Patient- and caregiver-reported impact of symptoms in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: To better understand the disease burden faced by individuals with Duchenne muscular dystrophy (DMD) of all ages and elucidate potential targets for therapeutics, this study determined the prevalence and relative importance of symptoms experienced by individuals with DMD and identified factors associated with a higher disease burden. METHODS: We conducted qualitative interviews with individuals with DMD and caregivers of individuals with DMD to identify potential symptoms of importance to those living with DMD. We subsequently performed a cross-sectional study to assess which symptoms have the highest prevalence and importance in DMD and to determine which factors are associated with a higher disease burden. RESULTS: Thirty-nine individuals, aged 11 years and above, provided 3262 quotes regarding the symptomatic burden of DMD. Two hundred participants (87 individuals with DMD and 113 caregivers) participated in a subsequent cross-sectional study. Individuals with DMD identified limitations with mobility or walking (100%), inability to do activities (98.9%), trouble getting around (97.6%), and leg weakness (97.6%) as the most prevalent and life altering symptomatic themes in DMD. The symptomatic themes with the highest prevalence, as reported by caregivers on behalf of those with DMD for whom they care, were limitations with mobility or walking (90.3%), leg weakness (89.2%), and emotional issues (79.6%). Steroid/glucocorticoid use (e.g., prednisone or deflazacort) was associated with a lower level of disease burden in DMD. DISCUSSION: There are many symptomatic themes that contribute to disease burden in individuals with DMD. These symptoms are identified by both individuals with DMD and their caregivers and have a variable level of importance and prevalence in the DMD population.

Racial and Ethnic Differences in Timing of Diagnosis and Clinical Services Received in Duchenne Muscular Dystrophy.

INTRODUCTION: Racial/ethnic differences in diagnostic and treatment services have been identified for a range of health conditions and outcomes. The current study aimed to analyze whether there are racial/ethnic differences in the timing of diagnostic testing and treatments for males with Duchenne muscular dystrophy (DMD). METHODS: Diagnostic and clinical data for male individuals with DMD born during 1990-2010 were analyzed from eight sites (Arizona, Colorado, Georgia, Iowa, Piedmont Region of North Carolina, Western New York, South Carolina, and Utah) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Seven milestones related to diagnosis/treatment experiences were selected as outcomes. Times to each milestone were estimated and compared by four racial/ethnic groups using Kaplan-Meier estimation and Cox proportional-hazards models. Times between initial evaluation or diagnostic testing and later milestones were also compared by race/ethnicity. RESULTS: We identified 682 males with definite or probable DMD of whom 61.7% were non-Hispanic white, 20.5% Hispanic, 10.6% other, and 7.2% non-Hispanic black. Seven milestone events were studied (initial evaluation, first neurology/neuromuscular visit, diagnosis, corticosteroid treatment first offered, corticosteroid treatment started, first electrocardiogram or echocardiogram, and first pulmonary function test). The first five milestone events occurred at an older age for non-Hispanic black individuals compared to non-Hispanic white individuals. Time to first offering of corticosteroids and initiation of corticosteroid therapy was later for Hispanic individuals compared to non-Hispanic white individuals. When accounting for timing of initial evaluation/diagnosis, offering of corticosteroids continued to occur later, but first pulmonary testing occurred earlier, among Hispanic individuals compared to non-Hispanic whites. No significant delays remained for non-Hispanic black individuals after accounting for later initial evaluation/diagnosis. CONCLUSION: We described racial/ethnic differences in ages at selected diagnostic and treatment milestones. The most notable differences were significant delays for five of seven milestones in non-Hispanic black individuals, which appeared to be attributable to later initial evaluation/diagnosis. Findings for Hispanic individuals were less consistent. Efforts to address barriers to early evaluation and diagnosis for non-Hispanic black children with DMD may promote more timely initiation of recommended disease monitoring and interventions.

Time to diagnosis of Duchenne muscular dystrophy remains unchanged: Findings from the Muscular Dystrophy Surveillance, Tracking, and Research Network, 2000-2015.

