Immune-mediated Necrotizing Myopathy Research Articles

Immune-Mediated Necrotizing Myopathy(IMNM)

Immune-mediated necrotizing myopathy (IMNM) has recently been classified from polymyositis, and it clinically shows subacute progressive proximal dominant muscle weakness. Laboratory examinations show a great increase in serum creatine kinase and prominent necrotic muscle fibers without any pathological invasion of inflammatory cells. It is thought to be an autoimmune disease because SRP and HMGCR antibodies have been detected in many cases. These two antibodies affect the pathophysiology of IMNM. Immuno-modulating therapies have usually been induced. Moreover, intensive treatments are necessary in cases of corticosteroid resistant IMNM.

Efgartigimod restores muscle function in a humanized mouse model of immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathies (IMNMs) are severe forms of myositis often associated with pathogenic anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs). Efgartigimod is an engineered human IgG1 Fc fragment that antagonizes the neonatal Fc receptor (FcRn), thereby preventing recycling and promoting lysosomal degradation of IgG, including aAbs. We evaluated the therapeutic effects of IgG reduction by efgartigimod in a humanized murine model of IMNM. Disease was induced in C5-deficient (C5def) or Rag2-deficient (Rag2-/-) mice receiving co-injections of anti-HMGCR+ IgG from an IMNM patient and human complement. C5def mice were treated in a preventive setting with s.c. injections of efgartigimod and Rag2-/- mice in a curative setting after disease was induced by anti-HMGCR+ IgG injections. Anti-HMGCR aAbs levels were monitored in mouse serum and muscle tissue. Histological analysis was performed on muscle sections. Muscle force was assessed by grip test or measurement of gastrocnemius strength upon electrostimulation. Administration of efgartigimod rapidly reduced total IgG levels, including the level of pathogenic anti-HMGCR aAbs, in both serum (P < 0.0001) and muscle (P < 0.001). In the preventive setting, efgartigimod prevented myofibre necrosis (P < 0.05), thus precluding loss of muscle strength (P < 0.05). In the therapeutic setting, efgartigimod prevented further necrosis and allowed muscle fibre regeneration (P < 0.05). Hence, muscle strength returned to normal (P < 0.01). Efgartigimod reduces circulating IgG levels, including pathogenic anti-HMGCR+ IgG aAbs, in a humanized mouse model of IMNM, preventing further necrosis and allowing muscle fibre regeneration. These results support investigating the therapeutic efficacy of efgartigimod through a clinical trial in IMNM patients.

Global disparities in the treatment of idiopathic inflammatory myopathies: results from an international online survey study.

We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. A cross-sectional ancillary analysis of the 'COVID-19 vaccination in auto-immune disease' (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.

The longitudinal study of muscle changes with ultrasound: differential changes in idiopathic inflammatory myopathy subgroups.

We investigated shear wave elastography (SWE), B mode US and power Doppler (PDUS) as imaging biomarkers for longitudinal follow-up in idiopathic inflammatory myopathy (IIM), with a particular focus on immune-mediated necrotizing myopathy (IMNM) and DM. Participants had serial SWE, PDUS on the deltoid (D) and vastus lateralis (VL) muscles on four occasions at intervals of 3-6 months. Clinical assessments included manual muscle testing, and patient- and physician-reported outcome scales. Thirty-three participants were included: IMNM = 17, DM = 12, overlap myositis = 3, PM = 1. Twenty were in a prevalent clinic group, and 13 were recently treated cases in an incident group. Differential changes in SWS and US domains occurred with time in both the prevalent and incident groups. In the VL-prevalent subgroup, echogenicity increased over time (P = 0.040), while in the incident cases there was a trend for reduction to normal over time (P = 0.097) with treatment. Muscle bulk reduced in the D-prevalent subgroup over time (P = 0.096), suggesting atrophy. SWS also reduced in the VL-incident subgroup over time (P = 0.096), suggesting a trend towards improvement in muscle stiffness with treatment. SWE and US appear promising as imaging biomarkers for patient follow-up in IIM and indicate changes over time, especially with echogenicity, muscle bulk and SWS in the VL. Due to the limitations of the participant numbers, additional studies with a larger cohort are needed to help evaluate these US domains further and outline specific characteristics within the IIM subgroups.

Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies

ObjectivesMyositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For...

