Recent Updates on the Pathogenesis of Inflammatory Myopathies.

PURPOSE OF REVIEW: This review aims to provide a comprehensive and updated overview of autoimmune myopathies, with a special focus on the latest advancements in understanding the role of autoantibodies. We will begin by examining the risk factors and triggers associated with myositis. Next, we will delve into recent research on how autoantibodies contribute to disease pathogenesis. Finally, we will explore the latest innovations in treatment strategies and their implications for our understanding of myositis pathogenesis. RECENT FINDINGS: Recent research has revealed that myositis-specific autoantibodies can infiltrate muscle cells and disrupt the function of their target autoantigens, playing a crucial role in disease pathogenesis. Significant advances in treatment include CD19 CAR-T cell therapy, JAK-STAT inhibitors, and novel strategies targeting the type 1 interferon pathway in dermatomyositis. Additionally, the ineffectiveness of complement inhibitors in treating immune-mediated necrotizing myositis has challenged established views on disease mechanisms. Autoimmune myopathies are a collection of disorders significantly influenced by specific autoantibodies that drive disease pathogenesis. This review highlights the critical role of autoantibody research in deepening our understanding of these conditions and discusses recent therapeutic advancements targeting key pathogenic pathways.

Inflammatory Myopathy: When Electromyography and Autoantibodies Don't Help the Diagnosis.

Inflammatory myopathies (IM) are the most treatable myopathies. Necrotizing autoimmune myositis is a distinct clinicopathologic entity that starts either acutely or subacutely. Autoimmunity is essencial in the pathogenesis of myositis and autoantibodies may be present in more than 50% of patients. We present the case of a 73-year-old man with elevated levels of CK and aldolase, and proximal symmetric muscle weakness and weight loss. The etiological investigation revealed, via muscle biopsy, a necrotizing autoimmune myositis, even though the majority of usual autoantibodies and electromyography were negative. The case demonstrates the importance of combining the patient's symptoms, neurological examination, and analytical changes to corroborate the suspicion of myopathy.

Pathogenic autoantibody internalization in myositis.

Objectives: Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins. Methods: Confocal immunofluorescence microscopy was used to localize antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to study the transcriptomic profiles of 668 samples from patients with myositis, disease controls, and healthy controls. Antibodies from myositis patients were introduced into cultured myoblasts by electroporation and the transcriptomic profiles of the treated myoblasts were studied by bulk RNA sequencing. Results: In patients with myositis autoantibodies, antibodies accumulated inside myofibers in the same subcellular compartment as the autoantigen. Each autoantibody was associated with effects consistent with dysfunction of its autoantigen, such as the derepression of genes normally repressed by Mi2/NuRD in patients with anti-Mi2 autoantibodies, the accumulation of RNAs degraded by the nuclear RNA exosome complex in patients with anti-PM/Scl autoantibodies targeting this complex, and the accumulation of lipids within myofibers of anti-HMGCR-positive patients. Internalization of patient immunoglobulin into cultured myoblasts recapitulated the transcriptomic phenotypes observed in human disease, including the derepression of Mi2/NuRD-regulated genes in anti-Mi2-positive dermatomyositis and the increased expression of genes normally degraded by the nuclear RNA exosome complex in anti-PM/Scl-positive myositis. Conclusions: In myositis, autoantibodies are internalized into muscle fibers, disrupt the biological function of their autoantigen, and mediate the pathophysiology of the disease.

Chronic Anti-HMG-CoA Reductase Positive Necrotizing Myositis With Remote Exposure to Statins.

