Myasthenia gravis (MG) is driven by the secretion of autoantibodies from pathogenic B cell maturation antigen (BCMA)-expressing plasma cells. In this phase 2b randomized, controlled, double-blind trial, we evaluated Descartes-08, an autologous BCMA-directed mRNA chimeric antigen receptor T cell therapy, in patients with generalized MG (gMG). Patients (n = 26) were randomly allocated to receive once-weekly intravenous infusions of Descartes-08 (n = 15) or placebo (n = 11) over 6 weeks. The primary endpoint was a ≥5-point improvement in the MG Composite (MGC) score at month 3. Secondary endpoints included the mean change from baseline in MGC, MG Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) scores by month 12. At month 3, the proportion of patients achieving a ≥5-point improvement in the MGC score was significantly higher for those treated with Descartes-08 compared to placebo in the overall population (66.7% (n = 10/15) versus 27.3% (n = 3/11), P = 0.0472) and in a subpopulation of those positive for autoantibodies to the acetylcholine receptor (63.6% (n = 7/11) versus 12.5% (n = 1/8), P = 0.0258). For patients treated with Descartes-08, the changes from baseline in mean MGC, MG-ADL and QMG scores at month 4 were -7.1, -5.5 and -4.8, respectively, with 83.0% of patients achieving a sustained and clinically meaningful response at month 12. Notably, 33.0% of patients achieved minimum symptom expression (MSE) (MG-ADL score ≤1) by month 6, which was sustained through month 12. Among biologic-naive patients, 55.60% achieved MSE by month 6, which was maintained through month 12 without additional treatment. Descartes-08 was generally safe and well tolerated. Infusion-related reactions were the most common adverse events reported (Descartes-08, 80.0% (n = 16/20); placebo, 56.3% (n = 9/16)). In summary, a single course of six once-weekly infusions of Descartes-08 was well tolerated and resulted in sustained clinically meaningful responses among patients with gMG. ClinicalTrials.gov identifier: NCT04146051 .

INTRODUCTION/AIMS:Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)-funded EAP for amyotrophic lateral sclerosis (ALS). METHODS:Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study. RESULTS:Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was -0.005, SE = 0.0078; 95% CI (-0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale-Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were -5.6 (0.67); 95% CI (-7.0, -4.3) and -4.53 (4.308); 95% CI (-13.55, 4.48)], respectively. No unexpected treatment-related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths). DISCUSSION:This EAP establishes a framework for implementing multi-center EAPs that complement data collected from RCTs. Additional NIH-funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study. TRIAL REGISTRATION:ClinicalTrials.gov: NCT05597436.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we assess ISRIB, a molecule that attenuates the integrated stress response (ISR). The ISR is an intracellular signaling network through which cells normally respond to stress, but in ALS it appears to be overactive, leading to the formation of "stress granules" which some but not all investigators believe can triggerapoptotic cell death. ISRIB can attenuate the formation of these stress granules while still allowing parts of protein synthesis to continue. Pre-clinical data demonstrate that ISRIB is beneficial in cell models of ALS. A small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects, though we have not been able to independently verify these benefits. There are no clinical trials evaluating ISRIB in any condition and questions about its solubility and bioavailability have arisen. Currently, we do not have enough evidence to endorse the use of ISRIB for treating ALS. We support further research in disease models and clinical trials to study pharmacokinetics, safety and efficacy.

Background The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). Methods and findings In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. Conclusions Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Trial registration Clintrials.gov ID:NCT04322149.

BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a peripheral nerve disorder characterised by weakness and sensory loss. We assessed the neonatal Fc receptor inhibitor rozanolixizumab for CIDP management.MethodsCIDP01 (NCT03861481) was a randomised, subject-blind, investigator-blind, placebo-controlled, phase 2a study. Adults with definite or probable CIDP receiving subcutaneous or intravenous immunoglobulin maintenance therapy were randomised 1:1 to 12 once-weekly subcutaneous infusions of rozanolixizumab 10 mg/kg or placebo, stratified according to previous immunoglobulin administration route. Investigators administering treatment and assessing efficacy, and patients, were blinded. The primary outcome was a change from baseline (CFB) to day 85 in inflammatory Rasch-built Overall Disability Scale (iRODS) score. Eligible patients who completed CIDP01 entered the open-label extension CIDP04 (NCT04051944).ResultsIn CIDP01, between 26 March 2019 and 31 March 2021, 34 patients were randomised to rozanolixizumab or placebo (17 (50%) each). No significant difference in CFB to day 85 in iRODS centile score was observed between rozanolixizumab (least squares mean 2.0 (SE 3.2)) and placebo (3.4 (2.6); difference –1.5 (90% CI –7.5 to 4.5)). Overall, 14 (82%) patients receiving rozanolixizumab and 13 (76%) receiving placebo experienced a treatment-emergent adverse event during the treatment period. Across CIDP01 and CIDP04, rozanolixizumab was well tolerated over up to 614 days; no clinically meaningful efficacy results were seen. No deaths occurred.ConclusionsRozanolixizumab did not show efficacy in patients with CIDP in this study, although this could be due to a relatively high placebo stability rate. Rozanolixizumab was well tolerated over medium-to-long-term weekly use, with an acceptable safety profile.

INTRODUCTION/AIMS:Prospective, randomized, controlled trials of intravenous immunoglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this trial, we evaluated the safety and efficacy of caprylate/chromatography-purified IVIG; (IGIV-C) in patients with generalized MG undergoing standard care. METHODS:Sixty-two patients enrolled in this phase 2, multicenter, international, randomized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week 21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score at week 24 versus baseline (primary endpoint) and percentage of patients with clinical improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living (MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse events (AEs). RESULTS:The change in QMG at 24 weeks was -5.1 for IGIV-C and -3.1 for placebo (p = .187). Seventy percent of patients in the IGIV-C group had improvement in MG-ADL (≥2-point decrease) versus 40.6% in the placebo group (p = .025). Patients showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for IGIV-C versus 59.4% for placebo (p = .442) and 60.0% for IGIV-C versus 53.1% for placebo (p = .610). IGIV-C was well tolerated; serious AEs were similar between arms. Three of four MG exacerbations requiring hospitalizations occurred in the IGIV-C arm with one death. DISCUSSION:Several efficacy parameters showed numerical results greater than those seen in the placebo group. This was a small study and may have been underpowered to see significant differences. Additional studies may be warranted to fully determine the efficacy of IVIG maintenance therapy in MG.

Background and Objectives Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. Methods In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II–Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. Results The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. Discussion In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. Trial Registration Information The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). Classification of Evidence This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Importance:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.Objective:To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.Design, Setting, and Participants:This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.Interventions:Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.Main Outcomes and Measures:The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.Results:A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).Conclusions and Relevance:Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.Trial Registration:ClinicalTrials.gov Identifier: NCT02450552.

Background and Objective To determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms. Methods Immunoglobulin (Ig) was purified from a patient with myasthenia gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified. Results Patient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4–MuSK interaction. Discussion Anti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4–MuSK interaction.

