Murine toxicology assessment of avgn7.2, a novel gene therapeutic for inclusion body myositis and other muscle wasting diseases.

ObjectiveTo investigate cardiac involvement in patients with sporadic inclusion body myositis (IBM) by cardiac magnetic resonance tomography (CMR).MethodsA case series of 20 patients with IBM underwent basic cardiac assessment and CMR including functional imaging, native and contrast-enhanced T1-weighted, and late gadolinium enhancement (LGE) imaging.ResultsAll IBM patients reported no cardiac symptoms. Echocardiography was normal in 16/17 IBM patients. In CMR, IBM patients had normal ejection fractions (mean LVEF 63 ± 7%) and ventricular mass. They had reduced left (mean 55 versus 88 ml) and right ventricular stroke volumes (mean 54 versus 86 ml) and increased early myocardial enhancement (pathological T1 Ratio in 44% versus 5%), as compared to age- and gender-matched controls. Since arterial hypertension was more often observed in IBM patients, hypertensive heart disease can also be causative for these changes. Late gadolinium enhancement did not differ statistically from healthy controls. There was no apparent association between elevated biomarkers, echocardiography and CMR.ConclusionCMR revealed subtle changes in cardiac geometry and tissue characterization in IBM patients when compared to a gender- and age-matched control group. Findings in CMR indicated a higher extent of diffuse myocardial fibrosis as well as smaller left ventricular stroke volumes. These alterations may be due to a higher prevalence of arterial hypertension in the IBM cohort.

Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.

Sleep disordered breathing in a cohort of patients with sporadic inclusion body myositis

The objective of this study is to evaluate the frequency and characteristics of facial involvement in inclusion body myositis (IBM) patients and to compare it to the one previously described in facioscapulohumeral dystrophy (FSHD) patients. Thirty-two IBM patients were included and compared to 29 controls and 39 FSHD patients. All participants were recorded in a video as they performed a series of seven facial tasks. Five raters independently assessed facial weakness using both a qualitative evaluation and a semi-quantitative facial weakness score (FWS). IBM patients had higher FWS than controls (7.89 ± 7.56 vs 1.06 ± 0.88, p < 0.001). Twenty IBM patients (63%) had a facial weakness with a FWS above the maximum value for controls. All facial tasks were significantly more impaired in IBM patients compared to controls (p < 0.001), task 2 evaluating orbiculari oculi muscle weakness being the most affected. IBM patients with facial weakness reported more swallowing troubles than IBM patients without facial weakness (p = 0.03). FSHD patients displayed higher FWS than IBM patients (12.16 ± 8.37 vs 7.89 ± 7.56, p = 0.01) with more pronounced facial asymmetry (p = 0.01). FWS inter-rater ICC was 0.775. This study enabled us to estimate the frequency of facial impairment in IBM in more than half of patients, to detail its characteristics and to compare them with those of FSHD patients. The standardized, semi-quantitative FWS is an interesting diagnostic help in IBM as it appeared more sensitive than qualitative evaluation to detect mild facial weakness.

Sporadic Inclusion Body Myositis (IBM) remains without proven treatment, reflecting a previous lack of preclinical disease models on which to evaluate potential therapies. We developed a panel of pathological outcome...

Characterizing local antibody responses in the muscle of inclusion body myositis patients.

Sporadic inclusion body myositis (IBM) is a progressive condition which commonly affects patients aged above 40. IBM does not respond to immunosuppression and no proven treatments are available. Up to 80% of patients develop some degree of swallowing impairment during the disease course. Dysphagia is a source of marked morbidity in IBM and predisposes patients to life-threatening complications such as aspiration pneumonia. The pathophysiology behind dysphagia in IBM is not fully understood. Evidence from imaging demonstrates that impaired swallowing is predominantly underpinned by oropharyngeal deficits. Changes in cricopharyngeal physiology is thought to be an important factor influencing dysphagia in IBM. However, it is unclear whether this is secondary to structural changes within the cricopharyngeus itself or driven by impairment of the muscles promoting pharyngeal clearance. The approach to dysphagia in IBM patients is limited by a lack of validated instruments to reliably assess swallowing function and an absence of effective therapeutic interventions derived from controlled trials targeting dysphagia. Imaging modalities such as the video fluoroscopic swallowing study (VFSS) are commonly used to evaluate dysphagia in IBM. Whilst VFSS is a commonly used technique in clinical practice; cumulative radiation exposure with repeated testing can be a limitation. Alternative imaging techniques could be developed further as outcome measures for assessing swallowing.In this review, we provide an overview of imaging techniques used to assess swallowing and the insight provided from such investigations into the mechanisms behind dysphagia in IBM. We suggest future directions for evaluation and outcome measurement of dysphagia in this population.

