Effect of efgartigimod on muscle group subdomains in participants with generalized myasthenia gravis: post hoc analyses of the phase 3 pivotal ADAPT study.

BACKGROUND AND PURPOSE: Generalized myasthenia gravis (gMG) is a rare, chronic, neuromuscular autoimmune disease mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Patients with gMG experience debilitating muscle weakness, resulting in impaired mobility, speech, swallowing, vision and respiratory function. Efgartigimod is a human IgG1 antibody Fc fragment engineered for increased binding affinity to neonatal Fc receptor. The neonatal Fc receptor blockade by efgartigimod competitively inhibits endogenous IgG binding, leading to decreased IgG recycling and increased degradation resulting in lower IgG concentration. METHODS: The safety and efficacy of efgartigimod were evaluated in the ADAPT study. Key efficacy outcome measures included Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Efgartigimod demonstrated significant improvement in both the MG-ADL and QMG scores. This post hoc analysis aimed to determine whether all subdomains of MG-ADL and QMG improved with efgartigimod treatment. Individual items of MG-ADL and QMG were grouped into four subdomains: bulbar, ocular, limb/gross motor and respiratory. Change from baseline over 10 weeks in each subdomain was calculated for each group. RESULTS: Greater improvements from baseline were seen across MG-ADL subdomains in participants treated with efgartigimod compared with placebo. These improvements were typically observed 1 to 2 weeks after the first infusion and correlated with reductions in IgG. Similar results were observed across most QMG subdomains. CONCLUSIONS: These post hoc analyses of MG-ADL and QMG subdomain data from ADAPT suggest that efgartigimod is beneficial in improving muscle function and strength across all muscle groups, leading to the observed efficacy in participants with gMG.

Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

A retrospective survey of patients with hereditary transthyretin-mediated (hATTR) amyloidosis treated with patisiran in real-world clinical practice in Belgium.

INTRODUCTION: Hereditary transthyretin-mediated (hATTR) amyloidosis, a genetic disease caused by mutations in the transthyretin gene, leads to progressive sensory and autonomic neuropathy and/or cardiomyopathy and is associated with renal and ophthalmologic manifestations and a poor prognosis. METHODS: This is a retrospective study based on data collected from the medical records of patients with hATTR amyloidosis treated with patisiran between 01 July 2018 and 01 February 2021. Six Belgian neuromuscular reference centers participated, covering all patisiran-treated hATTR amyloidosis patients at the study time. This study was conducted to collect data requested in the context of the reimbursement of patisiran in Belgium. RESULTS: Thirty-one patients were diagnosed with hATTR amyloidosis with polyneuropathy, Coutinho stage 1 or 2, and eligible for active treatment during the data collection period. Of the hATTR amyloidosis patients treated with patisiran (n = 12), seven and five had polyneuropathy stages 1 and 2, respectively. Six patients had cardiac symptoms (New York Heart Association class 2 or above). Follow-up information was available for nine patients. Following patisiran treatment, eight patients showed stable or improved assessments for most neurological or cardiological parameters. Only one patient presented with worsening statuses at the end of the data collection period. CONCLUSIONS: The patients with hATTR amyloidosis in Belgium have similar baseline demographics and disease characteristics to those studied in the patisiran APOLLO study and show a similar therapeutic response in the real-world, altering the expected disease progression in most patients.

Risk of malignant hyperthermia in patients carrying a variant in the skeletal muscle ryanodine receptor 1 gene.

Malignant hyperthermia is a life-threatening disorder, which can be prevented by avoiding certain anesthetic agents. Pathogenic variants in the skeletal muscle ryanodine receptor 1-gene are linked to malignant hyperthermia. We retrospectively studied 15 patients who presented to our clinic with symptoms of muscle dysfunction (weakness, myalgia or cramps) and were later found to have a variant in the skeletal muscle ryanodine receptor 1-gene. Symptoms, creatine kinase levels, electromyography, muscle biopsy and in vitro contracture test results were reviewed. Six out of the eleven patients, with a variant of unknown significance in the skeletal muscle ryanodine receptor 1-gene, had a positive in vitro contracture test, indicating malignant hyperthermia susceptibility. In one patient, with two variants of unknown significance, both variants were required to express the malignant hyperthermia-susceptibility trait. Neurologists should consider screening the skeletal muscle ryanodine receptor 1-gene in patients with myalgia or cramps, even when few to no abnormalities on ancillary testing.

Unraveling the Molecular Basis of the Dystrophic Process in Limb-Girdle Muscular Dystrophy LGMD-R12 by Differential Gene Expression Profiles in Diseased and Healthy Muscles.

Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), moderately (vastus lateralis) or mildly (rectus femoris) affected in this disease. We performed transcriptomics on these three muscles in 16 male LGMD-R12 patients and 15 age-matched male controls. Our results showed that LGMD-R12 dystrophic muscle is associated with the expression of genes indicative of fibroblast and adipocyte replacement, such as fibroadipogenic progenitors and immune cell infiltration, while muscle protein synthesis and metabolism were downregulated. Muscle degeneration was associated with an increase in genes involved in muscle injury and inflammation, and muscle repair/regeneration. Baseline differences between muscles in healthy individuals indicated that muscles that are the most affected by LGMD-R12 have the lowest expression of transcription factor networks involved in muscle (re)generation and satellite stem cell activation. Instead, they show relative high levels of fetal/embryonic myosins, all together indicating that muscles differ in their baseline regenerative potential. To conclude, we profiled the gene expression landscape in LGMD-R12, identified baseline differences in expression levels between differently affected muscles and characterized disease-associated changes.

Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients.

In the second most common dystrophy associated with predominant pelvic and shoulder girdle muscle weakness termed Limb-Girdle Muscular Dystrophy (LGMD), genetic complexity, large phenotypic variability, and clinical overlap can result in extensive diagnostic delays in certain individuals. In view of the large strides genetics has taken in this day and age, we address the question if muscle biopsies can still provide diagnostic evidence of substance for these patients. We reviewed and reanalyzed muscle biopsy characteristics in a cohort of LGMD patient pairs in which gene variants were picked up in CAPN3, FKRP, TTN, and ANO5, using histochemical-immunohistochemical-and immunofluorescent staining, and western blotting. We found that not the nature and severity of inflammatory changes, but the changed properties of the dystrophin complex were the most valuable assets to differentiate LGMD from myositis. Proteomic evaluation brought both primary and secondary deficiencies to light, which could be equally revealing for diagnosis. Though a muscle biopsy might, at present, not always be strictly necessary anymore, it still represents an irrefutable asset when the genetic diagnosis is complicated.

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. METHODS: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). RESULTS: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. CONCLUSIONS: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.

Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis. METHODS: We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry. This trial is registered with ClinicalTrials.gov, number NCT01925209; this report represents the final analysis. FINDINGS: Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab. INTERPRETATION: Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months. FUNDING: Novartis Pharma.

Idiopathic inflammatory myopathy: Interrater variability in muscle biopsy reading.

OBJECTIVE: To determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis. METHODS: We developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome-related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains. RESULTS: Despite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features. CONCLUSION: The assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.

INTRODUCTION: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. METHODS: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. RESULTS: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). DISCUSSION: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.

Seronegative patients form a distinctive subgroup of immune-mediated necrotizing myopathy.

Objectives: To investigate the characteristics of different clinico-serologic subgroups of immune-mediated necrotizing myopathy (IMNM). Methods: We retrospectively reviewed data from medical charts of 64 patients diagnosed with IMNM between 2012 and 2017 in 3 neuromuscular referral centers in The Netherlands and 1 in Belgium. Results: Seventeen patients had anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies (Abs), of whom 11 had a history of statin use, 15 had anti-signal recognition particle (SRP) Abs, 2 had anti-melanoma differentiation-associated protein 5 (MDA5) Abs, 22 patients were seronegative, and 9 patients did not have a complete Ab assessment. Moderate to severe disability in HMGCR Ab-positive and anti-SRP Ab-positive IMNM was common (71% and 60%, respectively) despite multimodality treatment. Compared with statin-associated anti-HMGCR Ab-positive IMNM, statin-naive anti-HMGCR Ab-positive IMNM patients were more often men (67% vs 45%), had lower rates of dysphagia (17% vs 45%), and more frequently had third-line therapy (50% vs 9%) and poor to fatal outcome (50% vs 0%). Compared with seropositive IMNM, seronegative IMNM was characterized by female predominance (1:3), frequent occurrence of associated connective tissue disorders (22% vs 9%), and significantly higher rates of extramuscular disease activity (50% vs 16%, p 0.014; 2-sided Fisher exact), also after excluding patients with an associated connective tissue disease (35% vs 7%, p 0.038; 2-sided Fisher exact). Conclusions: Our findings indicate that seronegative IMNM forms a subgroup with distinctive features from seropositive IMNM.

Single-centre experience on transthyretin familial amyloid polyneuropathy: case series and literature review.

