Auswahl der wissenschaftlichen Literatur zum Thema „Immune-mediated necrotizing myopathies“

Immune-mediated necrotizing myopathies (IMNMs) are a group of acquired autoimmune muscle disorders which are characterized by proximal muscle weakness, high levels of creatinine kinase, and myopathic findings on electromyogram (EMG). Muscle biopsy in IMNM differentiates it from the other subgroups of Idiopathic Inflammatory Myositis (IIM) by the presence of myofibre necrosis and prominent regeneration without substantial lymphocytic inflammatory infiltrates. Anti-signal recognition particle (SRP) and anti-3hydroxy-3 methylglutarylcoenzyme A reductase (HMGCR) autoantibodies were found in two-thirds of IMNM patients. In terms of treatment, IMNM is more resistant to conventional immunosuppressive treatment, therefore, other modalities of treatment such as Intravenous Immunoglobulin (IVIG) and rituximab are often required.

ObjectiveTo investigate the relevance of dysfunctional T cells in immune-mediated myopathies. We analyzed T-cell exhaustion and senescence, in the context of programmed cell death protein 1 (PD1)-related immunity in skeletal muscle biopsies from patients with immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis (sIBM), and myositis induced by immune checkpoint inhibitors (irMyositis).MethodsSkeletal muscle biopsies from 12 patients with IMNM, 7 patients with sIBM, and 8 patients with irMyositis were analyzed by immunostaining and immunofluorescence as well as by quantitative PCR. Eight biopsies from nondisease participants served as controls.ResultsCD3+CD8+ T cells in biopsies from IMNM, sIBM, and irMyositis were largely PD1-positive, while CD68+ macrophages were sparsely positive to the ligand of programmed cell death protein 1 (PD-L1). The sarcolemma of myofibers was PD-L2+ and was colocalized with major histocompatibility complex (MHC) class I. CD68+ macrophages were colocalized with PD-L2. Senescent T cells were strongly enriched in skeletal muscle of sIBM, revealing a distinct immunologic signature. Biopsies from patients with irMyositis showed mild signs of senescence and exhaustion.ConclusionPersistent exposure to antigens in IMNMs and sIBM may lead to T-cell exhaustion, a process controlled by the PD1 receptor and its cognate ligands PD-L1/PD-L2. To our knowledge, these data are the first evidence of presence of dysfunctional T cells and relevance of the PD1 pathway in IMNM, sIBM, and irMyositis. These findings may guide the way to a novel understanding of the immune pathogenesis of immune-mediated myopathies.

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies showing necrotic and regenerating fibers without noteworthy inflammatory cell infiltration on pathology. The pathologic findings are different from those of dermatomyositis or sporadic inclusion body myositis. Furthermore, the discovery of myositis-specific antibodies in patients with IMNM, such as anti-signal recognition particle or anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies, has enabled us to expand our knowledge of IMNM. However, the phenotype and pathological findings of IMNM are unremarkable; therefore, it is difficult to diagnose, and IMNM has been relatively unrecognized. In this review, we introduce the clinical features, diagnosis, pathomechanism, and treatment of IMNM for clinicians.