Becker Muscular Dystrophy Accompanied by Anti-HMGCR Antibody-positive Immune-mediated Necrotizing Myopathy.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease characterized by progressive muscle weakness that currently has no cure. Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune inflammatory myopathy characterized by proximal muscle weakness that is treated with immunosuppressive therapy. We herein report a patient diagnosed with BMD complicated with IMNM by a pathological analysis. Notably, the patient had an elevated serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody level. Oral glucocorticoid and methotrexate treatment partially improved the muscle weakness with decreased levels of serum creatine kinase. An accurate diagnosis is important for therapeutic decisions in these complicated cases.

Scapular Winging In Patients With Anti-Hydroxy Methyl Glutaryl CoA Reductase (HMGCR) Antibody Positive Immune Mediated Necrotizing Myopathy (IMNM): A Case Series (P9-8.005)

<h3>Objective:</h3> To report examination finding of scapular winging in two patients with Anti-hydroxymethylglutaryl CoA reductase (HMGCR) antibody positive immune mediated necrotizing myopathy (IMNM). <h3>Background:</h3> IMNM is a disabling auto-immune myopathy characterized by severe proximal muscle weakness, markedly elevated creatine kinase (CK) and muscle necrosis. Diagnosis is made via muscle biopsy and antibody testing in a patient with a suggestive history, examination and laboratory abnormalities. <h3>Design/Methods:</h3> Case Series <h3>Results:</h3> Patient 1, a 46 year old male presented for evaluation of muscular dystrophy. He had proximal lower extremity muscle weakness, dysphagia and 20 lbs weight loss over 1 year duration. He was on statin in the past which was discontinued after he was found to have elevated liver enzymes. Examination was notable for mild eye closure weakness, bilateral scapular winging, leg &gt; arm, proximal &gt; distal weakness and abdominal weakness. CK was elevated to 12, 000 u/L. HMCCoA Ab was positive with elevated titer to 435.8. He was started on methotrexate and IVIG Q2 weeks. CK level down trended to 2652 U/L. Patient had significant improvement in his symptoms. Patient 2, a 58 year-old male presented with proximal upper and lower extremity muscle weakness, dysphagia and 10 lbs weight loss of over 4 month duration. He was on atorvastatin for over 3 years which was discontinued 1 month after symptom onset. Examination was notable for proximal muscle weakness in bilateral upper and lower extremities, right scapular winging and neck flexion weakness. CK was elevated to 7500. HMG COA reductase antibody was positive with elevated titer to 169.4. He was started on methotrexate and IVIG Q2 weeks. He also noted improvement in his symptoms. <h3>Conclusions:</h3> Scapular winging can be seen with HMGCR Ab+ IMNM. Such patients can be misdiagnosed having muscular dystrophy. Neurologists should be aware of this clinical phenotype as these patients may respond favorably to immunotherapy. <b>Disclosure:</b> Dr. Katyal has nothing to disclose. Dr. Goyal has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Goyal has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. An immediate family member of Dr. Goyal has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Goyal has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion.

Atypical Overlapping Features Complicating Diagnoses of Dysferlinopathy and Immune-Mediated Necrotizing Myopathy. (P6-8.006)

<h3>Objective:</h3> To present overlapping features and atypical characteristics of dysferlinopathy and immune-mediated necrotizing myopathy (IMNM). <h3>Background:</h3> Dysferlinopathy typically presents with early onset progressive muscle weakness that can be proximal or distal. Definitive diagnosis is made with DYSF gene testing. Treatment is supportive. IMNM is an autoimmune inflammatory myopathy that affects older individuals and is often associated with occult malignancy. Aggressive immunotherapy improves outcomes. Muscle biopsy (MBx) reveals inflammatory infiltrates in both conditions. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case 1:</h3> A 35-year-old man presented with subacute progressive limb weakness and elevated creatine phosphokinase (CPK) &gt;8,000 units/L. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining; dystrophy stains were omitted due to the patient’s age and subacute symptoms. Anti-signal recognition peptide (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies and malignancy screen were negative. The patient was initially diagnosed with seronegative IMNM and treated with steroids, methotrexate and IVIG without improvement. He was subsequently diagnosed with dysferlinopathy based on genetic testing showing double heterozygous pathogenic DYSF gene mutations. <h3>Case 2:</h3> An 18-year-old man presented with 3-years of progressive proximal limb weakness associated with Gower’s sign and elevated CPK &gt;10,000 units/L. Broad muscular dystrophy genetic testing was negative. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining suggestive of IMNM. Anti-SRP and anti-HMGCR antibodies, serum paraneoplastic panel, and malignancy screening with tumor markers, contrasted CT imaging, and scrotal ultrasound were negative. The patient was diagnosed with early-onset seronegative IMNM. CPK improved and symptoms stabilized with prednisone, methotrexate and IVIG therapy. <h3>Conclusions:</h3> Dysferlinopathy and IMNM can have overlapping clinical features and MBx findings. Heightened awareness of atypical features aids in timely diagnosis. Accurate diagnosis of dysferlinopathy based on genetic testing limits further invasive workup and the side effects of ineffective empiric therapy, whereas early diagnosis of IMNM allows for prompt immunotherapy which is shown to improve prognosis. <b>Disclosure:</b> Dr. Stout has nothing to disclose. Dr. Su has nothing to disclose.

