[Magnetic resonance imaging T2 mapping could reflect disease status in patients with dermatomyositis or polymyositis].

This study aimed to explore the value of magnetic resonance imaging (MRI) T2 mapping in the assessment of dermatomyositis (DM) and polymyositis (PM). Thirty-three confirmed cases (myosin group) and eight healthy volunteers (healthy control group) at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Kunming Medical University, from October 2016 to December 2017, were collected and analyzed. Multiple parameters of the myosin group were quantified, including creatine kinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3, and complement C4. Disease status was evaluated using a panel of tools: myositis disease activity assessment tool-muscle (MDAAT-muscle), myositis disease activity assessment tool-whole (MDAAT-all), health assessment questionnaire (HAQ), medical outcomes study health survey short form-36 item (SF-36), hand muscle strength test (MMT-8) score, and MRI T2 mapping of muscle (22 muscles in the pelvis and thighs) T2 values. The results showed that in the myositis group, the measurements for CK, ESR, CRP, complement C3, and complement C4 were 457.2 (165.6, 1 229.2) IU/L, 20 (10, 42) mm/1h, 3.25 (2.38, 10.07) mg/L, 0.90 (0.83, 1.06) g/L, and 0.18 (0.14, 0.23) g/L, respectively. The scores for MMT-8, MDAAT-muscle, MDAAT-all, HAQ, and SF-36 were 57.12±16.23, 5.34 (4.00, 6.00), 34.63±12.62, 1.55 (0.66, 2.59), and 44.66±7.98, respectively. T2 values were significantly higher in all 22 muscles of the pelvis and thighs of patients with DM or PM compared with the healthy controls [(54.99±11.60)ms vs. (36.62±1.66)ms, P<0.001], with the most severe lesions in the satrorius, iliopsoas, piriformis, gluteus minimus, and gluteus medius muscles. The total muscle T2 value in the myositis group was positively correlated with CK, MDAAT-muscle, MDAAT-all, and HAQ (r=0.461, 0.506, 0.347, and 0.510, respectively, all P<0.05). There was a negative correlation between complement C4, SF-36, and MMT-8 scores (r=-0.424, -0.549, and -0.686, respectively, all P<0.05). Collectively, the findings from this study suggest that MRI T2 mapping can objectively reflect the disease status of DM and PM.

Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.

Impact of muscle biopsy on the clinical decision-making process in patients with suspected idiopathic inflammatory myopathy.

BACKGROUND: The significance of muscle biopsy as a diagnostic tool in idiopathic inflammatory myopathies (IIM) remains elusive. We aimed to determine the diagnostic weight that has been given to muscle biopsy in patients with suspected IIM, particularly in terms of clinical diagnosis and therapeutic decisions. MATERIAL AND METHODS: In this retrospective multicentric study, we analyzed muscle biopsy results of adult patients with suspected IIM referred to a tertiary center between January 1, 2007, and October 31, 2021. Information regarding referral department, suspected diagnosis, biopsy site, demographic, clinical, laboratory data, and imaging results were extracted. Statistical analyses included the level of agreement between suspected and histological diagnosis and calculation of diagnostic performance (positive and negative predictive values, positive and negative likelihood ratios, sensitivity, and specificity of muscle biopsy in relation to clinical diagnosis and/or treatment initiation). Performance was tested in different strata based on clinical pre-test probability. RESULTS: Among 758 muscle biopsies, IIM was histologically compatible in 357/758 (47.1%) cases. Proportion of IIM was higher if there was a solid clinical pre-test probability (64.3% vs. 42.4% vs. 48% for high, medium and low pre-test probability). Sensitivity and specificity of muscle biopsy were highest (82%) when the diagnosis by the clinician was used as outcome scenario. Negative predictive value was only moderate (between 63% and 80%) and lowest if autoantibodies were positive (35%). CONCLUSION: In patients with clinically suspected IIM, approximately 50% of biopsies revealed features indicative of IIM. Diagnostic performance of muscle biopsy was moderate to high depending on clinical pre-test probability.

Subclinical myocardial involvement in a cohort of patients with antisynthetase syndrome.