Abstract Skeletal muscle involvement by noncaseating granulomata occurs in a variety of conditions, including sarcoidosis, infections, and rarely in association with primary inflammatory myopathies such as inclusion body myositis (IBM) and dermatomyositis (DM). Sarcoid myopathy is typically asymptomatic; however, a picture of acute myositis with proximal muscle weakness has been described. Immune-mediated necrotizing myopathy (IMNM) is a subgroup of inflammatory myopathies typically presenting with proximal muscle weakness and markedly elevated muscle enzymes, mostly occurring in the setting of statin treatment. IMNM is associated with positive autoantibodies, but a subset of cases is antibody negative. Here we describe a case of myopathy occurring in association with sarcoidosis with combined features of granulomatous and necrotizing myopathy. The patient was a 54-year-old African American male with medical history significant for statin use 3 years ago, which was discontinued due to myalgia and elevated muscle enzymes and biopsy-proven sarcoidosis diagnosed on a pulmonary lymph node biopsy. He presented with progressive worsening of bilateral proximal weakness involving the upper and lower extremities. Electromyogram showed features of active myopathy with no evidence of peripheral neuropathy. Myositis panel was negative for the following antibodies: anti-Jo1, Mi-2, anti-Ku, PL-7, PL-12, OJ, EJ, and SRP. However, there was elevation of aldolase, CRP, and CK-MB. Biopsy of thigh and deltoid muscle showed necrotic muscle fibers, myophagocytosis with associated minimal inflammation, and multiple well-formed nonnecrotizing granulomas with multinucleated giant cells. Myopathic features include increased internalized nuclei, round atrophic fibers, and scattered split fibers. Specific features of IBM or DM were not present. Conclusion Myopathies developing or worsening after discontinuation of statin are rare. The association of necrotizing myopathy with sarcoidosis is not well described in the literature. Additional studies are warranted to elucidate this association.

AbstractThe inflammatory myopathies comprise disorders of immune-mediated muscle injury. The histopathology and clinical features help distinguish them. Juvenile dermatomyositis (JDM) is the most common form of myositis in children and adolescents. Children with JDM present with proximal muscle weakness and characteristic rashes. The presentation is similar in children and adults, but JDM is a primary disorder and the adult form often is concerning for a paraneoplastic syndrome. Proximal muscle weakness occurs with dermatomyositis, polymyositis, and immune-mediated necrotizing myopathy, but the latter two conditions have no dermatologic findings or distinct tissue changes which set them apart from dermatomyositis. Inclusion body myositis, also included in the inflammatory myopathies, presents with more distal involvement, and microscopically exhibits identifiable rimmed vacuoles. We review key features of these disorders, focusing in more detail on JDM because it is more often encountered by the child neurologist.

Objective:To describe the experience managing treatment-refractory immune-mediated necrotizing myopathies (IMNM) with high-dose cyclophosphamide (HiCy) therapy.Methods:Five patients with severe refractory IMNM who were treated with HiCy without stem cell rescue were identified. Their medical records were reviewed to assess demographic, clinical, and histologic characteristics as well as response to therapy.Results:Three patients with anti–signal recognition particle (SRP) and 2 patients with anti-HMG-CoA reductase autoantibodies were included. The mean follow-up time after HiCy therapy was 37 ± 28 months. Two patients demonstrated substantial response, evidenced by improved muscle strength and decreased muscle enzymes after HiCy therapy; both of these patients were anti-SRP positive. Four patients experienced febrile neutropenia after HiCy therapy, one of which required a prolonged intensive care unit stay for infectious complications, from which they eventually recovered.Conclusions:These data suggest that HiCy therapy without stem cell rescue may be considered as an alternative for the treatment of refractory IMNM.

Immune-mediated necrotizing myopathy, a new subgroup of inflammatory myopathies, usually begins with subacute onset of symmetrical proximal muscle weakness. A 35-year-old male presented with severe asymmetric iliopsoas atrophy and low back pain with a previous history of left lower extremity weakness. Although his first left lower extremity weakness occurred 12 years ago, he did not receive a clear diagnosis. Magnetic resonance imaging of both thigh muscles showed muscle edema and contrast enhancement in patch patterns, and the left buttock and thigh muscles were more atrophied compared to the right side. Serum creatine kinase levels were elevated, and serologic testings were all negative. Genetic testing using a targeted gene-sequencing panel for neuromuscular disease including myopathy identified no pathogenic variants. Muscle biopsy on the right vastus lateralis showed scattered myofiber necrosis with phagocytosis and an absence of prominent inflammatory cells, consistent with seronegative necrotizing myopathy. Thus, unusual asymmetric muscle weakness and atrophy can be a manifestation of inflammatory myopathy.

