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Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases with various subtypes, myositis-specific antibodies, and affect multiple systems. The treatment of IIMs remains challenging, especially for refractory myositis. In addition to steroids and traditional immunosuppressants, rituximab (RTX), a B cell-depleting monoclonal antibody, is emerging as an alternative treatment for refractory myositis. However, the therapeutic response to RTX remains controversial. This meta-analysis aimed to systematically evaluate the efficacy and safety of RTX in patients with IIMs, excluding sporadic inclusion body myositis. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and WanFang Data were searched for relevant studies. The overall effective rate, complete response rate, and partial response rate were calculated to assess the efficacy of RTX. The incidences of adverse events, infection, severe adverse events, severe infection, and infusion reactions were collected to evaluate the safety of RTX. Subgroup analyses were performed using IIM subtypes, affected organs, continents, and countries. We also performed a sensitivity analysis to identify the sources of heterogeneity. A total of 26 studies were included in the quantitative analysis, which showed that 65% (95% confidence interval [CI]: 54%, 75%) of patients with IIMs responded to RTX, 45% (95% CI: 22%, 70%) of patients achieved a complete response, and 39% (95% CI: 26%, 53%) achieved a partial response. Subgroup analyses indicated that the overall efficacy rates in patients with refractory IIMs, dermatomyositis and polymyositis, as well as anti-synthetase syndrome were 62%, 68%, and 62%, respectively. The overall efficacy rates for muscle, lungs, and skin involvement were 59%, 65%, and 81%, respectively. In addition, studies conducted in Germany and the United States showed that patients with IIMs had an excellent response to RTX, with an effective rate of 90% and 77%, respectively. The incidence of severe adverse events and infections was 8% and 2%, respectively. RTX may be an effective and relatively safe treatment choice in patients with IIMs, especially for refractory cases. However, further verification randomized controlled trials is warranted.

Background The activity of normal myoblasts is essential for the regeneration of skeletal muscle following injury. Nevertheless, the intrinsic mechanisms governing myoblast functions and muscle regeneration remain inadequately elucidated. PDZ binding kinase (Pbk) is a serine–threonine kinase that plays critical roles in various cellular functions and pathologies. However, its role in skeletal muscle remains largely unexplored. In this study, we have identified Pbk as a novel positive regulator of myoblast functions in vitro and muscle regeneration in vivo. Methods Herein, We analyzed the effects of Pbk on myoblast function and muscle regeneration through in vitro and in vivo experiments. In vivo, we analyzed the effects of Pbk on skeletal muscle regeneration through bioinformatic analysis combined with a mouse skeletal muscle injury model. In vitro, we analyzed the effects of Pbk knockdown or overexpression on myoblast proliferation, survival, and differentiation through lentivirus-mediated cell infection. Also, we further studied the molecular mechanisms by which Pbk affects myoblast differentiation and muscle regeneration combined with the molecular biology and biochemistry, and drug rescue approaches. Results In vitro experiments demonstrated that knockdown of Pbk results in impaired cell proliferation and accelerated apoptosis of myoblasts. Unlike proliferating myoblasts, Pbk is upregulated and restricted from translocating from the cytoplasm to the nucleus during myoblast differentiation. Notably, the positive effect of Pbk on myoblast differentiation and fusion is contingent upon its kinase activity. Mechanistic investigations revealed that Pbk facilitates myogenic autophagy by enhancing AMPK-mediated phosphorylation of ULK1, which ultimately contributes to myogenic differentiation and fusion. In vivo, we observed that Pbk is upregulated in embryonic myosin heavy chain (eMyHC) positive regenerative myofibers in muscle specimens from patients with Duchenne muscular dystrophy (DMD) and immune-mediated necrotizing myopathy (IMNM). Furthermore, in a murine model of skeletal muscle injury, Pbk knockdown hinders the regeneration of myofibers. Conclusions Collectively, our findings suggest that Pbk plays a positive regulatory role in myoblast differentiation and muscle regeneration by modulating AMPK/ULK1-mediated autophagy signaling. This pathway may represent a novel target for the manipulation of myoblast functions and the development of myoblast-based therapies for skeletal muscle injuries.