OBJECTIVES: There is an increasing interest in knowing whether patients with antisynthetase syndrome (ASSD) may have silent myocardial interstitial involvement. Mapping techniques in cardiac magnetic resonance (CMR) can detect subclinical myocardial involvement. The purpose of this study was to identify alterations in multiparametric CMR in ASSD patients without overt cardiac involvement. METHODS: Patients diagnosed with ASSD underwent a CMR along with the standard clinical workup, investigation of specific and associated myositis antibodies, and high-resolution chest CT. The CMR protocol includes routine morphologic, functional, and late gadolinium enhancement sequences in standard cardiac planes, as well as native T1 and T2 mapping sequences and extracellular volume (ECV) calculation. RESULTS: Twenty-five patients were included in this study (56% women; median age 56.3 years). Three patients were considered in the acute phase at the time of inclusion. Eight patients (32%) showed pathological findings in CMR (6 stable disease, 2 acute phase). Elevated T1, T2 and ECV mapping values were found in 20% (5/25), 17% (4/25) and 24% (6/25) of the group, respectively. Two patients in the acute phase had increased values of both T2 and ECV. CONCLUSIONS: Subclinical myocardial involvement in ASSD is not rare (32%) although its clinical significance is uncertain. Myocardial oedema (T2) was the most frequent finding, followed by increased T1 and/or ECV values likely signalling interstitial fibrosis. Of note, patients in the acute phase showed elevated T2 values.

Myxovirus resistance protein A (MxA) expression in myositides: Sarcoplasmic expression is common in both dermatomyositis and lupus myositis.

INTRODUCTION/AIMS: Myxovirus resistance protein A (MxA) is a type I interferon (IFN1) pathway activation marker and MxA sarcoplasmic expression is currently recognized as a highly specific marker for dermatomyositis (DM). However, we have frequently observed endothelial tubuloreticular inclusions (TRI), another surrogate IFN1 activation marker, in a variety of overlap myositides. The aim of this study was to examine MxA expression in those myositides. METHODS: We retrospectively performed MxA immunostaining on a wide range of myositides. RESULTS: MxA sarcoplasmic expression was present in DM (94.4%, 17/18), active lupus myositis (LM, 80%,16/20), inactive LM (36%, 4/11), antisynthetase syndrome (ASyS, 20%, 2/10), systemic sclerosis (13%, 2/15), Sjogren's syndrome (7.7%, 1/13), and human immunodeficiency virus (HIV) myositis (5.6%, 1/18) and was absent in immune-mediated necrotizing myopathy (IMNM, 0/16) and hydroxychloroquine myopathy (0/5). The sensitivity and specificity of MxA sarcoplasmic expression for LM and DM combined compared with all other myositides were 84.6% (95% CI: 69.5-94.1) and 92.1 (95% CI: 83.6-97.0), respectively, and superior to TRIs. MxA capillary expression was nonspecific. Histologically, 35% of LM cases demonstrated a unique panfascicular necrotizing myopathy pattern. The remainder of the LM cases had significant morphological overlap with DM/ASyS (20%), IMNM (20%), or polymyositis (15%). DISCUSSION: MxA sarcoplasmic expression is highly prevalent in LM and DM and is a useful marker in differentiating DM and LM from other myositides. LM can manifest in various pathology patterns that need to be differentiated from DM, IMNM, ASyS, and polymyositis.

Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.

Fatty infiltration in the posterior muscles of the lower extremities as an MRI feature in antimitochondrial antibody-associated myopathy.