The use of statins may be associated with muscle-related side effects ranging from myalgia to rhabdomyolysis. A rare adverse effect is statin-induced anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase (anti-HMGCR) necrotizing myositis, which may develop after exposure to statins due to autoantibodies against HMG-Co-A reductase. We present the case of a 76-year-old male who developed progressive muscle weakness three years after exposure to statins. He had significantly elevated creatine kinase (CK) levels, despite the discontinuation of statins three years prior. He complained of generalized muscle weakness, and examination revealed reduced strength, especially in the proximal musculature. MRI revealed inflammatory myositis of the medial and posterior compartments of bilateral thighs. Autoimmune workup was positive for anti-HMG-CoA reductase antibodies. Muscle biopsy showed endomysial inflammation with fibrosis and fat replacement, suggesting chronic but active myositis. A diagnosis of chronic anti-HMGCR necrotizing myositis was made. The patient was started on oral prednisone and methotrexate with improvement in symptoms and CK levels. This case highlights a chronic form of a rare cause of myositis that may be a challenge to diagnose given the remote exposure to statins.

Intravenous Immunoglobulin in Idiopathic Inflammatory Myopathies: a Practical Guide for Clinical Use.

PURPOSE OF REVIEW: Idiopathic inflammatory myopathies (IIM) are a complex family of autoimmune systemic disorders which often affect muscle and/or skin. IIM cause significant morbidity and mortality, but optimal treatment is uncertain. This review provides a practical guide for using intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) in the management of IIM, including dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myositis (IMNM), and spontaneous inclusion body myositis (IBM), based on relevant recent literature and experience. We summarize pertinent considerations when using IVIG in special circumstances, including myositis-related dysphagia, interstitial lung disease (ILD), calcinosis cutis, and pregnant patients. This review also discusses IVIG safety, available formulations, and costs. RECENT FINDINGS: While IVIG has been used de facto for severe IIM for over 30 years, prior clinical trials of IVIG were notably limited. Recently, however, IVIG has proven safe and effective against IIM in several high-impact publications, including a large prospective, randomized placebo-controlled phase III study in DM. IVIG is useful against both muscular and extra-muscular manifestations in many types of IIM. It can be used as a first-line, steroid-sparring agent or as add-on to other treatments, tailored to specific clinical IIM scenarios. It is generally well-tolerated and has good safety profile, but accessibility and cost still limit its use.

A machine learning analysis to evaluate the outcome measures in inflammatory myopathies.

OBJECTIVE: To assess the long-term outcome in patients with Idiopathic Inflammatory Myopathies (IIM), focusing on damage and activity disease indexes using artificial intelligence (AI). BACKGROUND: IIM are a group of rare diseases characterized by involvement of different organs in addition to the musculoskeletal. Machine Learning analyses large amounts of information, using different algorithms, decision-making processes and self-learning neural networks. METHODS: We evaluate the long-term outcome of 103 patients with IIM, diagnosed on 2017 EULAR/ACR criteria. We considered different parameters, including clinical manifestations and organ involvement, number and type of treatments, serum creatine kinase levels, muscle strength (MMT8 score), disease activity (MITAX score), disability (HAQ-DI score), disease damage (MDI score), and physician and patient global assessment (PGA). The data collected were analysed, applying, with R, supervised ML algorithms such as lasso, ridge, elastic net, classification, and regression trees (CART), random forest and support vector machines (SVM) to find the factors that best predict disease outcome. RESULTS AND CONCLUSION: Using artificial intelligence algorithms we identified the parameters that best correlate with the disease outcome in IIM. The best result was on MMT8 at follow-up, predicted by a CART regression tree algorithm. MITAX was predicted based on clinical features such as the presence of RP-ILD and skin involvement. A good predictive capacity was also demonstrated on damage scores: MDI and HAQ-DI. In the future Machine Learning will allow us to identify the strengths or weaknesses of the composite disease activity and damage scores, to validate new criteria or to implement classification criteria.

The pattern of MHC class I expression in muscle biopsies from patients with myositis and other neuromuscular disorders.

