Muscle Biopsy Specimens Research Articles

Clinicopathological Features of Mixed Connective Tissue Disease-Related Myositis: A Case Series.

Mixed connective tissue disease (MCTD) patients often have myositis, however, myopathological and clinical data for MCTD are limited. Recent reports have shown that the pathology of MCTD myositis resembles that of immune-mediated necrotizing myopathy (IMNM), whereas earlier reports described perifascicular atrophy or inflammatory infiltrates predominantly in the perivascular region in MCTD myositis. We aim to describe the clinical and myopathological features of MCTD myositis. We analyzed the clinical and myopathological findings of nine myositis patients with U1-RNP antibodies who fulfilled the diagnostic criteria for MCTD. Eight patients had muscle weakness in the proximal extremities, and overall, six patients had atypical weakness in the face, neck, wrist, or fingers. Four of those patients required additional intensive treatment (intravenous immunoglobulin or methylprednisolone). Therapeutic responses were consistently favorable overall, and there were no deaths during the observation period. In biopsied muscle specimens, common findings were mild myogenic change, increased necrotic and regenerating fibers, and inflammatory infiltrates predominating in the perivascular region. Two specimens were classified into the spectrum of dermatomyositis (DM); the remaining seven specimens, which had a smaller number of necrotic fibers and nonspecific infiltration, were unclassifiable. Patients with MCTD myositis often exhibit an axial or atypical distribution of muscle weakness, which may require intensive therapy. Histological study demonstrates the heterogeneity of myopathology of MCTD myositis and suggests that DM and underlying vasculopathy might be present in these patients.

Contrast of muscle magnetic resonance imaging and pathological findings of muscle tissue in patients with anti-aminoacyl transfer RNA synthetase antibodies.

Methods: Patients with idiopathic inflammatory myopathies (IIMs) diagnosed using the 2017 EULAR/ACR classification criteria in our university between 2005 and 2020 were retrospectively reviewed. IIMs were subclassified into the anti-ARS syndrome (ASSD), immune-mediated necrotizing myositis (IMNM), Dermatomyositis DM and others. Fat-suppressed T2-weighted MRI and muscle biopsy specimens were assessed in IIMs followed by the comparison among the four subgroups. MRI findings were available for 62 patients and histopathological findings were available for 27 patients. Perifascicular atrophy or necrosis in the muscle tissues from the patients with IIM was more frequently observed in patients with subcutaneous and fascial high signal intensity (HSI) on MRI than those without. Four-group comparison among ASSD, IMNM, DM and others revealed HSI in fasciae on MRI was more frequently observed in patients with ASSD and DM than others. Perifascicular atrophy or necrosis in muscle tissues was more frequently observed in patients with ASSD than in others. Patients with ASSD had distinct MRI features compared with anti-ARS negative patients. The fascial high signal intensity on MRI may reflect distinctive pathological features of muscles.

Muscle involvement in systemic sclerosis: high mortality not associated with nature of histological lesions.

The aim of this study was to determine the association between different histological patterns and prognosis in patients with SSc and histologically proven muscle involvement. A multicentre retrospective study was conducted of a cohort of scleroderma patients who had undergone muscle biopsy. The biopsies were reviewed in a coordinated manner to classify patients based on histological findings. Three different patterns were observed: fibrosing myopathy (FM), inflammatory myopathy (IM) and necrotizing myopathy (NM). Rates of survival, muscle relapse, and cardiac and pulmonary events were compared between these three groups. Among 71 scleroderma patients with muscle biopsy specimens available for review, 33 (46.5%) were classified in the FM group, 18 (25.5%) in the IM group, and 20 (28%) in the NM group. The median follow-up time was 6.4 years (interquartile range, 2.2-10.9 years) and 21 patients died during follow-up, primarily from heart disease and infections. The 10-year survival rate after the first non-Raynaud's disease symptom was 80% and the cumulative incidence of muscle relapse was 25%. Neither factor differed significantly between the three groups. The risk of pulmonary events was lowest in the OM group, significantly lower than in the FM group (hazard ratio, 0.17; 95% CI, 0.04-0.67) and non-significantly lower than in the IMNM group (hazard ratio, 0.28; 95% CI, 0.06-1.24). The risk of cardiac events did not differ significantly between the three groups. The mortality rate of scleroderma patients with muscle involvement was not associated with their histological patterns.

