Namita Goyal

Treatment of sporadic inclusion body myositis with bimagrumab

Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Conclusions: Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.

Electrical impedance myography as a biomarker to assess ALS progression

Abstract Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

Electrical impedance myography correlates with standard measures of ALS severity.

Introduction: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. Methods: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale‐Revised (ALSFRS‐R) score, and motor unit number estimation (MUNE). Results: Moderate strength correlations between EIM parameters and HHD were observed for both whole‐body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS‐R upper and lower extremity subscores, but not total ALSFRS‐R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. Conclusions: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS. Muscle Nerve 49:441–443, 2014

Improving electrophysiologic and histologic outcomes by photochemically sealing amnion to the peripheral nerve repair site

BACKGROUND The surgical approach used today in the repair of peripheral nerve injuries rarely achieves full functional recovery. This study determines whether isolation of the nerve repair site using photochemical tissue bonding (PTB) in combination with human amniotic membrane can improve both functional and histologic recovery. METHODS New Zealand white rabbits (n = 24) underwent transection of the right common peroneal nerve. Epineural nerve repair was performed using 10-0 nylon sutures. The repair site was then wrapped in a cuff of human amniotic membrane, which either was secured with sutures or sealed using PTB. Standard neurorrhaphy alone was assessed as a control group. Functional recovery was recorded at 30-day intervals postoperatively by electrophysiologic assessment. At 120 days, animals were killed humanely and nerves harvested for histomorphometry. RESULTS Nerves treated with amnion wraps and sealed with PTB demonstrated a statistically significant improvement across both functional and histologic parameters. Functional recovery, as measured by repeated electrophysiologic studies over time, revealed a 26.2% improvement over standard neurorrhaphy alone (P < .05). Nerves treated with PTB-sealed amnion wraps had significantly greater (P < .001) axon (5.08 +/- 1.06 microm) and fiber diameters (7.46 +/- 1.37 microm), as well as myelin thickness (2.39 +/- 0.7 microm) and the g ratio (axon diameter/fiber diameter ratio; 0.68 +/- 0.07) distal to the repair site compared to standard neurorrhaphy alone (4.98 +/- 1.81 microm, 6.77 +/- 1.94 microm, 1.79 +/- 0.42 microm, and 0.71 +/- 0.09, respectively). CONCLUSION Isolation of the repair site using a photochemically sealed amnion wrap improves electrophysiologic and histologic recovery compared to standard suture neurorrhaphy.

An overview of polymyositis and dermatomyositis

Polymyositis and dermatomyositis are inflammatory myopathies that differ in their clinical features, histopathology, response to treatment, and prognosis. Although their clinical pictures differ, they both present with symmetrical, proximal muscle weakness. Treatment relies mainly upon empirical use of corticosteroids and immunosuppressive agents. A deeper understanding of the molecular pathways that drive pathogenesis, careful phenotyping, and accurate disease classification will aid clinical research and development of more efficacious treatments. In this review we address the current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of polymyositis and dermatomyositis. Muscle Nerve 51:638–656, 2015

Experimental trials in amyotrophic lateral sclerosis: a review of recently completed, ongoing and planned trials using existing and novel drugs

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects roughly 2 subjects per 100,000 in the United States; however, given the rapid decline and mortality, there are low prevalence rates. Although ALS is considered a single disease, it, in truth, probably represents a series of disorders with different clinical patterns and different pathophysiologic mechanisms that eventually coalesce into a single entity. The challenge has been to target these different pathophysiologic abnormalities, and so far, most drug studies have focused on only one or two different pathways. Over 50 well-designed clinical trials have been conducted in ALS over the last 25 years and with the exception of the Riluzole trial, all have failed. Areas covered: In this review, the authors highlight some of the recently concluded, ongoing or planned Phase II and Phase III studies in ALS. Furthermore, they summarize the progress in the recently initiated stem-cell therapy trials in ALS. Expert opinion: The challenge remains for developing effective targeted therapeutic interventions for ALS. However, with improved recognition of the complex interplay of several factors that may contribute to ALS pathogenesis, in addition to improved patient selection criteria, outcome measures and biomarkers for drug development, advancements may be made in the future.

Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement

Objectives To explore phenotypic differences between individuals with sporadic inclusion body myositis (sIBM) who are seropositive for the NT5c1A antibody compared with those who are seronegative. Methods Cross-sectional clinical, serological and functional analysis in 25 consecutive participants with sIBM. Results All participants met criteria for clinically defined or probable sIBM. 18 of 25 participants with sIBM (72%) were seropositive for the NT5c1A antibody. No differences between median age and duration of illness between the two groups were seen. Females have higher odds of being seropositive (OR=2.30). Participants with seropositive sIBM took significantly longer to get up and stand (p=0.012). There were no significant differences between the two groups in terms of distance covered on a 6 min walk. Seropositive participants were more likely to require assistive devices such as a walker or wheelchair for mobility (OR=23.00; p=0.007). A number of secondary (exploratory) outcomes were assessed. NT5c1A seropositive sIBM cases had lower total Medical Research Council (MRC) sum score and MRC sum score on the right (p=0.03 and 0.02, respectively). Participants with the NT5c1A antibody were significantly more likely to have symptoms of dysphagia (OR=10.67; p=0.03) and reduced forced vital capacity (p=0.005). Facial weakness occurred in 50% of seropositive participants while it was only seen in 14% of seronegative participants. Conclusions Even though the small sample size limits definite conclusions, our cross-sectional study showed seropositivity to the NT5c1A antibody is associated with greater motor and functional disability in sIBM. The study also suggests more prominent bulbar, facial and respiratory involvement in individuals positive for NT5c1A antibodies.

Electrical impedance myography in Duchenne muscular dystrophy and healthy controls: A multicenter study of reliability and validity.

Introduction: Electrical impedance myography (EIM) is a non‐invasive, painless, objective technique to quantify muscle pathology. Methods: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3–12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6‐minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand‐held dynamometry). Results: EIM was well tolerated and had good inter‐ and intrarater reliability (intraclass correlation coefficient 0.81–0.96). The averaged EIM phase value from all muscles was higher (P < 0.001) in controls (10.45 ± 2.29) than boys with DMD (7.31 ± 2.23), and correlated (P ≤ 0.001) with 6MWD (r = 0.55), NSAA (r = 0.66), TFTs (r = –0.56), and strength (r = 0.44). Conclusion: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted. Muscle Nerve 52: 592–597, 2015

A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody–positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4–12 prednisone AUDTC when compared to placebo (difference MTX − placebo: −488.0 mg, 95% confidence interval −2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. Classification of evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

Respiratory and Nutritional Support in Amyotrophic Lateral Sclerosis

Opinion statementAmyotrophic lateral sclerosis (ALS) is an uncommon and almost invariably fatal neurodegenerative disease. There is no known cure for ALS, and only one disease-modifying therapy is currently approved. In the absence of robust pharmacologic treatment options, the value of nutritional and respiratory support in the management of the disease should not be underestimated. The primary causes of morbidity and mortality in ALS are complications from dysphagia, leading to malnutrition and respiratory insufficiency, and these require focused therapeutic attention. This article reviews the current evidence for nutritional and respiratory support in the management of ALS patients.