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Valosin-containing protein (VCP)-associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP-associated MSP have myopathy, but there is no consensus-based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb-girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single-variant testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives.

BackgroundAmyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.MethodsThe Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).ResultsSMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Clinical trial registrationClinicaltrials.gov identifier NCT02573467.Classification of evidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Introduction/Aims: Motor neuron disease (MND) is a progressive neurodegenerative condition with a limited life expectancy. There is very little data on mortality and its associated factors beyond 30 days following gastrostomy. We explored the demographic, clinical, and nutritional predictors for early mortality at 30, 90, and 180 days following gastrostomy in these patients. Methods: This was a retrospective study involving 94 MND patients in Western Australia who underwent gastrostomy between 2015 and 2021. Patients were divided into two groups based on mortality at 30, 90, and 180 days post‐gastrostomy. T‐test (or Mann–Whitney), chi‐square test and Fisher's exact test were used for detecting between‐group differences in various factors. Multivariable logistic regression was used to identify factors associated with post‐gastrostomy mortality at 90 and 180 days. Results: No mortality was attributable to gastrostomy‐related complications. Lower forced vital capacity (FVC) (p =.039) and greater weight loss (%) (p =.022) from diagnosis to gastrostomy were observed in those who died within 30 days post‐gastrostomy. Older age (p =.022), male sex (p =.041), lower FVC (p =.04), requiring but not tolerating noninvasive ventilation (p =.035), and greater weight loss (%) (p =.012) were independent predictors of 90‐day post‐gastrostomy mortality. However, only older age (p =.01) and greater weight loss (p =.009) were predictors of mortality at 180 days post‐gastrostomy. Discussion: Our data indicated that mortality at 90 and 180 days was influenced by the weight loss (%) from diagnosis to gastrostomy, highlighting the importance of nutritional care in the MND population. Gastrostomy placement prior to substantial weight loss may reduce the risk of weight loss‐associated mortality and warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic inflammatory myopathies (known as 'myositis') are a group of rare sporadic inflammatory muscle disorders that significantly impact function and quality of life. There are no standardised approaches in the use of assistive technologies in myositis. This study was initiated to investigate current use and perceived value of assistive technology (AT) by people with myositis. Methods: A cross‐sectional online questionnaire (Qualtrics) was designed to capture information regarding AT use and perceived value and demographic information from people with myositis across Australia. The questionnaire was distributed via the Myositis Association of Australia and specialist myositis clinics. Participants were asked to identify which AT items they owned and how frequently the item was used and to rate the 'usefulness' of those items. Information was also collected on participants' engagement with health professionals regarding assistive technologies. Consumer and community involvement: Consumer involvement via the Myositis Research Consumer Panel identified a knowledge gap regarding AT. The questionnaire was designed with consumer input and review. Results: One hundred two people (102) with myositis completed the questionnaire. One hundred (100) participants owned at least one AT device, with a median of 12.5 items and a maximum of 65 items. The most used devices were associated with toileting, personal care and mobility. Participants rated AT devices relating to environmental support, sleeping, seating and body support as most useful. There was a positive correlation between disease duration and number of devices used (r2 = 0.248, p = 0.012). Majority of participants (75.5%) were interested in talking to health professionals about AT; however, only 50% had done so. Conclusion: AT device usage is high among people with myositis, with most items deemed to be useful. Greater occupational therapy input into recommendations and potential funding options may improve knowledge and access to AT. [ABSTRACT FROM AUTHOR]

BackgroundThere is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years.ObjectiveBased on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians' views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients.MethodsThirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus.ResultsAll 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population.ConclusionsIn the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.