The idiopathic inflammatory myopathies are chronic diseases of the skeletal muscle that comprise various conditions, including dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and the antisynthetase syndrome. Although there are a number of distinguishing features, all these disorders are characterized by an immune and inflammatory response mainly directed against the muscle. Hence, therapy is geared toward curbing the autoimmune and inflammatory response. A quite wide range of medications are currently available to treat these disorders, but despite all therapeutic progress still a number of patients are unable to maintain a sustained remission. In this review article, we have marshaled a variety of potential therapeutic agents that may hold promise for the future treatment of the idiopathic inflammatory myopathies. It is to be expected that by increasing the therapeutic armamentarium with agents that have different mechanisms of action even challenging cases could be successfully managed, thus reducing disease burden and disability.

Les myopathies inflammatoires idiopathiques (MII) sont des maladies musculaires inflammatoires auto-immunes rares pouvant être séparées en 4 sous-groupes : le syndrome des anti-synthétases (SAS), les dermatomyosites (DM), les myopathies nécrosantes auto-immunes (MNAI) et les myosites à inclusions (MI). Ces sous-groupes diffèrent en termes de physiopathologie, de phénotype clinique et de pronostic. La caractéristique principale des MII est une faiblesse musculaire généralisée avec différents degrés de sévérité observés entre les sous-groupes. Les SAS et les DM ont des atteintes musculaires légères à modérées contrairement aux MNAI et MI qui présentent une faiblesse musculaire plus intense avec une faible récupération de la force musculaire après rémission. Les DM, MNAI et SAS ont une survenue rapidement progressive des symptômes, qui est plus lentement progressive pour les MI. L’activité des différentes MII est difficile à évaluer. Certains marqueurs existent mais ne sont pas applicables de la même manière à tous les sous-groupes. Dans ce travail de thèse, j’ai tout d’abord voulu voir si la myostatine, un régulateur de la masse musculaire pouvait être un marqueur d’activité dans les différents sous-groupes. Pour cela, le taux de myostatine a été dosé au niveau protéique dans le sérum et au niveau transcriptomique dans le muscle chez les patients MII et comparé à des donneurs sains. Le taux de myostatine est diminué chez les patients dans le sang ainsi que dans le muscle. Le niveau de myostatine sérique diminué chez les patients SAS et DM ayant une maladie active remonte une fois la maladie contrôlée. Le taux de myostatine pourrait donc être utilisé comme un marqueur d’activité dans ces sous-groupes. Chez les MNAI cependant, le taux de myostatine reste inchangé suggérant des mécanismes pathologiques sous-jacents différents pouvant expliquer la faible récupération de ces patients. Je me suis ensuite intéressée à la physiopathologie des MNAI. Les patients présentent une atteinte musculaire proximale avec une infiltration fibro-adipeuse participant à l’établissement d’une faiblesse musculaire ainsi que la présence de fibres nécrotiques, une infiltration macrophagique, et la présence d’auto-anticorps. J’ai dans un premier temps tenté de mettre au point des modèles cellulaires 2D et 3D in vitro de la maladie mais qui ne se sont pas révélés concluants. Je me suis alors tournée vers une analyse en transcriptomique spatiale des muscles de patients MNAI comparés aux sujets sains. Cette méthode permet d’avoir les transcrits de domaines tissulaires de 55µm répartis sur l’ensemble de la coupe du tissu musculaire. Trois clusters majoritaires se détachent : 2 clusters immunitaires principalement macrophagiques accompagnés d’une signature interféron, l’un pro-inflammatoire et l’autre anti-inflammatoire et un cluster avec une signature de progéniteurs fibro-adipeux (FAP). Ces progéniteurs ont la capacité de se différencier en fibroblastes ou en adipocytes et pourraient alors être à l’origine du l’infiltrat fibro-adipeux des patients. L’augmentation des FAPs a été confirmée par un marquage CD90 sur les biopsies musculaires des patients
Idiopathic inflammatory myopathies (IIM) are a group of rare autoimmune diseases which can be divided into four subgroups: antisynthetase syndrome (ASyS), dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). These subgroups differ in terms of physiopathogenesis, phenotype and prognosis. The main characteristic of IIM is muscle weakness with different degrees of severity being observed between subgroups. ASyS and DM patients have mild to moderate muscle involvement whereas IMNM and IBM patients display a more severe muscle weakness with poor recovery of muscle strength after remission. While most DM, IMNM, and ASyS patients present an acute onset of the symptoms, IBM is characterised by slowly progressing muscle weakness. Disease activity in IIM is difficult to assess. Some markers exist but are not applicable to all subgroups. In this thesis, I first wanted to see if myostatin, an inhibitor of muscle growth could be a marker of disease activity in IIM subgroups. For that, myostatin was dosed at the protein level in the serum and at the transcriptomic level in the muscle of IIM patients and healthy donors. Myostatin is decreased in patients in the blood and in the muscle. Lowered circulating myostatin levels in active ASyS and DM patients are increased when the disease is controlled. Myostatin could therefore be used as a disease activity biomarker in these subgroups. However, in IMNM patients, myostatin levels do not change with the disease activity, suggesting underlying specific pathomechanisms explaining the poor outcome of these patients. I was then particularly interested in IMNM pathogenesis. IMNM is characterised by proximal muscle weakness and a particular fibro-fatty infiltration in muscle over the course of the disease sustaining muscle weakness as well as necrotic fibers, macrophages infiltrates and auto-antibodies. I first tried to establish 2D and 3D in vitro cellular models but they were not conclusive. I then performed an analysis of patients’ muscle biopsies using spatial transciptomics and compared them to healthy donors biopsies. This method allows us to have transcripts of 55µm tissue domains across the entire muscle biopsy. Three major clusters emerge from this analysis: 2 macrophages clusters with an interferon signature, one being pro-inflammatory and the other one anti-inflammatory, and one fibro-adipogenic progenitors’ (FAP) cluster. These progenitors being able to differentiate either into fibroblasts or adipocytes, they could be the origin of the fibro-fatty infiltrate in IMNM patients. This FAPs increase was confirmed by a CD90 staining on muscle biopsies