Anti-HMGCR myopathy frequently coexists with other myositis-specific autoantibodies in Korean patients (P9-8.012)

<h3>Objective:</h3> To understand the characteristics of Korean patients with anti-HMGCR myopathy, we measured anti-HMGCR antibodies and analyzed clinical, radiological, and pathological features. <h3>Background:</h3> Immune-mediated necrotizing myopathy (IMNM) is an inflammatory myopathy subgroup characterized by subacute proximal weakness and prominent myofiber necrosis with minimal inflammatory cell infiltrate on muscle biopsy. Two autoantibodies have been reported in association with IMNM: antibodies against the signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR). To date, there only have been two case reports of Korea patients with anti-HMGCR myopathy. <h3>Design/Methods:</h3> We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy using the enzyme-linked immunosorbent assay. We also tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy. <h3>Results:</h3> Postivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years. Ten (59%) of the anti-HMGCR positive patients had taken statins. The most common symptoms were proximal muscle weakness in 15 (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/ml. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group (p = 0.027). <h3>Conclusions:</h3> In conclusion, our study is the first to measure anti-HMGCR antibodies with inflammatory myopathy, and identify new findings including the coexistence of other MSAs in Korean patients. <b>Disclosure:</b> Miss Lee has nothing to disclose. Ms. Oh has nothing to disclose. Kee Duk Park has nothing to disclose. Young-Chul Choi has nothing to disclose. Hyung Jun Park has nothing to disclose.

P154 Real-world audit of patients with idiopathic inflammatory myositis-related interstitial lung disease in a European population

Abstract Background/Aims The British Society for Rheumatology (BSR) has released guidelines for managing idiopathic inflammatory myositis (IIM). Our centre operates specialist clinics for scleroderma and lupus, but to date, IIM patients are seen in a general CTD clinic. As part of work to establish a dedicated myositis clinic, we collated data on 71 patients under active follow-up with myositis spectrum disease deemed appropriate for follow-up within a specialist clinic. We aimed to review patients diagnosed with IIM-ILD and review serological immune profile, screening practices for pulmonary involvement, findings on CT/pulmonary function tests (PFTs) and pharmacological management. Methods We performed a detailed retrospective review of the notes of suitable patients, identified using diagnostic codes attached to clinic letters. Results 71 patients were identified: 14 with anti-synthetase syndrome (ARS), 21 with dermatomyositis (DM), 13 with polymyositis (PM), 3 with immune-mediated necrotising myopathy (IMNM) and 17 with overlap syndrome. 65% (46/70) of adult IIM patients were screened for pulmonary involvement. Screening practices of patients based on antibody profile and myositis subtype are further described in the table. 31% of patients (22/70) had IIM-ILD, of which 12 had ARS, 4 had PM, 1 had DM and 5 had overlap disease (2 PM/scleroderma, 1 DM/ARS, 1 DM/scleroderma and 1 scleroderma/ARS). 21/22 underwent PFTs; 53% of patients had active ILD over an average of 51.8 months. On imaging, 76.2% (16/22) had changes consistent with ILD. Ground glass change and reticulation were demonstrated in 50% of scans. In comparison, honeycombing and traction bronchiectasis was found in 22% and 44% of scans, respectively. A non-specific interstitial pneumonia (NSIP) pattern was described in 44% of scans, organising pneumonia (OP) pattern in 22%, and 17% had a mixed OP and NSIP pattern. 20/22 patients were prescribed high-dose steroids, csDMARD therapy or aggressive immunosuppression (cyclophosphamide or rituximab). Conclusion Our review demonstrates that 65% of patients with adult IIM were screened for ILD. NSIP and OP were the most common radiological appearances. Half of our cohort required aggressive immunosuppression, cyclophosphamide being the most commonly prescribed agent and mycophenolate being preferred for maintenance therapy. No patients were prescribed tacrolimus or ciclosporin. Despite treatment, 52% of patients had evidence of progressive disease on serial PFTs. Disclosure A. Loganathan: Grants/research support; Arthritis Australia. S. Sturney: None. N. Foley: None. T. Hartley: None. S. Tansley: None.