OBJECTIVE: Diagnostic muscle biopsies are routinely immunostained for major histocompatibility complex class I (MHC-I) protein. In this study we analysed the prevalence and patterns of MHC-I immunostaining in biopsies from patients with different types of myopathies and neurogenic disorders. METHODS: All 357 diagnostic muscle biopsies processed at the Johns Hopkins Neuromuscular Pathology Laboratory from August 2013 to January 2017 were immunostained for MHC-I. The prevalence and patterns of MHC-I immunostaining were compared between patients with histologically normal muscle biopsies (n = 31), idiopathic inflammatory myopathies (IIMs; n = 170), non-inflammatory myopathies (n = 60) and neurogenic disorders (n = 96). RESULTS: MHC-I immunostaining was abnormal in most patients with DM (98%), sporadic IBM (sIBM; 100%), immune-mediated necrotizing myopathy (IMNM; 100%) and polymyositis (77%). In contrast, MHC-I immunostaining was less frequently present in non-inflammatory myopathies (32%) or neurogenic disorders (30%). Overall, abnormal MHC-I immunostaining had a sensitivity of 0.95 and a specificity of 0.82 for diagnosing IIMs. A focal MHC-I staining pattern was associated with IMNM, whereas a global pattern was more prevalent in sIBM and a perifascicular pattern was significantly more common in dermatomyositis. Among 18 DM biopsies without perifascicular atrophy, 50% had a perifascicular MHC-I staining pattern. Sarcoplasmic upregulation staining was more common than sarcolemmal staining across all groups. CONCLUSION: MHC-I immunostaining was useful to distinguish IIMs from non-inflammatory myopathies or neurogenic disorders. Of note, a perifascicular MHC-I staining pattern was present only in those with DM, including half of those without perifascicular atrophy; many of these biopsies may not otherwise have been diagnostic for DM.

A Rare Case of Rhabdomyolysis.

Rhabdomyolysis is a pathological condition presenting with symptoms of localized or generalized myalgia and weakness, associated with an increase in serum creatine kinase level and, often leading to myoglobinuria and acute kidney injury. It has a wide range of etiologies. Immune-mediated necrotizing myopathy (IMNM) is a rare type of inflammatory myopathy, that leads to rhabdomyolysis, and it is divided into three different subtypes: anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR, anti-signal recognition particle (anti-SRP), and seronegative. There are slight differences in incidence, age of onset, clinical course, and prognosis between these subtypes. We describe the case of a 67-year-old female with myalgias and weakness of the thighs for six weeks. Laboratory findings showed marked rhabdomyolysis and severe acute kidney injury. The workup led to the diagnosis of seronegative immune-mediated necrotizing myopathy (IMNM) and treatment with corticosteroid and methotrexate was introduced, which led to marked clinical improvement.

Hyperbaric oxygen therapy as adjuvant therapy for odontogenic necrotizing myositis: A case report.

In a young man affected by skin soft tissue infections complicated with myositis, the use of hyperbaric oxygen treatment as an adjuvant therapy to surgical debridement and antibiotic therapy could improve management and prognosis.

Therapeutic management of immune-mediated necrotizing myositis.

PURPOSE OF REVIEW: The idiopathic inflammatory myopathies are a heterogeneous group of autoimmune disorders characterized by skeletal muscle inflammation leading to chronic muscle weakness. Immune-mediated necrotizing myopathy (IMNM) is a distinct subgroup of inflammatory myopathy typically characterized by myofiber necrosis with minimal inflammatory infiltrates on muscle biopsy, highly elevated creatine kinase levels, and infrequent extra-muscular involvement. This review provides an overview of currently recommended treatment strategies for IMNM, including discussion of disease activity monitoring and recommended first-line immunomodulatory agents depending on clinical phenotype and autoantibody status. RECENT FINDINGS: IMNM can be divided into three subtypes based on autoantibody positivity: anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) IMNM, anti-signal recognition particle (SRP) IMNM, and antibody negative IMNM. Autoantibody status in IMNM has considerable correlation with clinical phenotype, prognosis, and recommended choice of immunosuppressive agent. Patients with anti-HMGCR IMNM tend to respond well to intravenous immunoglobulin (IVIG), and IVIG monotherapy may be sufficient treatment for certain patients. In anti-SRP IMNM, early rituximab is commonly favored. More generally, prompt initiation of aggressive immunosuppression is often indicated, as both anti-SRP and anti-HMGCR IMNM can potentially cause debilitating weakness, and muscle atrophy and irreversible fatty replacement happen early in the disease course. Patients with IMNM frequently require combination therapy to achieve disease control, and have a high rate of relapse when tapering immunosuppression. Young age of onset is a poor prognostic factor. SUMMARY: IMNM can be severely disabling and often requires aggressive immunosuppression. For any given patient, the treatment strategy should be informed by the severity of their presenting features and autoantibody status. While our ability to treat IMNM has certainly improved, there remains a need for more prospective trials to inform optimal treatment strategies.