OBJECTIVE: Idiopathic inflammatory myopathy (IIM) with antimitochondrial M2 antibody (AMA-M2) has been associated with distinct clinical characteristics. In this study, we explore the magnetic resonance imaging (MRI) findings of the muscles of the lower extremities in AMA-M2-positive IIM to gain more insight. METHODS: MRI of 22 lower extremity muscles was retrospectively evaluated in 14 patients with AMA-M2-positive IIM and 37 age- and sex-matched patients with AMA-M2-negative IIM. Muscles with inflammatory edema and fatty infiltration were assessed according to the Stramare and Mercuri criteria. RESULTS: Patients with AMA-M2-positive IIM had significantly higher incidence of MRI involvement with fatty infiltration in five lower extremity muscles, namely the adductor magnus (AM) (13/14 VS 14/37, p < 0.001), semimembranosus (SM) (13/14 VS 17/37, p = 0.002), biceps femoris (BF) (12/14 VS 15/37, p = 0.004), soleus (13/14 VS 23/37, p = 0.041), and the medial head of the gastrocnemius (Gastroc M) (13/14 VS 17/37, p = 0.002) than patients with AMA-M2-negative IIM. Furthermore, the severity scores of fatty infiltrations of the above five muscles in AMA-M2-positive IIM were significantly higher than those in patients with AMA-M2-negative IIM (p < 0.001). CONCLUSIONS: Severe fatty infiltrations of the AM, SM, BF, soleus, and Gastroc M in the posterior muscles of the lower extremities are dominant MRI features in our patients with AMA-M2-positive IIM. This unique muscle MRI character may be a helpful indicator in clinical practice for patients with AMA-M2-positive IIM. Key Points • Striking involvement and prominent fatty infiltrations of five lower extremity muscles (adductor magnus, semimembranosus, biceps femoris, soleus, and the medial head of the gastrocnemius) are interesting MRI performances. • Severe fatty infiltrations in the posterior muscles of the lower extremities are dominant MRI features in AMA-M2-positive IIM. • This unique muscle MRI character may be very helpful for the diagnosis of the AMA-M2-positive IIM.

Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis.

OBJECTIVE: To investigate pathogenic mechanisms underlying JDM, we defined the effect of type I IFN, IFN-α and IFN-ß, on pediatric skeletal muscle function and expression of myositis-related proteins using an in vitro engineered human skeletal muscle model (myobundle). METHODS: Primary myoblasts were isolated from three healthy pediatric donors and used to create myobundles that mimic functioning skeletal muscle in structural architecture and physiologic function. Myobundles were exposed to 0, 5, 10 or 20 ng/ml IFN-α or IFN-ß for 7 days and then functionally tested under electrical stimulation and analyzed immunohistochemically for structural and myositis-related proteins. Additionally, IFN-ß-exposed myobundles were treated with Janus kinase inhibitors (JAKis) tofacitinib and baricitinib. These myobundles were also analyzed for contractile force and immunohistochemistry. RESULTS: IFN-ß, but not IFN-α, was associated with decreased contractile tetanus force and slowed twitch kinetics. These effects were reversed by tofacitinib and baricitinib. Type I IFN paradoxically reduced myobundle fatigue, which did not reverse after JAKi. Additionally, type I IFN correlated with MHC I upregulation, which normalized after JAKi treatment, but expression of myositis-specific autoantigens Mi-2, melanocyte differentiation-associated protein 5 and the endoplasmic reticulum stress marker GRP78 were variable and donor specific after type I IFN exposure. CONCLUSION: IFN-α and IFN-ß have distinct effects on pediatric skeletal muscle and these effects can partially be reversed by JAKi treatment. This is the first study illustrating effective use of a three-dimensional human skeletal muscle model to investigate JDM pathogenesis and test novel therapeutics.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase.

BACKGROUND AND PURPOSE: Elevation of serum creatine kinase (CK) or hyperCKemia is considered a biological marker of myopathies. However, selective elevation of serum aldolase with normal CK has been reported in a few myopathies, including dermatomyositis, immune-mediated myopathy with perimysial pathology and fasciitis with associated myopathy. The aim was to investigate the disease spectrum of myopathies with isolated aldolase elevation. METHODS: Medical records were reviewed to identify patients >18 years old seen between December 1994 and June 2020 who had pathologically proven myopathies with elevated aldolase and normal CK level. Patients with alternative causes of aldolase elevation were excluded. RESULTS: Thirty-four patients with various types of myopathies were identified. Myopathies were treatable in 27 patients. The three most common etiologies were dermatomyositis (n = 8), overlap myositis (n = 4) and nonspecific myopathy (n = 4). Perimysial pathology comprising inflammation, fragmentation, vasculitis, calcified perimysial vessels or extracellular amyloid deposition was found in 17/34 patients (50%). Eight dermatomyositis patients with selective elevated aldolase were compared to 24 sex- and age-matched patients with dermatomyositis and hyperCKemia. Dermatomyositis patients with normal CK significantly (p < 0.05) had less frequent cutaneous involvement (50.0% vs. 100.0%) and fibrillation potentials (50.0% vs. 90.5%) but higher median erythrocyte sedimentation rate (33.5 vs. 13.5 mm/h) and more common perifascicular mitochondrial pathology (37.5% vs. 4.2%). CONCLUSION: Isolated aldolase elevation can be found in a greater variety of myopathies than initially thought and most were treatable. Dermatomyositis is the most common myopathy with selective elevation of aldolase in our cohort, which features some unique characteristics compared to dermatomyositis with hyperCKemia.