Anti-signal recognition particle positive necrotizing myopathy-sjogren’s syndrome overlap syndrome: a descriptive study on clinical and myopathology features

Background and objectiveThe aim of this study was to elucidate the clinical and myopathological characteristics of patients with anti-signal recognition particle (SRP) positive immune-mediated necrotizing myopathy (IMNM) overlap Sjogren’s syndrome (SS).Materials and methodsWe retrospectively analyzed the data of anti-SRP positive IMNM patients admitted in the Neurology Department of Tongji Hospital between January 2011 to December 2020. Patients were divided into two groups: anti-SRP IMNM overlap SS group and anti-SRP IMNM control group. The clinical features, laboratory results, histological features, treatment, and prognosis were compared between the two groups.ResultsA total of 30 patients with anti-SRP IMNM were included, including six anti-SRP IMNM overlap SS patients (two males, four females), with a median age of 39 years, and 24 anti-SRP IMNM patients (ten males, fourteen females), with a median age of 46 years. The anti-SRP IMNM overlap SS group had a lower prevalence of muscle atrophy (0 vs 50%, p = 0.019), and a higher prevalence of extramuscular manifestations, including cardiac abnormalities and ILD (Interstitial lung disease). CD4 + and CD68 + inflammatory infiltrations were significantly increased in anti-SRP IMNM overlap SS patients, with an increased presence of CD4 + cells in both necrotic(p = 0.023) and endomysial areas (p = 0.013), and more CD68 + cells (p = 0.016) infiltrated the endomysial area. Deposition of membrane attack complex (MAC) on sarcolemma (p = 0.013) was more commonly seen in the anti-SRP IMNM overlap SS group.ConclusionOur data revealed that anti-SRP IMNM-SS overlap patients may present with milder muscular manifestation, but worse extramuscular manifestations compared to anti-SRP IMNM patients without SS. CD4 + and CD68 + inflammatory infiltrations and MAC deposition were remarkably increased in anti-SRP IMNM-SS overlap patients.

Pediatric immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathy (IMNM) is a type of inflammatory myopathy. Most patients with IMNM produce anti-3-hydroxy-3-methylglutaryl coenzyme A reductase or anti-signal-recognition particle autoantibodies. IMNM is much rarer in children than in adults. We conducted this mini review focusing on pediatric IMNM to present current evidence regarding its epidemiology, clinical characteristics, diagnosis, and treatment. Our findings indicate that pediatric IMNM often causes severe muscle weakness and is refractory to corticosteroids alone. Furthermore, delayed diagnosis is common because of the clinicopathological similarity between IMNM and inherited myopathy. Raising awareness regarding pediatric IMNM may facilitate early diagnosis and effective treatment.

TWEAK and Fn14 are overexpressed in immune-mediated necrotizing myopathy: implications for muscle damage and repair.

TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor fibroblast growth factor-inducible 14 (Fn14) are involved in various inflammatory conditions. This study was performed to investigate the potential role of TWEAK/Fn14 in immune-mediated necrotizing myopathy (IMNM). Muscle biopsies from patients with IMNM (n = 37) and controls (n = 11) were collected. Human muscle cells were treated with TWEAK in vitro. Muscle biopsies and cultured muscle cells were analysed by immunostaining and quantitative PCR. Serum levels of TWEAK and Fn14 were detected by ELISA. TWEAK and Fn14 were overexpressed in IMNM muscle biopsies. The percentage of Fn14-positive myofibers correlated with disease severity, myonecrosis, regeneration and inflammation infiltrates. Fn14-positive myofibers tended to be surrounded or invaded by CD68+ macrophages. TWEAK treatment had a harmful effect on cultured muscle cells by inducing the production of multiple chemokines and pro-inflammatory cytokines. Serum Fn14 levels were increased in patients with IMNM and correlated with muscle weakness. TWEAK/Fn14 signalling was activated in IMNM, most likely aggravating muscle damage via amplifying inflammatory response and macrophages chemotaxis. Fn14 seems to be a biomarker for assessing disease severity in IMNM. In addition, Fn14 may also contribute to muscle injury repair.

The diagnostic value of serum YKL-40 for myocardial involvement in immune-mediated necrotising myopathy.