Novel Presentation of Aphasia and Tremor in Immune-Mediated Necrotizing Myopathy.

The authors present a unique case of immune-mediated necrotizing myopathy in a 60-year-old female who presented with aphasia, tremor, and progressive muscular weakness. To the best of our knowledge, the presentation of aphasia and tremor has not been previously reported in immune-mediated necrotizing myopathy. This rare presentation may mimic a variety of other central nervous system and myopathic disorders. Delays in prompt diagnosis and treatment of immune-mediated necrotizing myopathy can be detrimental to the physical and mental well-being of the patient and additionally leads to inefficient use of healthcare resources. Therefore, it is beneficial for clinicians to be aware of this symptomatic presentation in order to include immune-mediated necrotizing myopathy as a key differential diagnosis. Awareness of aphasia and tremor as potential symptoms of immune-mediated necrotizing myopathy will improve the quality of patient care.

A Rapidly Debilitating Myopathy: A Rare Case of Statin-Induced Necrotizing Myositis.

Statins are well tolerated in general but can be associated with myopathies. Statin-induced myopathies can range widely from mild myalgias to necrotizing autoimmune myopathies. We present a case of an 81-year-old man on statins for five years with no complications, who developed progressive muscle weakness, rhabdomyolysis, and dysphagia. His laboratory workup revealed elevated inflammatory markers with creatine kinase (CK) levels above 2000 U/L. The myositis panel was negative, and the anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody was positive. His muscle biopsy showed randomly scattered necrotic fibers with minimal perivascular inflammation confirming statin-induced necrotizing autoimmune myopathy (SINAM). Statins were discontinued immediately after initial suspicion. The patient was started on intravenous immunoglobulin followed by hydrocortisone and mycophenolate mofetil. The patient continued to have muscle weakness and progressive dysphagia to the point that he could not handle his secretions. His disease course was complicated by recurrent aspiration pneumonia. Percutaneous endoscopic gastrostomy tube placement was considered, but his family decided on hospice care given his overall comorbidities. Physicians should note that SINAM can occur after a few months to several years of statin use. This disease can be rapidly debilitating and progress even after discontinuation of statins, and treatment requires immunosuppressants, including steroids and steroid-sparing agents.

Statin-Induced Necrotizing Autoimmune Myositis: Diagnosis and Management.

Statins are among the most frequently prescribed drugs as they effectively lower cardiovascular mortality. Atherosclerotic plaques are stabilized and lipid levels are lowered, as statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Patients placed on these drugs frequently report muscle aches, but true myositis that would call for discontinuance of the drug is actually uncommon. Workup for statin-induced myositis would require ruling out other causes of myositis and muscular dystrophies, and this can often be perplexing for the primary care physician to whom these patients initially present. This case report and recommendations may serve as a helpful guide.

Fulminant necrotizing streptococcal myositis with dramatic outcome - a rare case report.