Clinical and pathological characteristics of OPDM4 patients in advanced disease.

Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5' UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease. We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP-PCR) were conducted to investigate underlying variants. OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non-ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62-positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti-glycine antibody and laboratory-made polyA-R1 antibody. RP-PCR unveiled an abnormal CGG repeat expansion in the 5' UTR of the RILPL1 gene. The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease.

Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy

Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy.

X-Linked Myotubular Myopathy and Mitochondrial Function in Muscle and Liver Samples.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy that commonly manifests with liver involvement. In most XLMTM cases, disease-causing variants have been identified in the myotubularin gene (MTM1) on chromosome Xq28, which encodes myotubularin protein (MTM1). The impairment of mitochondrial respiratory chain (MRC) enzyme activity in muscle has been observed in the XLMTM mouse model. Though several reports mentioned possible mechanisms of liver involvement in XLMTM patients and animal models, the precise underlying mechanisms remain unknown, and there is no report focused on mitochondrial functions in hepatocytes in XLMTM. We encountered two patients with XLMTM who had liver involvement. We measured MRC enzyme activities in two muscle biopsy specimens, and one liver specimen from our patients to investigate whether MTM1 variants cause MRC dysfunction and whether mitochondrial disturbance is associated with organ dysfunction. MRC enzyme activities decreased in skeletal muscles but were normal in the liver. In our patients, the impaired MRC enzyme activity found in muscle is consistent with previously reported mechanisms that the loss of MTM1-desmin intermediate filament and MTM1-IMMT (a mitochondrial membrane protein) interaction led to the mitochondrial dysfunction. However, our study showed that liver involvement in XLMTM may not be associated with mitochondrial dysfunction.

Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy

BackgroundImmune-mediated necrotizing myopathy (IMNM) is an idiopathic inflammatory myopathy (IIM). Though patients with IMNM were not considered to show skin rash, several reports have showed atypical skin conditions in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive IMNM (HMGCR-IMNM). The incidence and phenotype of skin conditions in patients with HMGCR-IMNM are not fully known.ResultsAmong the 100 IIM patients diagnosed from April 2015 through August 2022, 34 (34%) presented some form of skin condition, with 27 having typical skin rashes; this included 13 patients with dermatomyositis (DM), 8 with anti-synthetase syndrome (ASS), and 6 with IMNM. Meanwhile, 8 of 19 patients with HMGCR-IMNM (42%) presented atypical skin lesions, but no patients with other IIMs did (p < 0.001). Skin eruption with ash-like scales was observed in four HMGCR-IMNM patients, and non-scaly red patches and lumps in the other four patients; accordingly, their skin manifestations were considered as other dermal diseases except for IIM. However, skin and muscle biopsies revealed the atypical skin conditions of patients with HMGCR-IMNM to have the same pathological background, formed by Bcl-2-positive lymphocyte infiltrations.ConclusionsHMGCR-IMNM patients frequently have atypical skin conditions of the neck and back. Skin biopsy specimens from these lesions showed the same Bcl-2-positive lymphocytic infiltrations as muscle biopsy specimens regardless of the different gross dermal findings. Thus, such atypical skin conditions may be suggestive for HMGCR-IMNM.

Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: A systematic review

Pompe disease is a rare genetic disorder characterized by a deficiency of acid α-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, especially in skeletal muscles. The disease manifests as a large spectrum of phenotypes from infantile-onset Pompe disease (IOPD) to late-onset Pompe disease (LOPD), depending on the age of symptoms onset. Quantifying GAA activity and glycogen content in skeletal muscle provides important information about the disease severity. However, the distribution of GAA and glycogen levels in skeletal muscles from healthy individuals and those impacted by Pompe disease remains poorly understood, and there is currently no universally accepted standard assay for GAA activity measurement. This systematic literature review aims to provide an overview of the available information on GAA activity and glycogen content levels in skeletal muscle biopsies from patients with Pompe disease.A structured review of PubMed and Google Scholar literature (with the latter used to check that no additional publications were identified) was conducted to identify peer-reviewed publications on glycogen storage disease type II [MeSH term] + GAA, protein human (supplementary concept), Pompe, muscle; and muscle, acid alpha-glucosidase. A limit of English language was applied. Results were grouped by methodologies used to quantify GAA activity and glycogen content in skeletal muscle. The search and selection strategy were devised and carried out in line with Preferred Reporting of Items in Systematic Reviews and Meta-Analysis guidelines and documented using a flowchart. Bibliographies of papers included in the analysis were reviewed and applicable publications not already identified in the search were included.Of the 158 articles retrieved, 24 (comprising >100 muscle biopsies from >100 patients) were included in the analysis, with four different assays. Analysis revealed that patients with IOPD exhibited markedly lower GAA activity in skeletal muscles than those with LOPD, regardless of the measurement method employed. Additionally, patients with IOPD had notably higher glycogen content levels in skeletal muscles than those with LOPD. In general, however, it was difficult to fully characterize GAA activity because of the different methods used. The findings underscore the challenges in the interpretation and comparison of the results across studies because of the substantial methodological variations. There is a need to establish standardized reference ranges of GAA activity and glycogen content in healthy individuals and in Pompe disease patients based on globally standardized methods to improve comparability and reliability in assessing this rare disease.

Studying Edema Formation After Release of the Infraspinatus Muscle as an Experimental Model of Rotator Cuff Lesions in Sheep: A Histological Analysis

Background: Muscle edema formation and inflammatory processes are early manifestations of acute rotator cuff lesions in sheep. Histological analysis of affected muscles revealed edema formation, inflammatory changes, and muscle tissue disruption in MRs. Hypothesis: Edema contributes to inflammatory reactions and early muscle fiber degeneration before the onset of fatty infiltration. Study Design: Controlled laboratory study. Methods: Osteotomy of the greater tuberosity, including the insertion of the infraspinatus tendon, was performed on 14 sheep. These experimental animal models were divided into 2 groups: a nontrauma group with surgical muscle release alone (7 sheep) and a trauma group with standardized application of additional trauma to the musculotendinous unit (7 sheep). Excisional biopsy specimens of the infraspinatus muscle were taken at 0, 3, and 4 weeks. Results: Edema formation was histologically demonstrated in both groups and peaked at 3 weeks. At 3 weeks, signs of muscle fiber degeneration were observed. At 4 weeks, ingrowth of loose alveolar and fibrotic tissue between fibers was detected. Fatty tissue was absent. The diameter of muscle fibers increased in both groups, albeit to a lesser degree in the trauma group, and practically normalized at 4 weeks. Immunohistology revealed an increase in macrophage types 1 and 2, as well as inflammatory mediators such as prostaglandin E2 and nuclear factor kappa-light-chain-enhancer of activated B cells. Conclusion: Early muscle edema and concomitant inflammation precede muscle fiber degeneration and fibrosis. Edema formation results from tendon release alone and is only slightly intensified by additional trauma. Clinical Relevance: This study illustrates that early edema formation and inflammation elicit muscle fiber degeneration that precedes fatty infiltration. Should this phenomenon be applicable to human traumatic rotator cuff tears, then surgery should be performed as soon as possible, ideally within the first 21 days after injury.

Patchy FDG uptake on FDG PET/CT in a patient with vasculitic neuropathy in restricted lower‐limb vasculitis

AbstractA 54‐year‐old man with diabetes mellitus presented with fever, pain, muscle weakness, and sensory disturbances in the lower limbs. His serum C‐reactive protein level was markedly increased; However, no autoantibodies, other than anti‐glutamic acid decarboxylase antibody, were detected. Nerve conduction studies revealed axonal polyneuropathy. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography revealed patchy uptake patterns specific to restricted lower‐limb vasculitis. The muscle and nerve biopsy specimens suggested vasculitic neuropathy. Treatment with oral prednisolone and cyclophosphamide pulse therapy markedly improved his lower‐limb weakness and paresthesia. Clinicians should consider the involvement of vasculitic neuropathy, as well as myopathy, in patients with restricted lower‐limb vasculitis.

Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.

Contribution of Complement, Microangiopathy and Inflammation in Idiopathic Inflammatory Myopathies.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group characterized by muscle weakness and skin symptoms and are categorized into six subtypes: dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), immune-mediated myopathy (IMNM), inclusion body myopathy (IBM), and overlap myositis. Myositis-specific autoantibodies were detected for the diagnosis and classification of IIM. This review highlights the pathogenic contributions of the complement system, microangiopathy, and inflammation in IIM. Deposition of complement around capillaries and/or the sarcolemma was observed in muscle biopsy specimens from patients with DM, ASS, and IMNM, suggesting the pathomechanism of complement-dependent muscle and endothelial cell injury. A recent study using human muscle microvascular endothelial cells showed that Jo-1 antibodies from ASS induce complement-dependent cellular cytotoxicity in vitro. Based on both clinical and pathological observations, antibody- and complement-mediated microangiopathy may contribute to the development of DM and anti-Jo-1 ASS. Juvenile DM is characterized by the loss of capillaries, perivascular inflammation, and small-vessel angiopathies, which may be related to microinfarction and perifascicular atrophy. Several serum biomarkers that reflect the IFN1 signature and microangiopathy are elevated in patients with DM. The pathological observation of myxovirus resistance protein A (MxA), which suggests a type 1 interferon (IFN1) signature in DM, supports the diagnosis and further understanding of the pathomechanism of IIM. A recent report showed that an increase in triggering receptor expressed on myeloid cells (TREM-1) around perimysial blood vessels and muscles in patients with IIM plays a role in triggering inflammation and promoting the migration of inflammatory cells by secreting proinflammatory cytokines, such as tumor necrosis factor α. The deposition of complement in muscles and capillaries is a characteristic feature of DM, ASS, and IMNM. Microangiopathy plays a pathogenic role in DM, possibly resulting in perifascicular atrophy. Further understanding of the detailed pathomechanism regarding complement, microangiopathy, and inflammation may lead to novel therapeutic approaches for IIM.

The congenital muscular dystrophies

AbstractBackgroundCongenital muscular dystrophies (CMDs) are genetically and clinically heterogeneous inherited conditions. Onset is typically within the first year of life. Most CMDs are autosomal recessive, except for de novo dominant mutations in LMNA‐related muscular dystrophy and some collagen‐6‐associated disorders.ResultsCMD is characterized by progressive muscular weakness, hypotonia, multiple contractures with a variable degree, spinal stiffness, delay in motor milestones acquisition, and histologically dystrophic lesions. Also, some forms of CMD may feature structural and myelination abnormalities on brain magnetic resonance imaging, intellectual impairment, and structural abnormalities of the eye. Muscle biopsy specimens exhibit a dystrophic pattern, but the appearance is quite variable depending on the different stages and severity of the disorder. The prevalence of CMD is estimated to be one in 100 000 people. Over the last few years, with advances in molecular genetic diagnostics, knowledge about neuromuscular disorders, particularly CMDs, has increased dramatically. Thus, the incidence may be higher than originally thought.ConclusionThis article reviews the recent achievements related to the clinical, diagnostic, pathogenic, and therapeutic aspects of CMDs.

Skeletal Muscle Involvement in Patients With Truncations of Titin and Familial Dilated Cardiomyopathy

