[Immune-Mediated Necrotizing Myopathy].

Immune-mediated necrotizing myopathy (IMNM) is a form of autoimmune myositis characterized by the presence of necrotic and regenerating process as a major finding in the muscle. Anti-SRP and anti-HMGCR have been identified as IMNM-specific autoantibodies. Patients with this disease often present with severe muscle weakness and markedly elevated serum creatine kinase (CK) levels. Differentiation from muscular dystrophy is challenging in certain cases. When patients meet the condition "subacute onset", "hyperCKemia over 1000 IU/L", and "clinical diagnosis of muscular dystrophy lacking molecular diagnosis", the possibility of IMNM should be considered. Autoantibody measurement, including of anti-SRP and HMGCR antibodies, is recommended. Treatment with corticosteroid in combination with immunosuppressants, intravenous immunoglobulin, and rituximab can be performed.

Belimumab for Immune-Mediated Necrotizing Myopathy Associated With Anti-SRP Antibodies: A Case Report and Retrospective Review of Patients Treated With Anti-B-Cell Therapy in a Single Center and Literature.

Background: Immune-mediated necrotizing myopathy (IMNM) is characterized by markedly elevated creatinine kinase and histologically scattered necrotic muscle fibers and generally associated with autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coA-reductase (HMGCR). Poor clinical response to conventional therapies and relapses commonly occur in severe cases. Anti-B-cell therapies have been used in refractory/relapsing cases. Methods: The characteristics of a patient with IMNM associated with anti-SRP antibodies including physical examination, laboratory tests, and disease activity assessment were evaluated. Conventional therapy, belimumab treatment schedule, and follow-up data were recorded. Medical records of IMNM patients treated in our department from September 2014 to June 2021 were reviewed to evaluate the efficacy and safety of anti-B-cell therapy for anti-SRP IMNM. A literature review of patients with anti-SRP IMNM treated with anti-B-cell therapies was performed. Results: We describe a case of a 47-year-old woman with IMNM associated with anti-SRP antibodies who relapsed twice after conventional therapy but showed good response and tolerance to belimumab at 28 weeks follow-up. In this review, three patients from our department were treated with rituximab. Two of the three patients rapidly improved after treatment. Twenty patients and five retrospective studies were included in the literature review. All patients were administered rituximab as an anti-B-cell drug. Conclusion: Despite a lack of rigorous clinical trials, considerable experience demonstrated that anti-B-cell therapy might be effective for patients with IMNM associated with anti-SRP antibodies. Belimumab in association with steroids might be an encouraging option for refractory/relapsing cases.

The Significance of Autoantibodies in Juvenile Dermatomyositis.

Juvenile dermatomyositis is a chronic and rare autoimmune disorder classified into the spectrum of idiopathic inflammatory myopathies. Although this entity is mainly characterized by the presence of pathognomonic cutaneous lesions and proximal muscle weakness, the clinical manifestation can be highly heterogeneous; thus, diagnosis might be challenging. Current treatment recommendations for juvenile dermatomyositis, based mainly upon case series, include the use of corticosteroids, immunomodulatory, and immunosuppressive agents. Recently, several specific autoantibodies have been shown to be associated with distinct clinical phenotypes of classic dermatomyositis. There is a need to further evaluate their relevance in the formation of various clinical features. Furthermore, while providing more personalized treatment strategies, one should consider diversity of autoantibody-related subgroups of juvenile dermatomyositis.

Pathology Features of Immune and Inflammatory Myopathies, Including a Polymyositis Pattern, Relate Strongly to Serum Autoantibodies.