To investigate ANT1 and NF-κB expression in inclusion body myositis (IBM) muscle and to verify their possible roles in the pathogenesis of the disease, we collected muscle samples from five patients with IBM, polimyositis (PM) and controls. p65 form of NF-κB was analyzed using immunocytochemistry, Western blot and EMSA. Western blot of ANT1 was performed and confirmed by gene expression study. Mann-Whitney test was used for groups comparisons. NF-κB (p65) was found over-expressed both with western blot and EMSA, either in IBM or PM patients versus controls (p < 0.01). Expression of ANT1 were lower in IBM samples versus both PM and controls (p < 0.01). ANT1 reduction and NF-κB over-expression in IBM muscle could explain the lack of apoptosis in such disease. Normal ANT1 expression in PM could be related to the scarcity of mitochondrial abnormalities in the disease, but it could also suggest that these two conditions diverge in activating different anti-apoptotic pathways.

To describe new insights and developments in the pathogenesis, diagnosis and treatment of sporadic inclusion body myositis (IBM). Various hypothesis about the pathogenesis of IBM continue to be investigated, including autoimmune factors, mitochondrial dysfunction, protein dyshomeostasis, altered nucleic acid metabolism, myonuclear degeneration and the role of the myostatin pathway. Serum autoantibodies against cytosolic 5'-nucleotidase 1A have been identified in IBM showing moderate diagnostic performance. The differential diagnostic value of histopathological features, including different protein aggregates, continues to be evaluated. MRI may also be of monitoring value in IBM. New therapeutic strategies are being tested in IBM patients, namely the upregulation of the heat shock response and the antagonism of myostatin. Recent important advances have occurred in IBM. These advances, including recent and ongoing clinical trials, may lead to earlier diagnosis and improved understanding and treatment of the disease. Despite improved knowledge, IBM continues to be a puzzling disease and the pathogenesis remains to be clarified. An interdisciplinary, bench to bedside translational research approach is crucial for the successful identification of novel treatments for this debilitating, currently untreatable disorder.

Because weakness of finger flexors and atrophy of the forearms are frequent findings in inclusion body myositis (IBM) patients, we examined the forearm muscles by MRI to determine if involvement of the distal musculature has a characteristic diagnostic pattern. We performed MRI of the forearms in 21 randomly selected patients with histologically confirmed IBM and in 9 patients with other, age-matched, neuromuscular diseases who served as controls. In addition, we analyzed axial images of 10 individual forearm muscles blindly without knowledge of the clinical status or diagnosis of the patients. T1-weighted MR images showed marbled brightness of the flexor digitorum profundus (FDP) in 20 of 21 IBM patients, of the flexor carpi ulnaris in 7, the flexor digitorum superficialis (FDS) in 6, the flexor carpi radialis in 4, the supinator in 3, and the brachioradialis in 1. The extensors were normal. The abnormalities of the FDP correlated with the severity but not the duration of the disease and in some patients preceded overt clinical signs of FDP weakness. In contrast, the FDS was spared even late in the disease. We conclude that selective involvement of the FDP may occur early in the course of IBM and can be easily demonstrated by MRI in up to 95% of patients. Because selective FDP involvement appears to be a very frequent and characteristic finding in patients with IBM, MRI of the forearm is a useful noninvasive test in supporting the diagnosis of sporadic IBM.

The idiopathic inflammatory myopathies (IIM) represent a heterogeneous group of acquired muscle diseases. The three best-studied subgroups: dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (IBM), differ considerably both clinically and pathophysiologically. DM is a chiefly humoral endotheliopathy often associated with characteristic skin manifestations. In PM and IBM nonnecrotic muscle fibers are invaded by auto-aggressive cytotoxic T-cells and macrophages. IBM presents with additional structural abnormalities of myofibers, including rimmed vacuoles and depositions of ectopic proteins. Data accumulates implicating the chemokines in the immunopathogenesis of the different IIM. This review bundles current knowledge of the chemokine and chemokine receptor expression in the skeletal muscle of DM, PM and IBM patients. The IIM are characterized by a general increase of specific chemokines, while the chemokine distribution reflects the two different immune responses represented within these muscle diseases: (I) The endotheliopathy of DM is characterized by increased levels of CXCL12 and CCL2 in the affected blood vessels, (II) In the myocytotoxic immune response of PM and IBM, active invasion of nonnecrotic myofibers by inflammatory cells is associated with CXCL10 and CCL2 upregulation. The ever accumulating data illustrates the important role of the chemokine system in IIM, indicating the therapeutic potential of interfering agents. This raises hopes for future treatments for DM and PM with fewer side effects, and the possible establishment of a therapy suited for IBM, a myopathy which has proven unresponsive to all available immuno-modulating interventions up till now.

