Immune-Mediated Necrotizing Myopathy (IMNM): A Story of Antibodies.
Ontology highlight
ABSTRACT:
SUBMITTER: Julien S
PROVIDER: S-EPMC10885118 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
Publications
Immune-Mediated Necrotizing Myopathy (IMNM): A Story of Antibodies.
Julien Sarah S Challier Inès I Malleter Marine M Jouen Fabienne F Drouot Laurent L Boyer Olivier O
Antibodies (Basel, Switzerland) 20240207 1
Immune-mediated necrotizing myopathy (IMNM) is a rare and severe disease that corresponds to a specific entity of idiopathic inflammatory myopathy. Patients with IMNM suffer from proximal muscle weakness, and present high levels of creatine kinase and necrotic myofibers. Anti-Signal Recognition Particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies (HMGCR) have recently been identified in two thirds of patients with IMNM and are used as a hallmark of the disease. ...[more]
Similar Datasets
Project description: Not available
| S-EPMC11545544 | biostudies-literature
Project description:ObjectiveAnti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies are one of the myositis-specific antibodies which is associated with immune-mediated necrotizing myopathy (IMNM). However, the relationship between anti-HMGCR isotypes and prognosis has not yet been fully investigated. This study was conducted to gain insight into the association between anti-HMGCR isotypes and clinical, and prognosis in IMNM patients who were positive for anti-HMGCR antibodies.MethodsLevels of anti-HMGCR isotypes (IgG, IgA and IgM) were assessed by enzyme-linked immunosorbent assay (ELISA) in 123 consecutive serum samples obtained from 71 patients who were positive for anti-HMGCR IgG at baseline. Disease activity was assessed by manual muscle testing (MMT) 8, Physician's Global Assessment (PGA) visual analog scale (VAS), and muscle VAS.ResultsBaseline anti-HMGCR IgG levels were correlated with PGA VAS (r = 0.24; p = 0.04), muscle VAS (r = 0.32; p < 0.01), and MMT8(r=-0.24; p = 0.04), and baseline anti-HMGCR IgM levels were positively correlated with PGA VAS (r = 0.27, p = 0.02), muscle VAS (r = 0.24, p = 0.04). Anti-HMGCR IgM positive patients had a lower age of onset [29(25,46) vs. 51(33,65), p = 0.006], and a higher proportion of neck weakness (63.5% vs. 34.6%, p = 0.031) compared with anti-HMGCR IgM negative patients. Longitudinal analysis showed that the changes in anti-HMGCR IgG levels were correlated with the changes in the PGA VAS (β = 3.830; p < 0.0001), muscle VAS (β = 2.893; p < 0.0001), MMT8 (β=-19.368; p < 0.0001), and creatine kinase (CK) levels (β = 3900.05, p < 0.0001). Anti-HMGCR IgM levels were weakly correlated with anti-HMGCR IgA levels at baseline (r = 0.33, p < 0.01), and the variations in anti-HMGCR IgA levels were correlated with the changes in anti-HMGCR IgM levels during follow-up (β = 0.885; p < 0.0001). There were more patients with anti-HMGCR IgM who showed a refractory course than those who were with anti-HMGCR IgM negative (polycyclic course: 40% vs. 25%; chronic continuous course: 46.7% vs. 20.5%, p = 0.018).ConclusionIn anti-HMGCR IgG-positive IMNM patients, the levels of anti-HMGCR IgG are associated with disease activity, and anti-HMGCR IgM is associated with refractory outcome and poor prognosis.
| S-EPMC11389351 | biostudies-literature
Project description:Background: The therapeutic regimen of immune-mediated necrotizing myopathy (IMNM), a category of immune-related myopathies featuring progressive proximal muscle weakness and extremely high level of serum creatine kinase, remains a formidable barrier for clinicians. The proposed study intended to investigate new diagnostic biomarkers based on high-throughput sequencing data of IMNM and generate novel IMNM management strategies by bioinformatics technology. Methods: Eighteen IMNM patients were synthesized in a local sequencing cohort (high-throughput sequencing data) with Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis to pinpoint robust IMNM-related differentially expressed genes (DEGs). The definitive feature genes were categorized by employing the protein-protein interaction (PPI) network, Least Absolute Shrinkage Selection Operator (LASSO), and support vector machine recursive feature elimination (SVM-RFE), and their sample discriminatory utility was appraised by obtaining the area under the curve (AUC) of the receiver operating curve (ROC) curve. The expression difference of key genes was verified by quantitative real-time polymerase chain reaction (qRT-PCR). Enrichment analysis of predefined gene sets disclosed the hidden functions of diagnostic DEGs. The 28 immune cell abundance patterns in the IMNM cohort were measured using single-sample gene set enrichment analysis (ssGSEA). Results: We recognized 193 genes that were aberrantly upregulated in the IMNM population and were firmly affiliated with immune-inflammatory responses, regulation of skeletal and cardiac muscle contraction and lipidprotein metabolism. LTK, MYBPH, and MYL4 were authenticated as diagnostic markers for IMNM (all AUC = 1.00), and functional enrichment analysis highlighted that these genes were notably integrated with immune-inflammatory response, autophagy-lysosome pathway and myofiber differentiation and regeneration. Ultimately, ssGSEA revealed a pronounced immune cell infiltrative microenvironment in the IMNM population. The results revealed the most significant relationship among CD4 T cells, CD8 T cells, macrophages, natural killer cells, T helper cells, Th17 cells and dendritic cells. Conclusion: LTK, MYBPH, and MYL4 might be served as diagnostic molecules for IMNM and possibly yield innovative insights into the mechanisms of progression and therapeutic options for IMNM in the future.
