Diagnosis and Clinical Development of Sporadic Inclusion Body Myositis and Polymyositis With Mitochondrial Pathology: A Single-Center Retrospective Analysis

Winkler, M.; Landenberg, C. von; Kappes-Horn, Karin; Neudecker, Stephan; Kornblum, Cornelia; Reimann, Jens

doi:10.1093/jnen/nlab101

Cited by 9 publications

(22 citation statements)

References 31 publications

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“…3 Nevertheless, due to the limited number of published case series, it remains unclear whether there is a specific clinical syndrome (as seen, for example, in IBM) suggestive of the disease. 2,4 It is of importance that, in contrast to IBM, therapeutic response to immunosuppression has been reported in up to 70% of patients with PM-Mito. 2,3,5 Still, the pathophysiologic background of PM-Mito and its possible link to IBM remain unclear.…”

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confidence: 99%

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Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

et al. 2022

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Objective:To characterize morphological and molecular underpinnings of polymyositis with mitochondrial pathology (PM-Mito) in comparison to sporadic inclusion body myositis (IBM) and to define common and distinct pathophysiological features with a focus on interferon-associated inflammation and T-cell-response.Methods:In this cross-sectional study, skeletal muscle biopsy samples as well as clinical and laboratory data from PM-Mito and IBM patients were analyzed at Charité university hospital in Berlin, Germany. All available PM-Mito biopsy samples and an equal number of randomly selected IBM biopsy samples were included in the study as well as randomly selected non-diseased controls (NDC). Biopsy samples were studied by histopathology, immunohistochemistry, and quantitative PCR and compared to biopsies derived from NDC. Primary outcomes included cell counts for immunohistochemistry, and gene expression (fold-change values compared to NDCs) for quantitative PCR.Results:Twenty-five skeletal muscle biopsy samples of patients with PM-Mito and IBM were included in the study and compared to five biopsy samples from non-diseased controls. PM-Mito and IBM qualitatively harbored a strikingly similar molecular signature and shared important histopathological features. Expression of interferon-induced GBP6 and T-cell function-related KLRG1 distinguished IBM from PM-Mito biopsies with IBM patients showing significantly higher expression of GBP6 and KLRG1. Cryptic exon expression was detected in both patient groups with IBM patients showing higher expression levels. Skeletal muscle biopsies from IBM patients showed significantly more GBP6+ cells and KLRG1+ lymphocytes in comparison to biopsies from PM-Mito patients. CD45+, CD68+, CD57+, PD1+ and CD8+ cytotoxic T-cells were also significantly more abundant in IBM. Clinically, PM-Mito patients presented with a spectrum of muscle-related symptoms including myalgia, proximal paraparesis, proximal tetraparesis and incomplete IBM-like patterns. 13 out of 14 (93%) PM-Mito patients for whom clinical follow-up was available later developed clinically defined IBM. Notably, two follow-up biopsies obtained 5 and 7 years after the first ones were available in this cohort, both showing histopathological progress to net IBM including GBP6 and KLRG1 upregulation.Conclusions:Our combined data suggest that specific interferon-mediated inflammation plays a key role in both IBM and PM-Mito. GBP6 was identified as a new molecule of type II interferon-induced inflammation distinguishing IBM from PM-Mito. Skeletal muscles from both groups harbor dysfunctional T-cells of similar type, albeit in different quantity. T-cell senescence exemplified by KLRG1-positivity does not play a significant role in PM-Mito. Based on these findings, we propose to include PM-Mito in the spectrum of IBM (IBM-spectrum disease, IBM-SD) as a possible early form of this disease. The establishment of IBM-SD as a larger entity could potentially have a significant impact on the design of trials and therapeutic interventions.