The term idiopathic inflammatory myopathies (IIM) encompasses a heterogeneous group of muscle-dominant systemic autoimmune syndromes, including polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), and immune-mediated necrotizing myopathy (IMNM). The reported incidence of IIM ranges from 5 to 10 × 10–6. Patients with PM, DM, and IMNM characteristically present with the insidious onset of symmetric proximal weakness, while in sIBM the weakness can be asymmetric, and involve the distal upper limbs and quadriceps. Dermatomyositis may also be accompanied by a range of cutaneous manifestations. Raised serum creatine kinase levels, the presence of characteristic myositis-specific antibodies, myopathic triad on electromyography, and myoedema on muscle magnetic resonance imaging are helpful in supporting a diagnosis of IIM. Muscle biopsy is the definitive diagnostic test and serves to distinguish subsets of disease, which each have characteristic histopathological changes reflecting underlying differences in pathogenesis. Mortality remains elevated in patients with IIM, despite the advent of immunosuppressive therapies.

The idiopathic inflammatory myopathies are a heterogenous group of disorders characterized by muscle weakness, inflammation in muscle tissue, and with frequent extramuscular involvement. Autoantibodies are common, supporting the notion of these disorders being autoimmune. Typically, inflammatory cell infiltrates are found in muscle biopsies. Other organs are frequently involved such as skin, lungs, joints, gastrointestinal tract, and the heart. These heterogenous disorders can be subclassified based on clinical and histopathological features, or by autoantibody specificities. The idiopathic inflammatory myopathies have traditionally comprised polymyositis (PM), dermatomyositis (DM), juvenile DM, PM/DM overlapping with another connective tissue disease, and inclusion body myositis. More recently a subgroup with similar clinical features but with no or scarce inflammation and with pronounced muscle fibre necrosis has been identified and termed immune-mediated necrotizing myopathy.