BackgroundGenetic variants in titin (TTN) are associated with dilated cardiomyopathy (DCM) and skeletal myopathy. However, the skeletal muscle phenotype in individuals carrying heterozygous truncating TTN variants (TTNtv), the leading cause of DCM, is understudied. ObjectivesThis study aimed to assess the skeletal muscle phenotype associated with TTNtv. MethodsParticipants with TTNtv were included in a cross-sectional study. Skeletal muscle fat fraction was evaluated by magnetic resonance imaging (compared with healthy controls and controls with non-TTNtv DCM). Muscle strength was evaluated by dynamometry and muscle biopsy specimens were analyzed. ResultsTwenty-five TTNtv participants (11 women, mean age 51 ± 15 years, left ventricular ejection fraction 45% ± 10%) were included (19 had DCM). Compared to healthy controls (n = 25), fat fraction was higher in calf (12.5% vs 9.9%, P = 0.013), thigh (12.2% vs 9.3%, P = 0.004), and paraspinal muscles (18.8% vs 13.9%, P = 0.008) of TTNtv participants. Linear mixed effects modelling found higher fat fractions in TTNtv participants compared to healthy controls (2.5%; 95% CI: 1.4-3.7; P < 0.001) and controls with non-TTNtv genetic DCM (n = 7) (1.5%; 95% CI: 0.2-2.8; P = 0.025). Muscle strength was within 1 SD of normal values. Biopsy specimens from 21 participants found myopathic features in 13 (62%), including central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by autophagosomes, lysosomes, and abnormal mitochondria with mitophagy. ConclusionsMild skeletal muscle involvement was prevalent in patients with TTNtv. The phenotype was characterized by an increased muscle fat fraction and excessive accumulation of glycogen, possibly due to reduced autophagic flux. These findings indicate an impact of TTNtv beyond the heart.

Sarcoplasmic Myxovirus Resistance Protein A: A Study of Expression in Idiopathic Inflammatory Myopathy.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases affecting primarily proximal muscles. Major subtypes include dermatomyositis, polymyositis, inclusion body myositis, immune-mediated necrotizing myopathy and antisynthetase syndrome. Overexpression of sarcoplasmic myxovirus-resistance protein A (MxA) has been observed in muscle biopsy specimens of dermatomyositis but is rarely seen in other subtypes of IIM and other myopathies. We evaluate the expression of sarcoplasmic MxA and its diagnostic value in IIM and other myopathies. One hundred and thirty-eight muscle biopsy specimens with the diagnosis of IIM and other myopathies from 2011 to 2020 were reviewed and stained for MxA by immunohistochemistry. The difference of the expression of MxA between IIM and other myopathies was analyzed by Fisher's exact test, and the sensitivity and specificity of MxA immunohistochemistry in the diagnosis of IIM were assessed. MxA protein was positive in 16/138 (11.6%) specimens. All 12 dermatomyositis specimens positive for MxA protein were positive in perifascicular area pattern. Only dermatomyositis specimens had a significantly higher percentage of positive sarcoplasmic MxA expression than specimens of other subtypes of IIM (p<0.001). Sarcoplasmic MxA expression for dermatomyositis diagnosis had a sensitivity of 46.15% (95% CI 26.59-66.63%) and a specificity of 94.44% (95% CI 81.34-99.32%) with the positive and negative likelihood ratio of 8.31 (95% CI 2.03-34.01) and 0.57 (95% CI 0.40-0.82), respectively. The MxA immunohistochemistry is highly specific for dermatomyositis and should be added to a routine inflammatory panel of muscle biopsy. MxA expression should be cautiously interpreted to avoid pitfalls.