Effect of atorvastatin on muscle tissues of dermatomyositis and antisynthetase syndrome patients with dyslipidemia.

INTRODUCTION: In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an unprecedented way, the safety of atorvastatin on the muscular tissues of these patients. METHODS: Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia [6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo]. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed. RESULTS: In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I. CONCLUSION: Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Idiopathic inflammatory myopathies - The burden of disease: Cohort analysis focusing on damage and comorbidities.

INTRODUCTION/BACKGROUND: Idiopathic Inflammatory Myopathies (IIM) continue to be a major clinical challenge worldwide. The exact aetiopathogenesis of this chronic and disabling disease remains elusive, preventing the development of novel and effective therapeutic strategies and leading to a high incidence of damage. The complexity of treating these diseases is even greater due to the numerous comorbidities that affect these patients. METHODS: Retrospective review of the cohort of patients diagnosed with IIM and followed in a dedicated unit of a tertiary hospital between 1971 and December 2022, with particular attention to damage and comorbidities. Damage was assessed using the Myositis Damage Index. Comorbidities were recorded and analysed as a whole and also assessed using the Charlson Comorbidity Index. Health Assessment Questionnaire (HAQ) Disability Index (DI) was performed by phone call in December 2022, to all patients actively followed-up in the Unit. RESULTS: Analysis of 149 patients with a mean follow-up of 9 years (range 0-51) revealed >90% with damage and comorbidities. Most comorbidities were a consequence of the damage and were particularly related to prolonged steroid therapy. Cardiovascular damage, which occurred either as cardiovascular risk factors or as end-organ sequelae (cardiovascular disease and chronic kidney disease), was the main cause and a major contributor to death. Depression was also high on the list of associated comorbidities. Median HAQ was 2.09 representing high negative impact in quality of life. CONCLUSIONS: Although survival rates have increased in recent decades, patients with IIM carry a high burden of disease with poor quality of life, mainly caused by damage and comorbidities. While comorbidities accumulation is the major factor for poor quality of life, damage severity is the main predictor for mortality. Improved therapeutic strategies are needed to reduce the need for steroids and to introduce routine screening and management of comorbidities as an essential partner of immunosuppressive therapy, leading to comprehensive care of myositis patients and effective improvement of their quality of life.

Update on muscle imaging in myositis.

PURPOSE OF REVIEW: Imaging techniques such as MRI, ultrasound and PET/computed tomography (CT) have roles in the detection, diagnosis and management of myositis or idiopathic inflammatory myopathy (IIM). Imaging research has also provided valuable knowledge in the understanding of the pathology of IIM. This review explores the latest advancements of these imaging modalities in IIM. RECENT FINDINGS: Recent advancements in imaging of IIM have seen a shift away from manual and qualitative analysis of the images. Quantitative MRI provides more objective, and potentially more sensitive characterization of fat infiltration and inflammation in muscles. In addition to B-mode ultrasound changes, shearwave elastography offers a new dimension to investigating IIM. PET/CT has the added advantage of including IIM-associated findings such as malignancies. SUMMARY: It is evident that MRI, ultrasound and PET/CT have important roles in myositis. Continued technological advancement and a quest for more sophisticated applications help drive innovation; this has especially been so of machine learning/deep learning using artificial intelligence and the developing promise of texture analysis.