A 47-year-old man with hypercholesterolemia sought care for a 4-month history of progressive, proximal upper limb weakness and myalgia, followed by dysphagia, difficulty climbing stairs, and facial rash. Discontinuation of atorvastatin was of no benefit. Neurologic examination showed moderate weakness of the neck flexor muscles, shoulder girdle muscles, and finger extensors, and mild weakness of hip flexor and ankle dorsiflexor muscles. He had a heliotrope rash and Gottron sign. Serum testing showed an increased creatine kinase level. Needle electromyography showed myopathic changes with fibrillation potentials in proximal and axial muscles. Biopsy of the deltoid demonstrated a perifascicular pathologic process, including muscle fiber atrophy, and perivascular inflammatory exudate in the perimysium. Immunocytochemical studies showed patchy loss of intramuscular capillaries, some of which had complement (C5b9) deposition, and sarcoplasmic expression of myxovirus resistance protein A, mainly in the perifascicular regions. Immunologic testing was positive for autoantibodies to nuclear matrix protein 2 and negative for 3-hydroxy-3-methylglutaryl–coenzyme A reductase antibodies. Video swallow studies showed oropharyngeal dysphagia. Pulmonary function tests indicated mildly decreased maximal respiratory pressures but normal diffusing lung capacity for carbon monoxide. The findings were consistent with a diagnosis of dermatomyositis. The patient was started on oral prednisone and azathioprine, after checking for adequate thiopurine methyltransferase activity. Liver function tests and complete blood cell count with differential were assessed to monitor for potential azathioprine toxicity. Intravenous immunoglobulin was given. Follow-up examination revealed mild weakness of the shoulder girdle muscles after immunotherapy, and normal strength and creatine kinase value while on azathioprine monotherapy. Dermatomyositis is an idiopathic inflammatory myopathy. Idiopathic inflammatory myopathy is a group of autoimmune muscle diseases that includes dermatomyositis, polymyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and overlap myositis, including antisynthetase syndrome.

Introduction: Myopathies can be caused by various drugs, including statins and corticosteroids, and can be toxic or inflammatory, one example being necrotizing myositis triggered by statins. Objectives: Describe the case of a patient with weakness after statin use. Design and setting: Case report Methods: Analysis of medical record, photographic record of the diagnostic methods and literature review. Case description: 69-year-old female, obese, hypertensive, diabetic, dyslipidemic and hypothyroid, taking atorvastatin since 2017, referred by endocrinology for generalized myalgia in 2019, with increased creatine phosphokinase (CPK). Discontinued statin use since then, maintaining symptoms. Neurological examination showed tetraparesis, with proximal predominance. Electroneuromyography (ENMG) showed signs of myopathy. Corticotherapy with deflazacort was initiated, with improvement of symptoms and reduction of CPK levels. Investigation for paraneoplastic syndrome was performed, with negative results. He started using pioglitazone, prescribed by endocrinology, with reduced corticotherapy, for better glycemic control, presenting worsening weakness, frequent falls, and dyspnea on effort. The patient repeated ENMG in one month, without changes. Performed an anti-HMG-CoA reductase autoantibody test, with a positive result, concluding the diagnosis of immune-mediated necrotizing myositis triggered by statins, with a probable toxic myopathy after use of pioglitazone. Azathioprine was introduced, with gradual weaning from corticosteroids, and physical therapy was started. Conclusion: Several medications can cause myopathy, directly (toxic) or indirectly (immune-mediated), and this patient used 3 potentially myopathy-causing drugs (atorvastatin, deflazacort, and pioglitazone). The nonimprovement upon medication withdrawal suggested an immune-mediated inflammatory cause, confirmed in this case by the determination of a specific autoantibody for statin-induced necrotizing myositis.