Antineutrophil cytoplasmic antibody-associated vasculitis with predominant truncal muscle weakness: a retrospective case series.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently leads to mononeuritis multiplex, which are characterized by distal weakness associated with sensory disturbances. Although AAV has also been reported to be associated with myopathy, the pathogenesis and characteristics remain unclear. We aimed to show the clinical and laboratory findings in AAV-associated myopathy. This retrospective single-center study included patients with the diagnosis of AAV who had been admitted to the neurology department and had biopsy specimens of muscle and/or nerve tissue. We identified four patients with a distinct clinical presentation of muscle weakness in the trunk and proximal limbs. The weakness resembled that of inflammatory muscle disease. These patients denied symptoms associated with neuropathy, and had normal serum creatine kinase (CK) levels. Needle electromyography (needle EMG) showed spontaneous electrical activity at rest, and results of magnetic resonance imaging (MRI) suggested inflammatory myopathy. Muscle biopsy specimens from all four patients revealed vasculitis and inflammation in proximity to the affected vessels, without any discernible characteristics of other myopathies. The patients also complained of symptoms affecting other organs, such as the ears and kidneys, which is typical of AAV cases. Remission induction therapy, such as cyclophosphamide pulse therapy in addition to oral prednisolone, were effective for all four patients. However, relapses occurred in two patients during maintenance therapy and two patients died of aspiration pneumonia. The clinical course of our patients might represent a subtype of AAV that is characterized by muscle weakness of the trunk and proximal extremities and arises from vasculitis within the muscles. The clinical manifestations of our patients were similar to those of patients with inflammatory myopathy with regard to the distribution of muscle weakness, MRI and needle EMG findings. However, there are notable differences between AAV associated myopathy vs. inflammatory myositis like dermatomyositis; (1) the absence of elevated CK levels, (2) the presence of complications in other organs, (3) distinct pathological findings, and (4) severe outcomes. Awareness that AAV patients with muscle involvement could have a subtype of AAV that seriously affects various organs is critical for an accurate diagnosis and effective therapeutic management.

Clinical Characteristics of Systemic Sclerosis-associated Myopathy Patients Comparing Different Subgroups of Inflammatory Myopathies

Background: Available data regarding clinical characteristics of systemic sclerosis-associated myopathy (SSc-M) patients comparing different subgroups of muscle pathology are limited. We aimed to compare clinical and laboratory findings among different subgroups of Thai patients with SSc-M. Methods: From January 2010 to December 2019, 27 patients with suspected SSc-M underwent a muscle biopsy. Twenty-three patients with available frozen muscle biopsy specimens for repeating immunohistochemical stained for reviewing were included. There were three subgroups of pathological findings, including immune-mediated necrotizing myopathy (IMNM), non-specific myopthy (NsM), and polymyositis (PM). No fibrosing myopathy was observed. Baseline clinical data and laboratory findings were compared within those three inflammatory myopathies. Results: Of the 23 SSc-M, there were 14 females and 19 DcSSc with a mean age and disease duration of SSc of 53.6±7.7 years and 16.4±23.6 months, respectively. Their mean duration from weakness to muscle biopsy was 3.6±6.0 months. There were 14 (60.9%) patients with IMNM, 6 (26.1%) with NsM, and 3 (13.0%) with PM. At the biopsy date, IMNM had a greater prevalence of severe muscle weakness (42.6% vs. 0% vs. 0%) and arthritis (87.5% vs. 50% vs. 0%) than the NsM and PM groups. There was no significant difference among the three inflammatory patterns regarding baseline clinical characteristics, including age, gender, SSc subtype, disease duration, other organ involvements and median values of CK and ESR levels. Conclusion: In this study, we found that the pathological findings of Thai SSc-M were IMNM, NsM, and PM. No fibrosing myopathy was observed. SSc with IMNM tended to have more severe baseline muscle weakness and arthritis than the other inflammatory patterns.

Risk factors for intracellular fatty accumulation in rotator cuff muscle: a histologic analysis

Fatty accumulation in rotator cuff muscles has been associated with shoulder dysfunction, risk of repair failure, and poor postoperative outcomes. This study sought to assess risk factors associated with true fatty accumulation based on histologic analysis and determine whether preoperative function directly correlated with this fatty rotator cuff accumulation. Supraspinatus muscle biopsy specimens obtained prospectively from patients undergoing arthroscopic rotator cuff repair were stained with LipidTOX to quantify lipid accumulation. Two-step cluster analysis with Goutallier classification was used to define the fatty and non-fatty rotator cuff groups. We further performed a receiver operating characteristic curve analysis to confirm the group cutoff values. In total, 51 patients (aged 60.1±10.5 years) were included. There were 19 high-grade partial tears, 10 small tears, 7 medium tears, 10 large tears, and 5 massive tears. Both cluster and receiver operating characteristic curve analyses yielded a cutoff value of 30% LipidTOX/4',6-diamidino-2-phenylindole (DAPI) separating the fatty vs. non-fatty groups. In the univariate analysis, patients with fatty rotator cuffs were aged 63.2 years on average compared with 59.7 years in the non-fatty group (P=.038). Female patients made up 57.1% of the fatty cohort, which was statistically higher than the non-fatty group (P=.042). Massive and large tears were more likely to occur in the fatty group (P=.005). In the multivariate analysis, full tendon tears had the largest predictive status of falling into the fatty group (odds ratio, 15.4; P=.008), followed by female sex (odds ratio, 4.9; P=.036). Patients in the fatty group had significantly higher American Shoulder and Elbow Surgeons scores (P=.048) and lower visual analog scale scores (P=.002). This prospective histologic assessment revealed that full-thickness rotator cuff tears and female sex were the largest risk factors for intracellular lipid accumulation. Although tear size correlated with fatty accumulation, the sex disparity is a noteworthy finding that warrants further research.