Necrotizing myositis represents a rare, aggressive form of bacterial-induced soft tissue necrotizing infection. We present a fulminant case of a 44-year-old patient with a necrotizing soft tissue infection and a history of rheumatoid arthritis transferred to our service, Cluj-Napoca Emergency County Hospital, from a local hospital where he had been admitted two days before with chills and light-headedness after an accidental minor blunt trauma in the right thigh region. After admission to our hospital and first assessment, broad spectrum antibiotherapy was started with Meropenem, Vancomycin and Metronidazole along with surgical debridement. The evolution was fulminant with rapid development of multiple organ dysfunction syndrome, therefore he was transferred to the intensive care unit, intubated, and started the volemic resuscitation and vasopressor therapy. The blood culture was positive for group A beta-hemolytic streptococcus (GAS) and high dose Penicillin G was added to the therapeutic scheme. Despite all efforts, the patient developed disseminated intravascular coagulation syndrome and died in the next hours. The clinical picture together with the findings from the autopsy were suggestive for a streptococcal toxic shock syndrome developed as a complication of GAS induced necrotizing myositis.

Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.

PURPOSE: to describe an unusual case of necrotizing myositis in a rectus muscle, possibly related to BRAF inhibitor therapy. OBSERVATIONS: An 18-year old man with neurodegenerative Langerhans cell histiocytosis (LCH), recently started on the BRAF inhibitor dabrafenib, presented with right eye pain. Magnetic resonance imaging (MRI) orbits revealed a rectus muscle mass concerning for LCH recurrence or malignancy. Dabrafenib was stopped, and incisional biopsy of the mass was performed. The mass was absent on post-operative MRI, so no further treatment was pursued. Histopathologic evaluation was initially concerning for sarcoma, but on further analysis, appeared more consistent with necrotizing myositis. The mass did not recur, nor did the patient develop other signs or symptoms concerning for myositis or malignancy over a 24-month follow-up period. CONCLUSIONS: Necrotizing myositis has not been previously described in a rectus muscle or with BRAF inhibitor use, though myalgias and malignancies are established side effects. Necrotizing myositis may masquerade as sarcoma and should be on the differential diagnosis for a new mass in the setting of dabrafenib therapy.

Necrotizing myositis: highlighting the hidden depths - case series and review of the literature.

BACKGROUND: Necrotizing myositis (NM) is a life-threatening emergency. It causes focal muscle necrosis without abscess formation or extensive involvement of the overlying fascia and soft tissue. It is a clinical diagnosis requiring a high index of clinical suspicion. Usual presentation can readily be mistaken to represent more benign pathologies such as muscular injury, viral myopathy or deep venous thrombosis. The clinical course following initial misdiagnosis is rapid deterioration into profound sepsis and progressive multiorgan failure. Prompt treatment is associated with favourable outcomes, but early diagnosis is challenging due to initial absence of cutaneous signs and symptoms. Delayed referral to surgeons with appropriate expertise results in higher morbidity and mortality. The cornerstones to treatment are complete surgical debridement, intensive care management and accurate antimicrobial therapy. METHODS: We report four cases of NM demonstrating classical scenarios of initial misdiagnosis, delays in referral and review by an experienced surgeon. A review of the current literature to aid with overall management is also included. RESULTS: Review of literature that revealed the most common presentation was antecedent prodromal flu-like symptoms followed by rapidly progressing focal muscle pain. Patients were initially misdiagnosed followed by rapid deterioration into profound sepsis before surgical opinion was obtained. CONCLUSION: NM is a rare and potentially fatal disease that must be considered in the differential diagnoses of the young, healthy patient with acute limb pain and fever. A high index of suspicion will facilitate earlier management and reduce morbidity and mortality.

Necrotizing myositis case report and brief literature study.

Necrotizing myositis is an extremely rare soft tissue infection, mainly caused by Group A Streptococci. Although its presentation is nonspecific and seems harmless, it quickly leads to death in almost all cases. Therefore, diagnosis and treatment of necrotizing myositis are considered as medical emergencies. The 27 years old patient we report benefited from early diagnosis and care. Necrotic tissues were surgically removed 24 hours after the appearance of the first clinical signs. Intravenous antibiotherapy as well as immunoglobulin therapy were also given on the first day. Starting from this clinical case, we present a brief explanation of the pathogenesis, the key clinical features and appropriate tools for diagnosis. Then, adequate antibiotherapy, role of immunoglobulin therapy and interest of hyperbaric oxygenotherapy will be discussed.