2024-09-30 | GSE213055 | GEO
Project description:ObjectiveWe aimed to explore the efficacy and safety of efgartigimod in patients with refractory immune-mediated necrotizing myopathy (IMNM).MethodsThis open-label pilot observational study included seven patients with refractory IMNM, all of whom received intravenous efgartigimod treatment. The clinical response was assessed after 4 weeks of efgartigimod treatment according to the 2016 American College of Rheumatology-European League Against Rheumatism response criteria for adult idiopathic inflammatory myopathy. Serum levels of immunoglobulin as well as anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies were measured using enzyme-linked immunosorbent assays and commercial line immunoblot assays. Safety assessments included evaluations of adverse events and severe adverse events.ResultsThe seven patients with refractory IMNM included five cases with anti-HMGCR antibodies and two cases within anti-SRP antibodies. Four of the seven patients achieved clinical responses. The total improvement score for the responders at 4 weeks were 32.5, 40.0, 47.5, and 70.0, and those at 8 weeks were 27.5, 47.5, 57.5, and 70.0. In comparison to the responsive patients, the non-responsive patients had longer durations [8 (-) versus 2 (1-5) years, P = 0.03], and more chronic myopathic features by muscle biopsy (67% versus 0%, P = 0.046). Serum immunoglobulin G levels (11.2 ± 2.5 versus 5.7 ± 2.5, P = 0.007) and anti-HMGCR/SRP antibody levels (97.2 ± 6.9 versus 41.8 ± 16.8, P = 0.002) were decreased after treatment compared with baseline levels. Adverse events were reported in one of the seven patients, who showed mild headache.ConclusionsDespite its small size, our study demonstrated that promoting the degradation of endogenous immunoglobulin G may be effective for patients with IMNM. Efgartigimod may be a promising option for cases of refractory IMNM to shorten duration and minimize chronic myopathic features.
| S-EPMC11534618 | biostudies-literature
Project description:ObjectiveTo investigate the characteristics of cardiac involvement due to Immune-mediated Necrotizing Myopathy (IMNM).MethodsPatients diagnosed with Immune-mediated Necrotizing Myopathy (IMNM) who attended the Department of Neurology and the Department of Rheumatology and Immunology at the First Medical Center of the PLA General Hospital between February 2011 and June 2022 were collected. Clinicopathological diagnosis of IMNM was performed according to the criteria established by the European Neuromuscular Center (ENMC). All patients underwent muscle biopsy and Myositis-specific antibodies (MSAs) testing. Information included age, gender, disease duration, intramuscular and extramuscular manifestations, laboratory findings (including creatine kinase, lactate dehydrogenase levels, troponin T, myoglobin and atrial natriuretic peptide), electromyography, skeletal muscle pathology and immunohistochemical staining.ResultsA total of 57 patients were included in this study. Of the serological tests, 56.1% (32/57) were positive for SRP, 21.1% (12/57) were positive for HMGCR and 22.8% (13/57) were seronegative. Thirty patients (52.6%, 30/57) presented with varying degrees of cardiac involvement. We performed ECG in 23 patients and found 6 patients with arrhythmia (26.1%), 12 patients with myocardial ischemia (52.2%), and 7 patients with acute coronary syndrome (ST elevation and non-ST elevation myocardial infarction) (30.4%), and 4 patients with left axis deviation or left ventricular high voltage, suggesting left ventricular hypertrophy (17.4%). Cardiac ultrasound was performed in 14 patients and 3 showed pericardial effusion (21.4%); Decreased left ventricular ejection fraction and atrial enlargement were 2 each; 8 showed a decrease in left ventricular diastolic function (57.1%). In addition, one patient had myocardial edema.ConclusionCardiac involvement is not uncommon in IMNM. However, besides clearly statistically significant differences in the disease course, and in the values of troponin T and myoglobin, our data did not show any statistically significant difference in other features of cardiac involvement between patients with different subtypes of IMNM.