Objectives To characterize the clinical and myo-fascial histopathological features, along with long-term treatment outcomes of patients with eosinophilic fasciitis (EF). Methods We performed a retrospective analysis of the clinical, serological, myo-fascial pathological features, as well as the long-term follow-up outcomes of EF patients between January 2011 and August 2023 at our neuromuscular disorder (NMD) center. Results Seventeen patients were included, and a male predominance (12/17, 70.6%) was identified. The most common clinical manifestation was skin thickening (100%), always distal to the elbow and knee joints, occupied by limited joint mobility (12/17, 70.6%). The “prayer sign” was observed in 7 (41.2%) patients. Eosinophilia was identified in only 7 (41.2%) patients, including 6 in the blood and 3 in tissue. Anti-Ha antibody was confirmed in one patient (P17). Typical fascial edema with or without involvement of the adjacent subcutaneous tissues was exhibited on magnetic resonance imaging (MRI) in all 9 patients. The perifascicular pattern of MHC-I and/or MHC-II upregulation without MxA expression was identified in 56.3% (9/16) of the patients’ muscle specimens. Typical perifascicular atrophy was identified in 4 patients. Complete recovery was noted in 5 patients, including 4 patients treated with prednisone as monotherapy, and 1 patient treated with prednisone combined with D-penicillamine. Conclusions The “prayer sign” might be an important clinical feature of EF. Perifascicular upregulation of MHC-I and/or MHC-II but negative expression of MxA, with or without PFA, represents a unique pathological phenotype of EF. Most patients show favorable outcome following steroid monotherapy or in combination with immunosuppressants, underscoring the autoimmune pathogenic nature of this disease.

ObjectiveTo characterize the clinical and pathological features of anti-HMGCR myopathy.MethodsThe presence of anti-HMGCR antibody in the serum of 227 patients with idiopathic inflammatory myopathy (IIM) and 100 healthy control individuals was assessed by ELISA. All ELISA positive samples were retested by indirect immunofluorescence assay (IIFA) on HEK293 cells. The clinical findings, muscle pathological features, and treatment outcomes of patients with anti-HMGCR myopathy, along with comparisons between anti-HMGCR myopathy with and without dermatomyositis (DM)-like skin rashes, and among MSA-based subgroups were analyzed.ResultsWe established an optimized ELISA cutoff for anti-HMGCR antibody positivity as ≥ 5.28 U. The overall concordance between ELISA and IIFA was 96.83%. Twenty-one out of 227 IIM patients were anti-HMGCR-positive by both assays. Of these 21 patients, 9 had DM-like skin rashes, and 16 showed remarkable muscle inflammation; 5 patients were juvenile-onset, and 2 received statin treatment. The muscle biopsies from these patients demonstrated variable muscle necrosis and T cell infiltration. Most anti-HMGCR-positive patients achieved favorable outcomes following prednisone and additional immunotherapies. The anti-HMGCR myopathy patients with DM-like rashes, compared to those without DM-like rashes, were younger and had a shorter disease duration.ConclusionsOptimization of cutoff of anti-HMGCR antibody assays with confirmation by alternative assays can result in higher sensitivity and specificity. DM-like skin rashes and lymphocytic infiltrates were not rare in patients with anti-HMGCR myopathy. These findings suggest that while anti-HMGCR myopathy may overlap with DM-like rash, it is pathologically different from classic DM, and should be considered a distinct subgroup of IIM.

Objective Limb-girdle muscular dystrophy (LGMD) is usually confused with idiopathic inflammatory myopathy (IIM) in clinical practice. Our study aimed to establish convenient and reliable diagnostic models for distinguishing between LGMD and IIM. Methods A total of 71 IIM patients, 24 LGMDR2 patients and 22 LGMDR1 patients diagnosed at our neuromuscular center were enrolled. Differences in clinical, laboratory and histopathological characteristics were comprehensively compared. A nomogram and a decision tree were developed to distinguish between LGMD and IIM patients. Results Compared to patients with LGMD, IIM patients exhibited a significantly older age of onset, a higher prevalence of cervical flexor weakness and a more commonly diffuse MHC-I expression on muscle pathology. The ratio of synchronous serum myoglobin (Mb, ng/ml) to creatine kinase (CK, U/L) before immunotherapy was significantly higher in IIM patients than in LGMD patients. Receiver operating characteristic analysis indicated a high differential diagnostic efficiency of synchronous Mb/CK with a cutoff value of 0.18. A nomogram prediction model and a decision tree were developed based on four independent indicators (age of onset, cervical flexor weakness, synchronous Mb/CK and diffuse MHC-I expression). Five-fold cross-validation and bootstrapping techniques substantiated the discriminate efficacy of the nomograph and decision tree. Conclusion We developed two practical differential diagnosis models for LGMD and IIM based on the analysis of four accessible indicators, including the age of onset, cervical flexor weakness, the ratio of synchronous Mb/CK values and diffuse MHC-I expression. Further studies with larger samples are needed to refine the predictive efficiency of the differential diagnostic models.