Objective: To determine the effects of mexiletine (MEX) on cortical neuronal and peripheral motor nerve hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Background: Transcranial magnetic stimulation (TMS) and axonal excitability studies have established the presence of cortical and axonal nerve hyperexcitability in ALS, potentially contributing to pathogenesis. MEX is a sodium channel blocker that could reduce hyperexcitability in this disease. Design/Methods: 20 ALS subjects from 10 centers were randomized 1:1:1 to placebo, MEX 300 mg, and MEX 600 mg per day for 4 weeks followed by 4 weeks off treatment. The primary and key secondary endpoints were resting motor threshold (RMT) and motor evoked potential (MEP) amplitude, expressed as percentage of the compound muscle action potential response. Results: 20% of screened subjects were cortically inexcitable. RMT was significantly reduced over 4 weeks with MEX (combined active therapies) compared to placebo by mixed model analysis (mean±SE: placebo=4.7%±2.2, MEX 300 mg=−2.4%±2.3, MEX 600 mg=0.8%±2.2, p=0.039). Dose-dependent reductions of the MEP amplitude was evident at 4 weeks (ratio [95% CI]: placebo=1.308 [0.249 to 0.965], MEX 300 mg=0.589 [0.315 to 1.102], MEX 600 mg=0.490 [0.249 to 0.965], p=0.013). Accommodation half-time was significantly reduced over 4 weeks with MEX (mean±SE: placebo=5.4ms±2.1, MEX 300 mg=−2.6ms±2.1, MEX 600 mg=−1.2ms±2.3, p=0.002). Conclusions: 20% of ALS subjects demonstrated cortical inexcitability by TMS at screening, comparable to other recent studies. The reduction of RMT by MEX was unexpected but could result from motor neurons recovering from depolarization block as well as unaccounted medications influencing TMS. The change in MEP amplitude supports a reduction of cortical hyperexcitability by MEX therapy in ALS. The change in accommodation halftime supports reduced excitability of peripheral motor nerve axons with treatment. The study was underpowered due to significant challenges with recruitment and further study is warranted. Disclosure: Dr. Weiss has received research support from ALS Association and ALS Finding a Cure. Yes - DSMB member for Shire Human Genetic Therapys and for Novartis, Steering Committee member for a Biogen trial, advisory board member for Cerevance, Intrance, and Inventram Yes - My institution received research funding on my behalf from Amylyx Pharmaceuticals, GlaxoSmithKline, Mitsubishi Tanabe Pharma AmericaDr. McIlduff has nothing to disclose. Dr. Vucic has nothing to disclose. Dr. Wainger has nothing to disclose. Dr. Kiernan has nothing to disclose. Yes - scientific advisory for Biogen, IFT PharmaYes - Speaking: CSL Behring Scientific Advisory boards in the past year: MT Pharma, Alexion, Genzyme/Sanofi, Sarepta, ArgenyxDr. Rutkove has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myolex, Biogen, Axcella Health, Merck. Dr. Rutkove has received personal compensation in an editorial capacity for Annals of Neurology. Dr. Rutkove has received compensation for serving on the Board of Directors of Myolex, Inc. Dr. Rutkove holds stock and/or stock options in Myolex, Inc. Yes - Amylyx Advisory BoardDr. Chen has nothing to disclose. Dr. Harms has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi, and Maze Therapeutics. Dr. Harms has received research support from Biogen. Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Grifols, Ionis, Akcea, Alnylam, Shire, and CSL Behring. Dr. Brannagan has received research support from Ionis, Alnylam, Viromed, Catalyst, Pharnext, Flexpharma, Novartis, Grifols. Dr. Lacomis has nothing to disclose. Dr. Zivkovic has nothing to disclose. Dr. Ma has nothing to disclose. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Argenx.. Dr. Wang holds stock and/or stock options in GWPH, Spark Therapeutics. Dr. Wang has received research support from Fulcrum Therapeutic. Dr. Simmons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biohaven, Biogen, Cytokinetics.. Dr. Simmons has received personal compensation in an editorial capacity for Muscle & Nerve. Dr. Simmons has received research support from Biogen, Biohaven, Cytokinetics, Genzyme, Mallinckrodt, .Dr. Rivner has nothing to disclose. Yes - I received personal compensation from Cytokinetics, Avexis, Revalasio, Biohaven, Neurosense, MTPA, and Otsuka, for consulting regarding design of ALS trials Yes - I received personal compensation for serving as neuromuscular section editor for UpToDate. Yes - Research support received from Cytokinetics, Biogen, Brainstorm, MTPA, Amylyx.Dr. Cudkowicz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with takeda, biogen, cytokinetics, sunovian, immunitypharm, avexis.Dr. Atassi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, GSK, MT Pharma, and Neuropore Therapies.

BACKGROUND:To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. METHODS:Twenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). RESULTS:RMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine. CONCLUSIONS:The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Introduction Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). Methods DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P <= .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P <= .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. Discussion Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

OBJECTIVE To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized myasthenia gravis (MG) patients. METHODS This study is a post hoc analysis of data from the randomized trial of thymectomy in myasthenia gravis (MGTX). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone versus prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100mg on alternate-days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone, was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS MG patients in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, P<0.001) over the 5-year study period. Prednisone associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS Thymectomy benefits MG patients by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. TRIAL REGISTRATION The trial was registered on clinicaltrials.gov, number NCT00294658Classification of Evidence: This study provides Class II evidence that for generalized MG patients with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.