Comprehensive transcriptomic analysis and machine learning reveal unique gene expression profiles in patients with immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness and muscle fiber necrosis, yet its pathogenesis remains unclear. So far, there are few bioinformatics studies on underlying pathogenic genes and infiltrating immune cell profiles of IMNM. Therefore, we aimed to characterize differentially expressed genes (DEGs) and infiltrating cells in IMNM muscle biopsy specimens, which may be useful for elucidating the pathogenesis of IMNM. Three datasets (GSE39454, GSE48280 and GSE128470) of gene expression profiling related to IMNM were obtained from the Gene Expression Omnibus database. Data were normalized, and DEG analysis was performed using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using clusterProfiler. The CIBERSORT algorithm was performed to identify infiltrating cells. Machine learning algorithm and gene set enrichment analysis (GSEA) were performed to find distinctive gene signatures and the underlying signaling pathways of IMNM. DEG analysis identified upregulated and downregulated in IMNM muscle compared to the gene expression levels of other groups. GO and KEGG analysis showed that the pathogenesis of IMNM was notable for the under-representation of pathways that were important in dermatomyositis and inclusion body myositis. Three immune cells (M2 macrophages, resting dendritic cells and resting natural killer cells) with differential infiltration and five key genes (NDUFAF7, POLR2J, CD99, ARF5 and SKAP2) in patients with IMNM were identified through the CIBERSORT and machine learning algorithm. The GSEA results revealed that the key genes were remarkably enriched in diverse immunological and muscle metabolism-related pathways. We comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.

High‐throughput transcriptomic profiling of mRNAs and lncRNAs in the dermatomyositis muscle by RNA sequencing

AbstractBackgroundDermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM). In this study, we investigated the mRNAs and long noncoding RNAs (lncRNAs) in muscle biopsy specimens that are differentially expressed among patients with DM, patients with other IIM, and healthy controls (HCs).MethodsIn total, three patients with DM, 10 patients with other IIM, and three HCs were included. Muscle biopsy specimens were collected for RNA‐sequencing. Gene ontology and pathway analyses were employed to characterize the biological processes and signaling pathways.ResultsCompared with HCs, 372 differentially expressed mRNAs were identified within the DM group, including 275 upregulated and 97 downregulated ones. Moreover, 692 differentially expressed lncRNAs were identified in the DM group compared with HCs, of which 407 were upregulated and 285 were downregulated. Bioinformatic analysis indicated that the type‐I interferon signaling pathway and biological processes of innate immunity were significantly influenced by the differentially expressed mRNAs. Notably, 11 of the top 20 upregulated mRNAs were involved in the type‐I interferon signaling pathway. Reverse transcription polymerase chain reaction analysis verified the RNA‐sequencing data. Target gene prediction analysis suggested that the lncRNA NONHSAG043573.2 potentially targeting transporter associated with antigen processing 1, a key regulator of interferon signaling genes, might play an important role in the pathogenesis of DM.ConclusionsOur study assessed the transcriptomic profiles of differentially expressed mRNAs and lncRNAs in the DM muscle tissue and revealed that the upregulated mRNAs are significantly involved in the innate immune response and the type‐I interferon signaling pathway, which might play important roles in the pathogenesis of DM.