Objective: Inclusion body myositis (IBM) is a progressive late‐onset muscle disease characterised by preferential weakness of quadriceps femoris and finger flexors, with elusive causes involving immune, degenerative, genetic and age‐related factors. Overlapping with normal muscle ageing makes diagnosis and prognosis problematic. Methods: We characterised peripheral blood leucocytes in 81 IBM patients and 45 healthy controls using flow cytometry. Using a random forest classifier, we identified immune changes in IBM compared to HC. K‐means clustering and the random forest one‐versus‐rest model classified patients into three immunophenotypic clusters. Functional outcome measures including mTUG, 2MWT, IBM‐FRS, EAT‐10, knee extension and grip strength were assessed across clusters. Results: The random forest model achieved a 94% AUC ROC with 82.76% specificity and 100% sensitivity. Significant differences were found in IBM patients, including increased CD8+ T‐bet+ cells, CD4+ T cells skewed towards a Th1 phenotype and altered γδ T cell repertoire with a reduced proportion of Vγ9+Vδ2+ cells. IBM patients formed three clusters: (i) activated and inflammatory CD8+ and CD4+ T‐cell profile and the highest proportion of anti‐cN1A‐positive patients in cluster 1; (ii) limited inflammation in cluster 2; (iii) highly differentiated, pro‐inflammatory T‐cell profile in cluster 3. Additionally, no significant differences in patients' age and gender were detected between immunophenotype clusters; however, worsening trends were detected with several functional outcomes. Conclusion: These findings unveil distinct immune profiles in IBM, shedding light on underlying pathological mechanisms for potential immunoregulatory therapeutic development. [ABSTRACT FROM AUTHOR]

Objectives We investigated shear wave elastography (SWE), B mode US and power Doppler (PDUS) as imaging biomarkers for longitudinal follow-up in idiopathic inflammatory myopathy (IIM), with a particular focus on immune-mediated necrotizing myopathy (IMNM) and DM. Methods Participants had serial SWE, PDUS on the deltoid (D) and vastus lateralis (VL) muscles on four occasions at intervals of 3–6 months. Clinical assessments included manual muscle testing, and patient- and physician-reported outcome scales. Results Thirty-three participants were included: IMNM = 17, DM = 12, overlap myositis = 3, PM = 1. Twenty were in a prevalent clinic group, and 13 were recently treated cases in an incident group. Differential changes in SWS and US domains occurred with time in both the prevalent and incident groups. In the VL-prevalent subgroup, echogenicity increased over time (P  = 0.040), while in the incident cases there was a trend for reduction to normal over time (P  = 0.097) with treatment. Muscle bulk reduced in the D-prevalent subgroup over time (P  = 0.096), suggesting atrophy. SWS also reduced in the VL-incident subgroup over time (P  = 0.096), suggesting a trend towards improvement in muscle stiffness with treatment. Conclusion SWE and US appear promising as imaging biomarkers for patient follow-up in IIM and indicate changes over time, especially with echogenicity, muscle bulk and SWS in the VL. Due to the limitations of the participant numbers, additional studies with a larger cohort are needed to help evaluate these US domains further and outline specific characteristics within the IIM subgroups. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated necrotising myopathy and sporadic inclusion body myositis, all of which present with variable symptoms and disease progression. The identification of effective biomarkers for IIMs has been challenging due to the heterogeneity between IIMs and within IIM subgroups, but recent advances in machine learning (ML) techniques have shown promises in identifying novel biomarkers. This paper reviews recent studies on potential biomarkers for IIM and evaluates their clinical utility. We also explore how data analytic tools and ML algorithms have been used to identify biomarkers, highlighting their potential to advance our understanding and diagnosis of IIM and improve patient outcomes. Overall, ML techniques have great potential to revolutionize biomarker discovery in IIMs and lead to more effective diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Anti–3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune‐mediated necrotising myopathy (IMNM). Aims: To determine clinical associations of anti‐HMGCR antibodies for anti‐HMGCR–associated IMNM (HMGCR‐IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity. Methods: Adult patients with positive anti‐HMGCR antibodies detected by enzyme‐linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results. Results: Among 26 patients with positive anti‐HMGCR antibodies, 23 were diagnosed with HMGCR‐IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti‐HMGCR antibody level at diagnosis was low (r = 0.04). Anti‐HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients. Conclusions: The PPV of anti‐HMGCR antibodies for HMGCR‐IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti‐HMGCR antibodies did not correlate with CK levels at diagnosis. [ABSTRACT FROM AUTHOR]