Single cell RNA sequencing sheds light on infiltrating T cells in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM), also referred to as "myositis," are a group of heterogeneous autoimmune disorders characterised by muscle weakness, atrophy and progressive reduced mobility (Lundberg et al, 2021). IIM represent a significant health burden in adult populations, affecting individuals at a mean age of 50 with an estimated prevalence of 2.9-34 per 100,000 (Dobloug et al, 2015; Svensson et al, 2017). IIM encompass several subtypes including dermatomyositis, immune-mediated necrotising myopathy, inclusion-body myositis, antisynthetase syndrome and polymyositis, which are characterised by specific clinical features, histopathological findings and autoantibody status (Pinal-Fernandez et al, 2020).

Toll-like receptors and IL-7 as potential biomarkers for immune-mediated necrotizing myopathies.

We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune-mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP+ and HMGCR+ muscle samples (p < 0.0001 in SRP+ and p = 0.0316 for HMGCR+ ), with higher values for SRP+ (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll-like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP+ compared to HMGCR+ patients. Within IMNM group, only IL-7 was differentially expressed between SRP+ and HMGCR+ patients, with higher values in SRP+ patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL-7 represent potential immune biomarkers able to differentiate between SRP+ and HMGCR+ patients.

Pembrolizumab-Induced Fatal Myasthenia, Myocarditis, and Myositis in a Patient with Metastatic Melanoma: Autopsy, Histological, and Immunohistochemical Findings-A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) represent a major advance in cancer treatment. The lowered immune tolerance induced by ICIs brought to light a series of immune-related adverse events (irAEs). Pembrolizumab belongs to the ICI class and is a humanized IgG4 anti-PD-1 antibody that blocks the interaction between PD-1 and PD-L1. The ICI-related irAEs involving various organ systems and myocarditis are uncommon (incidence of 0.04% to 1.14%), but they are associated with a high reported mortality. Unlike idiopathic inflammatory myositis, ICI-related myositis has been reported to frequently co-occur with myocarditis. The triad of myasthenia, myositis, and myocarditis must not be underestimated as they can rapidly deteriorate, leading to death. Herein we report a case of a patient with metastatic melanoma who fatally developed myasthenia gravis, myocarditis, and myositis, after a single cycle of pembrolizumab. Considering evidence from the literature review, autopsy, histological, and immunohistochemical investigations on heart and skeletal muscle are presented and discussed, also from a medical-legal perspective.

Muscle fiber necroptosis in pathophysiology of idiopathic inflammatory myopathies and its potential as target of novel treatment strategy.

Idiopathic inflammatory myopathies (IIMs), which are a group of chronic and diverse inflammatory diseases, are primarily characterized by weakness in the proximal muscles that progressively leads to persistent disability. Current treatments of IIMs depend on nonspecific immunosuppressive agents (including glucocorticoids and immunosuppressants). However, these therapies sometimes fail to regulate muscle inflammation, and some patients suffer from infectious diseases and other adverse effects related to the treatment. Furthermore, even after inflammation has subsided, muscle weakness persists in a significant proportion of the patients. Therefore, the elucidation of pathophysiology of IIMs and development of a better therapeutic strategy that not only alleviates muscle inflammation but also improves muscle weakness without increment of opportunistic infection is awaited. Muscle fiber death, which has been formerly postulated as "necrosis", is a key histological feature of all subtypes of IIMs, however, its detailed mechanisms and contribution to the pathophysiology remained to be elucidated. Recent studies have revealed that muscle fibers of IIMs undergo necroptosis, a newly recognized form of regulated cell death, and promote muscle inflammation and dysfunction through releasing inflammatory mediators such as damage-associated molecular patterns (DAMPs). The research on murine model of polymyositis, a subtype of IIM, revealed that the inhibition of necroptosis or HMGB1, one of major DAMPs released from muscle fibers undergoing necroptosis, ameliorated muscle inflammation and recovered muscle weakness. Furthermore, not only the necroptosis-associated molecules but also PGAM5, a mitochondrial protein, and reactive oxygen species have been shown to be involved in muscle fiber necroptosis, indicating the multiple target candidates for the treatment of IIMs acting through necroptosis regulation. This article overviews the research on muscle injury mechanisms in IIMs focusing on the contribution of necroptosis in their pathophysiology and discusses the potential treatment strategy targeting muscle fiber necroptosis.