We asked whether myopathology features of immune or inflammatory myopathies (IIM), without reference to clinical or laboratory attributes, correlate with serum autoantibodies. Retrospective study included 148 muscle biopsies with: B-cell inflammatory foci (BIM), myovasculopathy, perimysial pathology (IMPP), myofiber necrosis without perimysial or vessel damage or inflammation (MNec), inflammation and myofiber vacuoles or mitochondrial pathology (IM-VAMP), granulomas, chronic graft-versus-host disease, or none of these criteria. 18 IIM-related serum autoantibodies were tested. Strong associations between myopathology and autoantibodies included: BIM with PM/Scl-100 (63%; odds ratio [OR] = 72); myovasculopathies with TIF1-γ or NXP2 (70%; OR = 72); IMPP with Jo-1 (33%; OR = 28); MNec with SRP54 (23%; OR = 37); IM-VAMP with NT5C1a (95%; OR = 83). Hydroxymethylglutaryl-CoA reductase (HMGCR) antibodies related to presence of myofiber necrosis across all groups (82%; OR = 9), but not to one IIM pathology group. Our results validate characterizations of IIM by myopathology features, showing strong associations with some serum autoantibodies, another objective IIM-related marker. BIM with PM/Scl-100 antibodies can be described pathologically as polymyositis. Tif1-γ and NXP2 antibodies are both common in myovasculopathies. HMGCR antibodies associate with myofiber necrosis, but not one IIM pathology subtype. Relative association strengths of IIM-related autoantibodies to IIM myopathology features versus clinical characteristics require further study.

TDP-43 prevents endogenous RNAs from triggering a lethal RIG-I-dependent interferon response.

RIG-I-like receptors (RLRs) are involved in the discrimination of self versus non-self via the recognition of double-stranded RNA (dsRNA). Emerging evidence suggests that immunostimulatory dsRNAs are ubiquitously expressed but are disrupted or sequestered by cellular RNA binding proteins (RBPs). TDP-43 is an RBP associated with multiple neurological disorders and is essential for cell viability. Here, we demonstrate that TDP-43 regulates the accumulation of immunostimulatory dsRNA. The immunostimulatory RNA is identified as RNA polymerase III transcripts, including 7SL and Alu retrotransposons, and we demonstrate that the RNA-binding activity of TDP-43 is required to prevent immune stimulation. The dsRNAs activate a RIG-I-dependent interferon (IFN) response, which promotes necroptosis. Genetic inactivation of the RLR-pathway rescues the interferon-mediated cell death associated with loss of TDP-43. Collectively, our study describes a role for TDP-43 in preventing the accumulation of endogenous immunostimulatory dsRNAs and uncovers an intricate relationship between the control of cellular gene expression and IFN-mediated cell death.

Immunotherapy reversed myopathy but not cardiomyopathy in a necrotizing autoimmune myopathy patient with positive anti-SRP and MDA-5 autoantibodies.

BACKGROUND: Necrotizing autoimmune myopathy (NAM) is pathologically characterized by myofiber necrosis and regeneration with paucity or absence of inflammatory cells in muscle biopsy. Two autoantibodies, namely anti-signal recognition particle (SRP)-antibodies and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-antibodies, are typically specific with NAM. Anti-SRP-positive NAM can be associated with cardiomyopathy which responds well to immunotherapy. Here we reported an anti-SRP-antibody and anti-MDA5-antibody NAM patient who developed severe cardiomyopathy after gaining significant improvement of myopathy and subsequently accepted heart transplantation. CASE PRESENTATION: A NAM case with both positive anti-SRP and MDA-5 antibodies who gained significant improvement of the skeletal muscle weakness with immunotherapy, but 3 years later he developed severe dilated cardiomyopathy and at last received heart transplantation. Myocardial biopsy showed disarranged and atrophic myofibers, remarkable interstitial fibrosis without inflammatory infiltrates. Immunohistochemistry analysis revealed increased polyubiquitin-binding protein p62/SQSTM1 protein expression and the positive staining of cleaved-caspase 3 in a few cardiomyocytes. After the transplantation, the patient was symptom-free on oral prednisone (10 mg/day) and tacrolimus (2 mg/day). CONCLUSIONS: We described the first case of anti-SRP and anti-MAD5 positive NAM who had received heart transplantation because of cardiopathy. Though the myopathy had been clinically improved after immunotherapy, the cardiomyopathy remained progressive and lethal. The processes of dysfunctional autophagy and augmented apoptosis were putatively pathophysiological mechanisms underlying cardiac damage in anti-SRP and anti-MAD5 positive NAM.

Influenza A (H3N2) infection followed by anti-signal recognition particle antibody-positive necrotizing myopathy: A case report.