This study aimed to determine the diagnostic value of YKL-40 for myocardial involvement in immune-mediated necrotising myopathy (IMNM). We retrospectively analysed the data of patients with IMNM admitted to the Neurology Department at Tongji Hospital between April 2013 and August 2022. Clinical data including patients' demographics, clinical characteristics (disease duration, muscle strength, atrophy, rash, dysphagia, dyspnoea, and myalgia) and laboratory test results were collected from the electronic medical record system. Serum YKL-40 levels were measured using an enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve was calculated to evaluate the diagnostic value of YKL-40 for cardiac involvement in IMNM. 29 patients with IMNM and15 sex and age-matched volunteers without history of heart diseases were recruited for the study. Compared with the healthy controls, serum YKL-40 levels were notably up-regulated [96.3 (55.5 120.6) pg/ml versus 19.6 (13.8 20.9) pg/ml; p=0.000] in patients with IMNM. We compared 14 patients with IMNM with cardiac abnormalities and 15 patients with IMNM without cardiac abnormalities. The most important finding was that serum YKL-40 levels were higher in the patients with IMNM with cardiac involvement based on cardiac magnetic resonance (CMR) examination [119.2 (88.4 185.69) pm/ml versus 72.5 (35.7 98) pm/ml; p=0.002]. YKL-40 had a specificity and sensitivity of 86.7% and 71.4% respectively, at a cut-off value of 105.46 pg/ml for predicting myocardial injury in patients with IMNM. YKL-40 could be a promising non-invasive biomarker for diagnosing myocardial involvement in IMNM. However, larger prospective study is warranted.

STATIN ASSOCIATED IMMUNE MEDIATED NECROTIZING MYOPATHY (SA-IMNM) AND SUBSEQUENT USE OF NON-STATIN LDL-C LOWERING DRUGS

STATIN ASSOCIATED IMMUNE MEDIATED NECROTIZING MYOPATHY (SA-IMNM) AND SUBSEQUENT USE OF NON-STATIN LDL-C LOWERING DRUGS

Characteristics of cardiac involvement in immune-mediated necrotizing myopathy.

To investigate the characteristics of cardiac involvement due to Immune-mediated Necrotizing Myopathy (IMNM). Patients 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. A 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. Cardiac 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.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs)...

Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase (CK) values, and autoantibodies recognizing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or the signal recognition particle (SRP). There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants. Detection of complement-activating anti-HMGCR and anti-SRP autoantibodies and the presence of complement deposition on the sarcolemma of non-necrotic myofibers led to the hypothesis that complement activation may be pathogenic in IMNM, therefore zilucoplan, a complement component 5 (C5) inhibitor, could be a potential therapy. IMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) evaluated efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM. Participants were randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension. Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels. Secondary endpoints included safety. Between 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. There were no unexpected adverse safety or tolerability findings. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively. The most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively]). C5 inhibition does not appear to be an effective treatment modality for IMNM. Rather than driving myofiber necrosis, complement activation may be secondary to muscle injury. Study funded by Ra Pharmaceuticals (now part of UCB Pharma).

Immune-mediated necrotizing myopathy following vaccination with the AstraZeneca (AZD1222) COVID-19 vaccine: A case report and brief review

Immune-Mediated Necrotizing Myopathy (IMNM) after vaccination has been reported previously, however it is rare after COVID-19 vaccination. We report the first case of IMNM two weeks after vaccination with the AstraZeneca (AZD1222) COVID-19 vaccine. There was a probable temporal relationship between the COVID-19 vaccination and the development of IMNM due to lack of known causative factors for IMNM. This may have been due to 1) autoimmunity directly caused by the vaccine, 2) exacerbation of autoimmunity triggered by the vaccine or 3) autoimmune syndrome triggered by the vaccine adjutants. Further studies are needed to assess the underlying mechanisms.

Elevated Expression of ADAM10 in Skeletal Muscle of Patients with Idiopathic Inflammatory Myopathies Could Be Responsible for FNDC5/Irisin Unbalance.

Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory infiltrates. Muscle biopsies and laboratory tests are helpful in diagnosis, but currently, few biomarkers of disease activity and progression are available. In this context, we conducted a cohort study of forty-one DM and IMNM patients, aged 40-70 years. In comparison with control subjects, in the muscle biopsies of these patients, there was a lower expression of FNDC5, the precursor of irisin, a myokine playing a key role in musculoskeletal metabolism. Expectedly, the muscle cross-sectional areas of these patients were reduced, while, surprisingly, serum irisin levels were higher than in CTRL, as were mRNA levels of ADAM10, a metalloproteinase recently shown to be the cleavage agent for FNDC5. We hypothesize that elevated expression of ADAM10 in the skeletal muscle of DM and IMNM patients might be responsible for the discrepancy between irisin levels and FNDC5 expression. Future studies will be needed to understand the mechanisms underlying exacerbated FNDC5 cleavage and muscle irisin resistance in these inflammatory myopathies.