuropathies, Familial/diagnosis , Amyloid Neuropathies, Familial/physiopathology , Cohort Studies , Disability Evaluation , Female , Humans , International Cooperation , Male , Middle Aged , Neural Conduction/drug effects , Neural Conduction/physiology , Outcome Assessment, Health CareABSTRACT
INTRODUCTION: The etiology of neuropathy was idiopathic in 20%-30% of patients despite thorough investigation, based on results from the 1980s and 1990s. Since then, new etiologies have been recognized, and skin biopsy has been used to confirm small-fiber neuropathy. METHODS: The authors reviewed the charts of 373 patients with idiopathic neuropathy who were referred to a neuropathy center between 2002 and 2012. RESULTS: Among the 284 eligible patients, 93 (32.7%) remained idiopathic. The most common cause was impaired glucose metabolism (72 patients, 25.3%), including diabetes in 26 and prediabetes in 46. Other etiologies were chronic inflammatory demyelinating polyneuropathy (CIDP) in 57 (20%) and monoclonal gammopathy in 20 (7%), as well as toxic, Sjögren disease, celiac disease, other immune-mediated diseases, vitamin B12 deficiency, amyloidosis, vitamin B1 and B6 deficiency, vasculitis, hypothyroidism, hereditary, Lyme disease, and anti-sulfatide antibody. CONCLUSIONS: The major causes of undiagnosed neuropathies were impaired glucose metabolism, CIDP, and monoclonal gammopathies. Despite thorough evaluation 32.7% remained idiopathic. Muscle Nerve 53: 856-861, 2016.
Subject(s)
Paraproteinemias/complications , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/etiology , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/complications , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Neuromuscular diseases such as polymyositis, dermatomyositis, peripheral neuropathy, and disorders of neuromuscular transmission are reported to be complications of hematopoietic stem cell transplantation (HSCT). Although cases have been reported with allogeneic HSCT in the setting of chronic graft versus host disease, they are also known to occur without evidence thereof and even occur in the setting of autologous HSCT. The 2005 National Institutes of Health Consensus Criteria classify polymyositis and dermatomyositis as "distinctive" features, and neuropathy and MG as "other" features. These neuromuscular complications present very similarly to the idiopathic autoimmune disorders and respond to similar treatment modalities.
Subject(s)
Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Neuromuscular Diseases/etiology , Postoperative Complications/etiology , HumansABSTRACT
Familial amyloidotic polyneuropathy is the hereditary form of transthyretin amyloidosis that is rapidly progressive. Discordant expression of Val30Met transthyretin amyloid in monozygotic twins has been reported in the past, in Europe and Asia. We report the first case of discordant expression of Lys35Thr transthyretin amyloid in female monozygotic twins in North America with eye involvement and peripheral neuropathy.
Subject(s)
Amyloid Neuropathies, Familial/genetics , Lysine/genetics , Prealbumin/genetics , Threonine/genetics , Twins, Monozygotic/genetics , Female , Humans , Middle Aged , PhenotypeABSTRACT
Intravenous immunoglobulin (IVIg) has been widely used in the treatment of autoimmune neuromuscular diseases. Compared to other treatment modalities, such as corticosteroids and chemotherapy for autoimmune disorders, IVIg has relatively few side effects and favorable therapeutic outcomes in certain neuromuscular diseases. There is Class I evidence for IVIg as an initial treatment for patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy. It is as effective as plasma exchange in GBS and CIDP. In myasthenia gravis, IVIg is used for myasthenic crisis and exacerbations, though it is also helpful as maintenance therapy, particularly in patients with a suboptimal response or contraindications to prednisone or other immunosuppressive agents. IVIg has been demonstrated to be beneficial in placebo-controlled, double-blind, randomized studies in dermatomyositis and Lambert-Eaton syndrome. IVIg has also been beneficial in select patients with polymyositis and other autoimmune peripheral neuropathies. Clinical trials in amyotrophic lateral sclerosis, inclusion body myositis, and anti-myelin-associated glycoprotein neuropathy have been negative.