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confidence: 99%

“…2,4 It is of importance that, in contrast to IBM, therapeutic response to immunosuppression has been reported in up to 70% of patients with PM-Mito. 2,3,5 Still, the pathophysiologic background of PM-Mito and its possible link to IBM remain unclear.…”

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confidence: 99%

Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

et al. 2022

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“…This notion is exemplified by the concept of PM with mitochondrial pathology (PM-Mito) [ 4 , 60 ]. The extent of rimmed vacuoles might vary among IBM specimens, with some authors defining patients, that might otherwise be classified as IBM, due to the absence of rimmed vacuoles as having PM-Mito [ 60 , 77 ]. The available studies do not currently allow for a conclusive statement as to whether PM, PM-Mito and IBM are clearly distinct disease entities or whether they belong to a common spectrum of IIM.…”

Section: Polymyositis—an Iim Entity At the Crossroadsmentioning

confidence: 99%

“…Clinico-pathological progression from HIV-PM to HIV-IBM was emphasized by a consecutive study [ 33 ]. The sporadic occurrence of PM-Mito in the context of HIV infection was similarly described to progress to an IBM-like phenotype in a number of studies [ 70 , 77 ]. Of note, only the age at manifestation was different between HIV-IBM (51 years) and sporadic IBM (69 years), while clinical and histopathological features were reported to be similar [ 33 ].…”

Section: Ibm and The Human Immunodeficiency Virusmentioning

confidence: 99%

Inclusion body myositis and associated diseases: an argument for shared immune pathologies

Nelke

Kleefeld

Preuße

et al. 2022

acta neuropathol commun

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Inclusion body myositis (IBM) is the most prevalent idiopathic inflammatory myopathy (IIM) affecting older adults. The pathogenic hallmark of IBM is chronic inflammation of skeletal muscle. At present, we do not classify IBM into different sub-entities, with the exception perhaps being the presence or absence of the anti-cN-1A-antibody. In contrast to other IIM, IBM is characterized by a chronic and progressive disease course. Here, we discuss the pathophysiological framework of IBM and highlight the seemingly prototypical situations where IBM occurs in the context of other diseases. In this context, understanding common immune pathways might provide insight into the pathogenesis of IBM. Indeed, IBM is associated with a distinct set of conditions, such as human immunodeficiency virus (HIV) or hepatitis C—two conditions associated with premature immune cell exhaustion. Further, the pathomorphology of IBM is reminiscent of other muscle diseases, notably HIV-associated myositis or granulomatous myositis. Distinct immune pathways are likely to drive these commonalities and senescence of the CD8+ T cell compartment is discussed as a possible mechanism of pathogenesis. Future effort directed at understanding the co-occurrence of IBM and associated diseases could prove valuable to better understand the enigmatic IBM pathophysiology.

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“…Patients with endomysial inflammation and prominent mitochondrial dysfunction, but without rimmed vacuoles or protein aggregates, are sometimes referred to as having “polymyositis with mitochondrial pathology” (PM-Mito) ( 38 ). It remains debatable whether this should be considered a separate entity, given the high prevalence of mitochondrial abnormalities in IBM and as a significant proportion of these patients are eventually diagnosed with IBM ( 39 – 41 ). A less common muscle biopsy finding in IBM is the presence of granulomas.…”

Section: Diagnosismentioning

confidence: 99%

Inclusion body myositis: Update on the diagnostic and therapeutic landscape

Naddaf

2022

Front. Neurol.

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Inclusion body myositis (IBM) is a progressive muscle disease affecting patients over the age of 40, with distinctive clinical and histopathological features. The typical clinical phenotype is characterized by prominent involvement of deep finger flexors and quadriceps muscles. Less common presentations include isolated dysphagia, asymptomatic hyper-CKemia, and axial or limb weakness beyond the typical pattern. IBM is associated with marked morbidity as majority of patients eventually become wheelchair dependent with limited use of their hands and marked dysphagia. Furthermore, IBM mildly affects longevity with aspiration pneumonia and respiratory complications being the most common cause of death. On muscle biopsy, IBM is characterized by a peculiar combination of endomysial inflammation, rimmed vacuoles, and protein aggregation. These histopathological features are reflective of the complexity of underlying disease mechanisms. No pharmacological treatment is yet available for IBM. Monitoring for swallowing and respiratory complications, exercise, and addressing mobility issues are the mainstay of management. Further research is needed to better understand disease pathogenesis and identify novel therapeutic targets.

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Diagnosis and Clinical Development of Sporadic Inclusion Body Myositis and Polymyositis With Mitochondrial Pathology: A Single-Center Retrospective Analysis

Cited by 9 publications

References 31 publications

Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis

Inclusion body myositis and associated diseases: an argument for shared immune pathologies

Inclusion body myositis: Update on the diagnostic and therapeutic landscape

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