INTRODUCTION/AIMS: With current and anticipated disease-modifying treatments, including gene therapy, an early diagnosis for Duchenne muscular dystrophy (DMD) is crucial to assure maximum benefit. In 2009, a study from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) showed an average diagnosis age of 5 years among males with DMD born from January 1, 1982 to December 31, 2000. Initiatives were implemented by the US Centers for Disease Control and Prevention (CDC) and patient organizations to reduce time to diagnosis. We conducted a follow-up study in a surveillance cohort born after January 1, 2000 to determine whether there has been an improvement in time to diagnosis. METHODS: We assessed the age of diagnosis among males with DMD born from January 1, 2000 to December 31, 2015 using data collected by six US MD STARnet surveillance sites (Colorado, Iowa, western New York State, the Piedmont region of North Carolina, South Carolina, and Utah). The analytic cohort included 221 males with definite or probable DMD diagnosis without a documented family history. We computed frequency count and percentage for categorical variables, and mean, median, and standard deviation (SD) for continuous variables. RESULTS: The mean [median] ages in years of diagnostic milestones were: first signs, 2.7 [2.0]; first creatine kinase (CK), 4.6 [4.6]; DNA/muscle biopsy testing, 4.9 [4.8]; and time from first signs to diagnostic confirmation, 2.2 [1.4]. DISCUSSION: The time interval between first signs of DMD and diagnosis remains unchanged at 2.2 years. This results in lost opportunities for timely genetic counseling, implementation of standards of care, initiation of glucocorticoids, and participation in clinical trials.

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Time is muscle: A recommendation for early treatment for preterm infants with spinal muscular atrophy.

Implementation of newborn screening for spinal muscular atrophy (SMA) in 33 US states and increased genetic carrier screening have led to an increase in early, presymptomatic diagnosis of SMA. Early treatment is critically important and is recommended for presymptomatic infants with two to four copies of survival motor neuron 2. Currently, no specific treatment recommendations exist for preterm infants with SMA. The US Food and Drug Administration does not recommend using onasemnogene abeparvovec-xioi in preterm infants. Some insurance companies interpret "preterm" to be less than 40 weeks gestational age (GA) instead of the commonly accepted 37 weeks GA, which can be a barrier to treatment access. Given the risk of rapid decline in some infants, we recommend treatment of preterm infants when they reach 37 weeks GA, based on the definitions of term GA from the World Health Organization and Centers for Disease Control and Prevention, assuming all other treatment criteria are met.

Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.

INTRODUCTION/AIM: Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP). METHODS: Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies. RESULTS: Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], -1.00 [P < .0001]; placebo/DCP [n = 20], -0.63 [P = .01] and DCP/DCP, -2.25 [P < .0001]; placebo/DCP, -1.69 [P = .01]). Relatively smaller median decreases in weekly attack and severity-weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; -0.14 [P = .1] and -0.24 [P = .09]) than among those switching from placebo to DCP after 9 weeks (n = 16; -1.04 [P = .049] and -2.72 [P = .08]). Common adverse events (AEs) were paresthesia and cognition-related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution. DISCUSSION: One-year open-label DCP treatment after a 9-week randomized, controlled study confirmed long-term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition-related AEs) were manageable in most patients.

The Spinal Muscular Atrophy Health Index: A novel outcome for measuring how a patient feels and functions.

INTRODUCTION: The Spinal Muscular Atrophy Health Index (SMA-HI) is a multifaceted, disease-specific, patient-reported outcome to measure an SMA patient's perception of their disease burden. In preparation for upcoming therapeutic trials, we examine the validity, reliability, and usability of the SMA-HI in adults, teenagers, and children with SMA. METHODS: Using data from a cross-sectional study of 359 international adult patients with SMA, we identified the most relevant symptoms to include in the SMA-HI. We utilized factor analysis, patient interviews with adults and minors (age 8-15 years), known-group validity testing, and test-retest reliability assessments to evaluate and refine the SMA-HI. RESULTS: The SMA-HI measures overall disease burden and 15 areas of SMA health. Fifteen adult patients and five patients, age 8 to 15 years, participated in semistructured qualitative interviews and found the SMA-HI to be comprehensive, easily completed, and to have clear meaning. The final SMA-HI and its subscales demonstrated good internal consistency (Cronbach α = 0.77-0.96), high test-retest reliability (intraclass correlation coefficient = 0.60-0.96), and an ability to differentiate between SMA groups with different disease severities affecting areas such as employment and ambulation (P < .0001 for both). DISCUSSION: This research provides evidence that the SMA-HI is a valid, relevant, and reliable outcome measure to assess multifaceted patient-reported disease burden in older children, teenagers, and adults with SMA. The SMA-HI provides an opportunity for researchers and clinicians to measure a SMA patient's perception of their health and determine relevant changes in response to therapeutic intervention or disease progression.

Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.

BACKGROUND: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. METHODS: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. CONCLUSIONS: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.

Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy.

PURPOSE: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018. METHODS: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion. RESULTS: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy. CONCLUSION: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

Spinal muscular atrophy and Farber disease due to ASAH1 variants: A case report.

Genetic variations in the ASAH1 gene are associated with a spectrum of disorders ranging from Farber disease (FD) to spinal muscular atrophy with or without progressive myoclonic epilepsy (SMA-PME). FD presents most commonly in infants with subcutaneous joint nodules, progressive arthritis and granulomas of the larynx and epiglottis leading to a hoarse cry. SMA-PME is characterized by childhood onset progressive weakness due to motor neuron disease followed by progressive epilepsy, tremor, and sensorineural hearing loss. We present a case of a 4-year-old boy with phenotypic features of both FD and SMA who was found to have two previously unreported heterozygous variants in the ASAH1 gene.

Myasthenia gravis patient and physician opinions about immunosuppressant reduction.

INTRODUCTION: To reduce myasthenia gravis (MG) patient risk of immunosuppressant (IS) exposure adverse events (AEs), such as infections and malignancies, and to reduce treatment burden, international guidelines recommend decreasing IS dose in stable MG patients. METHODS: Online surveys were conducted of self-identified MG patients and MG physician experts about the importance of IS dose reduction for MG patients who achieve prolonged periods of disease stability. RESULTS: Eighty-four percent of MG patients (n = 283) and 100% of physicians (n = 45) were concerned about long-term IS-associated AEs. Although both groups favored attempting IS reduction, they raised concerns including MG relapse, hospitalization, and uncertainty about the future. Presented with an estimated 12% significant relapse rate with IS dose reduction, 76% of patients would be willing to enroll in a randomized IS dose reduction trial. DISCUSSION: Patients and physicians favor considering IS dose reduction but are also concerned about potential negative sequelae.

Nusinersen for older patients with spinal muscular atrophy: A real-world clinical setting experience.

INTRODUCTION: Clinical trials data concerning use of nusinersen in older spinal muscular atrophy (SMA) patients is lacking. We describe our center's experience in using intrathecal nusinersen for older patients in the clinical setting. METHODS: Retrospective study. RESULTS: Twelve patients (12-52 years old) were treated with nusinersen. Mean follow-up duration was 17.4 months (range, 4-26 months). All patients had scoliosis; 10 had spinal fusion/instrumentation. All procedures (30 cervical and 57 lumbar punctures) were technically successful. The only side effects were postprocedural headache (9%) and site pain (5.7%). Functional assessments showed stability in 6/9 patients and improvement in 3/9 patients. Subjective improvements in endurance, hand strength, and bulbar functioning critical for activities of daily living were reported in 8/12 patients. None of the patients has discontinued treatment so far. DISCUSSION: Intrathecal nusinersen can be safely delivered in older SMA patients. Available functional outcome measures are not adequate to capture meaningful subjective improvements.

The care of patients with Duchenne, Becker, and other muscular dystrophies in the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in the reorganization of health-care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon-skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health-care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth.

Spinal muscular atrophy care in the COVID-19 pandemic era.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19.

Validation of the Italian version of the Charcot-Marie-Tooth Health Index.