| S-EPMC10011453 | biostudies-literature
Project description:ObjectivesEvidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM.MethodsMuscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package.ResultsFemale sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate-severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months.ConclusionEarly IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.
| S-EPMC9434226 | biostudies-literature
Project description:mRNA profiling in immune mediated necrotizing myopathy
| PRJNA878838 | ENA
Project description:Statin-induced necrotizing autoimmune myopathy is an immune-mediated necrotizing myopathy related to the use of statins. It is a very rare disease, which usually presents with proximal muscle weakness and frank elevation in creatine kinase levels. Stopping statin and the use of immunosuppressive therapy are considered the mainstay therapy. Use of steroids in patients with inflammatory myopathy can be complicated by steroid-induced myopathy. Herein, we present a case of a 55-year-old patient with statin-induced necrotizing autoimmune myopathy based on the presence of proximal muscle weakness, magnetic resonance findings, suggestive muscle biopsy features, and positive anti-HMGCR autoantibodies. The patient was treated with triple immunosuppressive therapy with a particularly good response to intravenous immunoglobulin. This report highlights the importance of timely diagnosis and early use of combined immunosuppressive therapy to improve patients' outcome affected by this rare disease.
| S-EPMC9173901 | biostudies-literature
Project description:BackgroundImmune-mediated necrotizing myopathies (IMNM) is a rare disease that was first described in 2004. Due to the lack of large case series, there are no formal treatment recommendations for IMNM.MethodsWe presented a case of a 47-year-old woman who experienced progressive limb weakness, starting from the lower limbs and gradually affecting the upper limbs. She also reported experiencing dyspnea after engaging in daily activities. When she was admitted to the hospital, her upper limbs were almost unable to move and she could not stand even with support. Her Creatine kinase (CK) level significantly increased (> 3500 u/l). Electromyography showed myogenic damage, anti-Signal recognition particle (anti-SRP) and anti-Ro52 antibodies were highly positive. Pathological biopsy of the right biceps muscle showed necrotizing myopathy in the skeletal muscle. She was ultimately diagnosed with anti-SRP IMNN, and was given monotherapy with methylprednisolone and combination therapy with immunoglobulin, but her symptoms continued to worsen. The patient refused to bear the possible further liver dysfunction and blood system damage caused by Cyclophosphamide and Rituximab, and she chose to try to use Ofatumumab (OFA).ResultsAfter receiving three doses of OFA treatment without any adverse reactions, she reported that her muscle strength had basically recovered and she was able to walk independently. The B cells in the circulatory system have been depleted, and blood markers such as liver function have consistently remained within normal range. During the follow up, her activity tolerance continued to improve.DiscussionWe have presented a severe case of SRP-IMNM in which the patient showed poor response to conventional immunotherapy. However, rapid symptom relief was achieved with early sequential use of OFA treatment. This provides a new option for the treatment of SRP-IMNM, and more large-scale studies will be needed in the future to verify our results.
| S-EPMC10758405 | biostudies-literature
Project description:Patients suffering from immune-mediated necrotizing myopathies (IMNM) harbor, the pathognomonic myositis-specific auto-antibodies anti-SRP54 or -HMGCR, while about one third of them do not. Activation of chaperone-assisted autophagy was described as being part of the molecular etiology of IMNM. Endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR)-stress accompanied by activation of the unfolded protein response (UPR) often precedes activation of the protein clearance machinery and represents a cellular defense mechanism toward restoration of proteostasis. Here, we show that ER/SR-stress may be part of the molecular etiology of IMNM. To address this assumption, ER/SR-stress related key players covering the three known branches (PERK-mediated, IRE1-mediated, and ATF6-mediated) were investigated on both, the transcript and the protein levels utilizing 39 muscle biopsy specimens derived from IMNM-patients. Our results demonstrate an activation of all three UPR-branches in IMNM, which most likely precedes the activation of the protein clearance machinery. In detail, we identified increased phosphorylation of PERK and eIF2a along with increased expression and protein abundance of ATF4, all well-documented characteristics for the activation of the UPR. Further, we identified increased general XBP1-level, and elevated XBP1 protein levels. Additionally, our transcript studies revealed an increased ATF6-expression, which was confirmed by immunostaining studies indicating a myonuclear translocation of the cleaved ATF6-form toward the forced transcription of UPR-related chaperones. In accordance with that, our data demonstrate an increase of downstream factors including ER/SR co-chaperones and chaperones (e.g., SIL1) indicating an UPR-activation on a broader level with no significant differences between seropositive and seronegative patients. Taken together, one might assume that UPR-activation within muscle fibers might not only serve to restore protein homeostasis, but also enhance sarcolemmal presentation of proteins crucial for attracting immune cells. Since modulation of ER-stress and UPR via application of chemical chaperones became a promising therapeutic treatment approach, our findings might represent the starting point for new interventional concepts.
| S-EPMC9616093 | biostudies-literature