A 60-year-old Japanese woman presented with subacute progressive muscle pain and weakness in her proximal extremities. She was diagnosed with influenza A (H3N2) infection a week before the onset of muscle pain. At the time of admission, she exhibited weakness in the proximal muscles of the upper and lower limbs, elevated serum liver enzymes and creatinine kinase, and myoglobinuria. She did not manifest renal failure and cardiac abnormalities, indicating myocarditis. Electromyography revealed myogenic changes, and magnetic resonance imaging of the upper limb showed abnormal signal intensities in the muscles, suggestive of myopathy. Muscle biopsy of the biceps revealed numerous necrotic regeneration fibers and mild inflammatory cell infiltration, suggesting immune-mediated necrotizing myopathy (IMNM). Necrotized muscle cells were positive for human influenza A (H3N2). Autoantibody analysis showed the presence of antibodies against the signal recognition particle (SRP), and the patient was diagnosed with anti-SRP-associated IMNM. She was resistant to intravenous methylprednisolone pulse therapy but recovered after administration of oral systemic corticosteroids and immunoglobulins. We speculate that the influenza A (H3N2) infection might have triggered her IMNM. Thus, IMNM should be considered as a differential diagnosis in patients with proximal muscle weakness that persists after viral infections.

Tonsillectomy Improved Therapeutic Response in Anti-SRP Myopathy With Chronic Tonsillitis.

Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

Immune-mediated necrotising myopathy in asymptomatic patients with high creatine kinase.

Subacute symmetrical proximal muscle weakness and persistent elevated creatine kinase levels are typical of immune-mediated necrotising myopathy (IMNM). These conditions are accompanied by copious myofibre necrosis, degeneration and regeneration with minimal to no inflammation on muscle biopsy. We report two cases (case 1 and case 2) of asymptomatic IMNM from different families with hyperCKaemia associated with positive anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, respectively, and we also reviewed the literature. There are only a few previous descriptions of patients with asymptomatic IMNM.The disease onset could be insidious and lead to delayed diagnosis and treatment. We recommend testing for the anti-HMGCR and anti-SRP antibodies in patients with idiopathic hyperCKaemia because they could show no symptoms of this disorder.

Immune-mediated necrotizing myopathy: clinical features and pathogenesis.

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.

Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) axis in idiopathic inflammatory myopathies and its association with laboratory and clinical parameters: a pilot study.

Idiopathic inflammatory myopathies (IIM) are rare connective tissue diseases, which can lead to internal organ involvement. IL-33/ST2 pathway is involved in the pathogenesis of numerous diseases including autoimmune disorders. IL-33 fulfils cardioprotective function, while soluble ST2 (sST2) is a decoy receptor that reduces protective impact of IL-33. The aim of the study was to evaluate the concentrations of sST2 and IL-33 in sera of patients with IIM and evaluate its associations with the clinical course of the disease. Patients with IIM as well as age- and sex-matched healthy controls were recruited. Concentrations of sST2 and IL-33 were assessed with ELISA in sera of both patients and controls. Patients were asked to fill in the questionnaires concerning clinical symptoms and physical functioning. Concentrations of sST2 and IL-33 were correlated with the results of laboratory tests and clinical symptoms. Concentrations of sST2 were significantly higher in IIM group than in healthy subjects (median sST2 in IIM 26.51 vs in healthy controls 21.39; p = 0.03). In the majority of patients, IL-33 concentrations did not exceed the detection limit. Anti-SRP-positive patients presented significantly higher concentrations of sST2 as compared to anti-SRP-negative patients (p = 0.04). In patients with anti-Ro52 antibodies, sST2 concentrations were significantly lower than in anti-Ro52-negative patients (p = 0.02). Concentrations of sST2 correlated with the degree of disability evaluated with Health Assessment Questionnaire. sST2 is increased in patients with IIM and its concentration correlates with the degree of disability. In patients with anti-SRP antibodies, levels of sST2 are exceptionally high.

Refractory Myositis Affecting the Intrinsic Muscles of the Hand.

Myositis generally affects the proximal muscles. However, we herein report a case of a 48-year-old woman with intractable myositis affecting the intrinsic muscles of the hands. Her myositis, which developed in childhood, was refractory to treatment with steroids and several immunosuppressants, causing walking disability. After experiencing pain and swelling in the hands for six months, she was diagnosed with myositis of the intrinsic muscles of the hands and tested positive for the anti-signal recognition particle antibody. Intravenous immunoglobulin therapy improved the myositis of the hands. This case suggests that inflammation caused by intractable myositis can extend to the hands.

Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation.

BACKGROUND: Necrotizing myopathy (NM) is defined by the dominant pathological feature of necrosis of muscle fibers without substantial lymphocytic inflammatory infiltration. Anti-signal recognition particle (SRP)-antibody-positive myopathy is related to NM. Anti-SRP-antibody-positive myopathy can comorbid with other disorders in some patients, however, comorbidity with malignant tumor and myopericarditis has still not been reported. CASE PRESENTATION: An 87-year-old woman with dyspnea on exertion and leg edema was referred to our hospital because of suspected heart failure and elevated serum creatine kinase level. Upon hospitalization, she developed muscle weakness predominantly in the proximal muscles. Muscle biopsy and immunological blood test led to the diagnosis of anti-SRP-antibody-positive myopathy. A colon carcinoma was also found and surgically removed. The muscle weakness remained despite the tumor resection and treatment with methylprednisolone. Cardiac screening revealed arrhythmia and diastolic dysfunction with pericardial effusion, which recovered with intravenous immunoglobulin (IVIg) treatment. CONCLUSIONS: We reported the first case of anti-SRP-positive myopathy comorbid with colon carcinoma and myopericarditis. This case is rare in the point that heart failure symptoms were the first clinical presentation. The underlying mechanism is still not clear, however, physicians should be carefully aware of the neoplasm and cardiac involvement in anti-SRP-antibody positive-myopathy patients and should consider farther evaluation and management.

Benign acute viral myositis in African migrants: A clinical, serological, and pathological study.

BACKGROUND: Several viruses have been described as causes of acquired inflammatory myopathies; however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series. METHODS: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis. RESULTS: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading nonnecrotic muscle fibers, CD68+ macrophages and major histocompatibility complex class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients. CONCLUSIONS: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients.

Anti-signal Recognition Particle Antibody-positive Necrotizing Myopathy with Secondary Cardiomyopathy: The First Myocardial Biopsy- and Multimodal Imaging-proven Case.

A 69-year-old Japanese woman was admitted to our hospital with progressive muscle weakness and dysphagia. She was taking pitavastatin for dyslipidemia. Her serum creatine kinase was 6,300 U/L. Pitavastatin was stopped, but her symptoms deteriorated, and cardiac congestion appeared. A muscle biopsy showed necrotizing myopathy (NM), and anti-signal recognition particle (SRP) antibody was positive. 18F-fluorodeoxyglucose-positron emission tomography showed an abnormal uptake, and magnetic resonance imaging showed abnormal gadolinium enhancement in the left ventricular wall. An endomyocardial biopsy revealed inflammatory cardiomyopathy. Steroid, tacrolimus, and intravenous immunoglobulins were effective against the symptoms. This is the first case of biopsy-proven secondary cardiomyopathy due to anti-SRP-positive NM.

Coexistence of anti-Jo1 and anti-signal recognition particle antibodies in a polymyositis patient. / Coexistencia de anticuerpos anti-histidil-tRNA-sintetasa y anti-partícula de reconocimiento de la señal en un paciente con polimiositis.

Idiopathic inflammatory myopathies are a heterogeneous group of potentially treatable myopathies. They are classified, on the basis of clinical and histopathological features, into four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis and inclusion-body myositis. Myositis-associated antibodies and myositis-specific autoantibodies are frequently found in patients with idiopathic inflammatory myopathies, and are useful in the diagnosis and classification. Anti-histidyl transfer RNA synthetase antibody is the most widely prevalent and is highly specific for polymyositis. Signal recognition particle antibody is also a specific autoantibody for polymyositis, but it is infrequent and rarely found in patients having other myositis-specific autoantibodies. We present a man with polymyositis who had both antibodies in serum, which is considered an extremely rare clinical situation. Here we analyze the clinical course and findings, and examine the effect of the coexistence and possible interaction on prognosis.

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy.

OBJECTIVES: In autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM. METHODS: IgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA). RESULTS: Passive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease. CONCLUSION: This study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.