The Charcot-Marie-Tooth Health Index (CMT-HI) is a disease-specific patient-reported outcome measure measuring overall disease burden in Charcot-Marie-Tooth (CMT) patients, designed for natural history studies and clinical trials in English-speaking affected individuals. We developed and validated its Italian Charcot-Marie-Tooth Health Index (I-CMT-HI) version. The questionnaire was translated and culturally adapted from source into Italian by two neurologists experienced in CMT and neuromuscular disorders (NMDs). The two translations were reviewed by a panel of seven experts in CMT and NMD. The provisional version was back-translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the panel and a patient representative from ACMT-Rete. A series of clinically and genetically characterized CMT patients completed the final questionnaire; 11 participated in a test-retest reliability assessment of the instrument. The I-CMT-HI was administered to 30 CMT patients (13 CMT1A, eight CMTX1, two CMT1B, two CMT1E, two CMT2I, one CMT2A, one CMT2N, one distal Hereditary Motor Neuropathy), with test-rest in 11:14 females and 16 males, aged (mean ± SD) 48.0 ± 16.4 years (range 18-81), with CMT Examination Score (CMTES) = 10.0 ± 4.4 (range 2-18). The I-CMT-HI mean total score was 29.4 ± 21.2 (range 0.1-60.3). The I-CMT-HI showed a high test-retest reliability: intraclass correlation coefficient = 0.95 (95% confidence interval, 0.84-0.99). No patient had difficulty in completing the questionnaire and none reported any problem with the questions' formulation. The total CMT-HI score was positively correlated with age and CMTES, with higher disease burden with increasing age and disease severity according to the CMTES. The I-CMT-HI is now ready for use in clinical studies in the Italian population.

Left ventricular dysfunction in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction. METHODS AND RESULTS: Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed between 1 January, 1982 and 31 December, 2011, were identified from the Muscular Dystrophy Surveillance Tracking and Research Network database. Two non-mutually exclusive groups were created: patients with ≥2 echocardiograms and non-invasive positive pressure ventilation-compliant patients with ≥1 recorded ejection fraction. Quantitative left ventricular dysfunction was defined as an ejection fraction <55%. Qualitative dysfunction was defined as mild, moderate, or severe. Progression of quantitative left ventricular dysfunction was modelled as a continuous time-varying outcome. Change in qualitative left ventricle function was assessed by the percentage of patients within each category at each age. Forty-one percent (n = 403) had ≥2 ejection fractions containing 998 qualitative assessments with a mean age at first echo of 10.8 ± 4.6 years, with an average first ejection fraction of 63.1 ± 12.6%. Mean age at first echo with an ejection fraction <55 was 15.2 ± 3.9 years. Thirty-five percent (140/403) were non-invasive positive pressure ventilation-compliant and had ejection fraction information. The estimated rate of decline in ejection fraction from first ejection fraction was 1.6% per year and initiation of non-invasive positive pressure ventilation did not change this rate. CONCLUSIONS: In our cohort, we observed that left ventricle function in patients with Duchenne muscular dystrophy declined over time, independent of non-invasive positive pressure ventilation use. Future studies are needed to examine the impact of respiratory support on cardiac function.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing.

Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20-50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the BCR repertoire of AChR-MG, MuSK-MG, and healthy subjects to generate ∼518,000 unique VH and VL sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naive and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the VH CDR and altered VH CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naive and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG, indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.

Health profile of a cohort of adults with Duchenne muscular dystrophy.

INTRODUCTION: As the Duchenne muscular dystrophy (DMD) population ages, it is essential that we understand the late-stage health profile and provide the appropriate care for this emerging population. METHODS: We undertook a descriptive study to document the health profile of a cohort of adults with DMD using data from the Muscular Dystrophy Surveillance Tracking and Research network (MD STARnet). Data included information collected from Arizona, Colorado, Iowa, Georgia, and 12 counties in western New York on individuals born since January 1982 and followed through December 2012. RESULTS: In 208 adults with DMD, the number of individuals (N) and median ages (years) at which certain critical milestones were crossed and interventions initiated were as follows: development of cardiomyopathy, N = 145 (16.7); initiation of non-invasive ventilation, N = 99 (18.0); gastrostomy, N = 47 (19.0); and death, N = 59 (21.8). DISCUSSION: These population-based data provide critical information about late-stage health profiles among adults with DMD for developing appropriate models of care. Muscle Nerve 58: 219-223, 2018.