Familial amyloid polyneuropathy (FAP) is a most often length-dependent axonal neuropathy, often part of a multisystem disorder also affecting other organs, such as cardiac, gastrointestinal, genitourinary, renal, meningeal and eye tissue. It is most frequently the result of a mutation in the TTR gene, most commonly a p.Val50Met mutation. TTR-FAP is a rare autosomal dominant heritable disabling, heterogeneous disease in which early diagnosis is of pivotal importance when attempting treatment. This paper discusses the course of four Belgian FAP patients with different TTR mutations (p.Val48Met; p.Val52Ala; p.Ala59Val; p.Val50Met). We also review the diagnosis and differential diagnosis of TTR-FAP, diagnostic studies, follow-up, its current treatment and those in development, prognosis and the importance of genetic counseling. At first, TTR-FAP is often misdiagnosed as a chronic inflammatory demyelinating polyneuropathy or chronic idiopathic axonal polyneuropathy. Genetic testing is obligatory to confirm the diagnosis of TTR-FAP, except in familial cases. Biopsy samples are an asset in diagnosing TTR-FAP but can be falsely negative. At the moment, tafamidis meglumine is considered as first-line treatment in stage I neurological disease. Patients eligible for liver transplantation should be carefully selected when first-line therapy fails.

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism.

Alongside well-known nuclear factor κB (NFκB) and its associated cytokine networks, nuclear factor of activated T cells 5 (NFAT5), the master regulator of cellular osmoprotective programs, comes forward as an inflammatory regulator. To gain insight into its yet unexplored role in muscle disease, we studied the expression of NFAT5 target proteins involved in osmolyte accumulation: aldose reductase (AR), taurine transporter (TauT), and sodium myo-inositol co-transporter (SMIT). We analyzed idiopathic inflammatory myopathy and Duchenne muscular dystrophy muscle biopsies and myotubes in culture, using immunohistochemistry, immunofluorescence, and western blotting. We report that the level of constitutive AR was upregulated in patients, most strongly so in Duchenne muscular dystrophy. TauT and SMIT expression levels were induced in patients' muscle fibers, mostly representing regenerating and atrophic fibers. In dermatomyositis, strong staining for AR, TauT, and SMIT in atrophic perifascicular fibers was accompanied by staining for other molecular NFAT5 targets, including chaperones, chemokines, and inducible nitric oxide synthase. In these fibers, NFAT5 and NFκB p65 staining coincided, linking both transcription factors with this important pathogenic hallmark. In sporadic inclusion body myositis, SMIT localized to inclusions inside muscle fibers. In addition, SMIT was expressed by a substantial subset of muscle-infiltrating macrophages and T cells in patient biopsies. Our results indicate that osmolyte pathways may contribute to normal muscle functioning, and that activation of AR, TauT, and SMIT in muscle inflammation possibly contributes to the tissue's failing program of damage control.

Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed.

Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy.

Familial amyloid polyneuropathy (FAP) is a progressive systemic autosomal dominant disease caused by pathogenic mutations in the transthyretin (TTR) gene. We studied clinical, electrophysiological, histopathological, and genetic characteristics in 15 (13 late-onset and two early-onset) patients belonging to 14 families with polyneuropathy and mutations in TTR. In comparison, we analysed the features of nine unrelated patients with an idiopathic polyneuropathy, in whom TTR mutations have been excluded. Disease occurrence was familial in 36 % of the patients with TTR-associated polyneuropathy and the late-onset type was observed in 86 % (mean age at onset 65.5 years). Clinically, all late-onset TTR-mutant patients presented with distal weakness, pansensory loss, absence of deep tendon reflexes, and sensorimotor hand involvement. Afferent-ataxic gait was present in 92 % leading to wheelchair dependence in 60 % after a mean duration of 4.6 years. Autonomic involvement was observed in 60 %, and ankle edema in 92 %. The sensorimotor polyneuropathy was from an axonal type in 82 %, demyelinating or mixed type in 9 % each. Compared to the TTR-unmutated idiopathic polyneuropathy patients, we identified rapid progression, early ambulatory loss, and autonomic disturbances, associated with a severe polyneuropathy as red flags for TTR-FAP. In 18 % of the late-onset TTR-FAP patients, no amyloid was found in nerve biopsies. Further diagnostic pitfalls were unspecific electrophysiology, and coincident diabetes mellitus (23 %) or monoclonal gammopathy (7 %). We conclude that a rapid disease course, severely ataxic gait, hand involvement, and autonomic dysfunction are diagnostic hallmarks of late-onset TTR-FAP. Genetic analysis should be performed even when amyloid deposits are lacking or when polyneuropathy-causing comorbidities are concomitant.