ObjectiveTo investigate atrophy patterns in hypothalamic subunits at different stages of ALS and examine correlations between hypothalamic subunit volume and clinical information.MethodsWe used the King’s clinical staging system to divide 91 consecutive ALS patients into the different disease stages. We investigated patterns of hypothalamic atrophy using a recently published automated segmentation method in ALS patients and in 97 healthy controls. We recorded all subjects’ demographic and clinical information.ResultsCompared with healthy controls, we found significant atrophy in the bilateral anterior–superior subunit and the superior tubular subunit, as well as a reduction in global hypothalamic volume in ALS patients. When we used the King’s clinical staging system to divide patients into the different disease stages, we found neither global nor specific subunit atrophy until King’s stage 3 in the hypothalamus. Moreover, specific subunit volumes were significantly associated with body mass index.ConclusionsIn a relatively large sample of Chinese patients with ALS, using a recently published automated segmentation method for the hypothalamus, we found the pattern of hypothalamic atrophy in ALS patients differed greatly across King’s clinical disease stages. Moreover, specific hypothalamic subunit atrophy may play an important role in energy metabolism in ALS patients. Thus, our findings suggest that hypothalamic atrophy may have potential phenotypic associations, and improved energy metabolism may become an important component of individualised therapy for ALS.

Background Using in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients. Methods In this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup. Results We found that compared with HCs, ALS patients had a significantly higher CP volume ( p  < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction ( p  = 0.006 and p  < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score ( r = -0.226; p  = 0.005) and the Qalb ( r  = 0.479; p  < 0.001) in ALS patients. Conclusion Our study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

Hereditary myopathy with early respiratory failure (HMERF) is a subtype of myofibrillar myopathy. Mutations located on exon 344 of the titin-A band, the 119th fibronectin-3 domain (FN3 119), are responsible for HMERF. In this article, we retrospectively analyzed the clinical features, findings of muscle imaging, muscle pathology, immunohistochemistry, and ultrastructural characteristics of seven patients diagnosed with HMERF at a single center in China. Muscle MRI showed the involvement of semitendinosus in four patients. The common pathological features were variability in fiber diameter, increased internal nuclei, endomysial fibrosis, and cytoplasmic bodies. On immunohistochemical examination, the cytoplasmic bodies stained positive for calpain-3, p53, and programmed death-ligand 1. Electron microscopy showed cytoplasmic bodies, distorted sarcomere architecture, glycogen pool, and subsarcolemmal accumulation of mitochondria and lysosomes. We retrospectively reviewed four reported HMERF patients in China. Among the 11 patients, the median age at onset was 34 years (range 14–54). Allelic frequency of mutation c.95195C > T was 36.36%. This study characterizes the phenotype and genotype spectrum of HMERF in China.

Distal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused by TCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reported TCAP mutations related to LGMD2G were recessive frameshift or nonsense variants. Here, we described four Chinese patients from unrelated families with LGMD2G due to TCAP mutations. The clinical symptoms of our patients were similar to those previously reported in LGMD2G patients. Three different pathogenic TCAP variants were identified in these patients, including two frameshift variants and one intronic variant. Autophagolysosomes have been observed in one patient by electron microscopy. Our research expands the genetic spectrum of TCAP mutations in China, indicating c.165-166insG is likely the common pathogenic variant. We also provide evidences that autophagy may be involved in the pathophysiology of LGMD2G.

BackgroundLipid-storage myopathy (LSM), defined by triglyceride accumulation in muscle fibres, is a heterogeneous group of lipid metabolic disorders predominantly affecting skeletal muscle. In the past 15 years, more than 200 cases of LSM have been reported in the Chinese literature, but the accurate pathogenic mechanisms are still unknown.ObjectiveIn order to gain more insight into the metabolic and genetic dysfunctions of LSM, the authors described a group of Chinese patients with LSM who were very responsive to isolated riboflavin treatment (riboflavin responsive LSM, RR-LSM).MethodsNineteen consecutive LSM patients collected during 1995–2007 in our Neuromuscular Laboratory who were dramatically responsive to riboflavin and presented with proximal muscle weakness, exercise intolerance and elevated serum CK but without episodic encephalopathy were subjected to pathological, biochemical and molecular analysis.ResultsOn the basis of muscle pathology, all 19 patients were diagnosed as LSM. Seventeen patients were suspected of having multiple acyl-coenzyme A dehydrogenase deficiency (MADD) according to blood acylcarnitine profiles and urine organic acid analysis. Genetic analysis identified 19 novel mutations in ETFDH gene in 18 patients, among which one was homozygote, 16 were compound heterozygotes, and one was a single heterozygote. No pathogenic mutation was detected in ETFA or ETFB genes. Western blot analysis showed there was no significant decrease in ETF:QO expression except for one patient.ConclusionsThe research findings suggest that the majority of Chinese patients with RR-LSM are caused by a mild type of MADD with unique myopathy which is due to ETFDH gene mutation.