G.P.65: Obstructive sleep apnoea and subclinical impairment of respiratory function are common in sporadic inclusion body myositis

P.94 Clinical and pathologic features of clinically diagnosed inclusion body myositis (IBM) patients in Korea

Preface Part I. Overview of Pathologic and Pathogenic Comparison Between Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: 1. Newest approaches to diagnosis and pathogenesis of sporadic inclusion-body myositis and hereditary inclusion-body myopathies, including molecular-pathologic similarities to Alzheimer disease Part II. Historical Perspective: 2: Evolving concepts of inclusion-body myositis Part III. Sporadic Inclusion-Body Myositis - Clinical and Diagnostic Considerations: 3: Sporadic inclusion-body myositis: Clinical and laboratory features and diagnostic criteria 4: Inclusion-body myositis: natural history 5: Uncommon clinico-pathological forms of sporadic inclusion-body myositis: Report of four cases 6: Inclusion-body myositis: pathological changes 7: Unusual pathological forms of inclusion-body myositis, and neuromuscular disorders with IBM-like changes 8: Electrophysiological findings in inclusion-body myositis 9: Genetic factors in sporadic inclusion-body myositis Part IV. Hereditary Inclusion-Body Myopathies - Clinical and Diagnostic Considerations: 10: Hereditary inclusion-body myopathy in Jews of Persian origin: Clinical and laboratory data 11. Hereditary inclusion-body myopathy (h-IBM) with quadriceps sparing: epidemiology and genetics 12: Familial autosomal-recessive inclusion-body myositis with asymptomatic leukoencephalopathy 13: Welander distal myopathy - clinical, pathophysiological, and molecular aspects 14. Tibial muscular dystrophy - clinical, genetic, and morphological characteristics 15. Distal myopathy with rimmed vacuoles, inclusion-body myositis and related disorders in Japan 16. Inclusion-body myopathies 17. Is the muscle fiber in inclusion body-myositis an antigen-presenting cell of an innocent bystander? 18. Viruses, immunodeficiency and inclusion-body myositis 19. Myonuclear abnormalities may play a central role in the pathogenesis of muscle fiber damage in inclusion-body myositis 20. Nuclear degeneration and rimmed vacuole formation in neuromuscular disorders 21. Mitochondrial alterations in sporadic inclusion-body myositis 22. mtDNA analysis in muscle of patients with sporadic inclusion-body myopathy Part V. Treatment: 23. Evaluation of treatment for sporadic inclusion-body myositis 24. Personal experience in treating sporadic inclusion-body myositis Subject index.

ObjectiveTo evaluate survival and associated comorbidities in inclusion body myositis (IBM) in apopulation-based, case-control study.MethodsWe utilized the expanded Rochester Epidemiology Project medical records-linkage system,including 27 counties in Minnesota and Wisconsin, to identify patients with IBM, otherinflammatory myopathies (IIM), and age/sex-matched population-controls. We compared thefrequency of various comorbidities and survival among groups.ResultsWe identified 50 IBM patients, 65 IIM controls and 294 population controls. Dysphagiawas most common in IBM (64%) patients. The frequency of neurodegenerative disorders(dementia/parkinsonism) and solid cancers was not different between groups. Rheumatoidarthritis was the most common rheumatic disease in all groups. A total of 36% of IBMpatients had a peripheral neuropathy, 6% had Sjögren’s syndrome and 10% had ahaematologic malignancy. T-cell large granular lymphocytic leukaemia was only observedin the IBM group. None of the IBM patients had hepatitis B or C, or HIV. IBM patientswere 2.7 times more likely to have peripheral neuropathy, 6.2 times more likely to haveSjögren’s syndrome and 3.9 times more likely to have a haematologic malignancy thanpopulation controls. IBM was associated with increased mortality, with a 10-yearsurvival of 36% from index, compared with 67% in IIM and 59% in population controls.Respiratory failure or pneumonia (44%) was the most common cause of death.ConclusionsIBM is associated with lower survival, and higher frequency of peripheral neuropathy,Sjögren’s syndrome and haematologic malignancies than the general population. Closemonitoring of IBM-related complications is warranted.