Immune-mediated Necrotizing Myopathy Research Articles

Perivascular and endomysial macrophages expressing VEGF and CXCL12 promote angiogenesis in anti-HMGCR immune-mediated necrotizing myopathy.

To study the phenotype of macrophage infiltrates and their role in angiogenesis in different idiopathic inflammatory myopathies (IIMs). The density and distribution of the subpopulations of macrophages subsets (M1, inducible nitric oxide+, CD11c+; M2, arginase-1+), endomysial capillaries (CD31+, FLK1+), degenerating (C5b-9+) and regenerating (NCAM+) myofibres were investigated by immunohistochemistry in human muscle samples of diagnostic biopsies from a large cohort of untreated patients (n: 81) suffering from anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR)+ immune mediated necrotizing myopathy (IMNM), anti-signal recognition particle (anti-SRP)+ IMNM, seronegative IMNM, DM, PM, PM with mitochondrial pathology, sporadic IBM, scleromyositis, and anti-synthetase syndrome. The samples were compared with mitochondrial myopathy and control muscle samples. Compared with the other IIMs and controls, endomysial capillary density (CD) was higher in anti-HMGCR+ IMNM, where M1 and M2 macrophages, detected by confocal microscopy, infiltrated perivascular endomysium and expressed angiogenic molecules such as VEGF-A and CXCL12. These angiogenic macrophages were preferentially associated with CD31+ FLK1+ microvessels in anti-HMGCR+ IMNM. The VEGF-A+ M2 macrophage density was significantly correlated with CD (rS: 0.98; P: 0.0004). Western blot analyses revealed increased expression levels of VEGF-A, FLK1, HIF-1α and CXCL12 in anti-HMGCR+ IMNM. CD and expression levels of these angiogenic molecules were not increased in anti-SRP+ and seronegative IMNM, offering additional, useful information for differential diagnosis among these IIM subtypes. Our findings suggest that in IIMs, infiltrating macrophages and microvascular cells interactions play a pivotal role in coordinating myogenesis and angiogenesis. This reciprocal crosstalk seems to distinguish anti-HMGCR associated IMNM.

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy

Autoantibodies against 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ± 213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ± 0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ± 111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ± 0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ± 20.8 mm/1 h; SRP, 35.7 ± 26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ± 36.6 mg/dL; SRP, 207.6 ± 40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ± 13.9 mg/dL; SRP, 46.2 ± 17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.

Immune‐mediated necrotizing myopathy: Unusual presentations of a treatable disease

Immune-mediated necrotizing myopathy (IMNM) is an immune-mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific, myopathological findings. Atypical cases however can mimic other inherited or acquired myopathies, depriving patients of treatment. We describe a cohort of such patients. We retrospectively identified IMNM patients who either previously carried a diagnosis of an inherited myopathy established on clinicopathological grounds or whose muscle biopsies displayed atypical features suggestive of a different myopathy. Among 131 IMNM patients, seven previously unreported patients (5%) met one of the above criteria. Three patients were diagnosed with limb-girdle muscular dystrophy on the basis of a chronic progressive course of weakness and family history of myopathy or cardiomyopathy. The other four patients displayed atypical histological features (two prominent mitochondrial abnormalities, one myofibrillar pathology, and one granulomatous inflammation). Immunostaining of biopsies from 12 additional IMNM patients did not identify myofibrillar pathology. The patient with granulomatous inflammation was known to have pulmonary sarcoidosis. Genetic testing for inherited myopathies was unrevealing. Antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle were identified in 5 and 1 patients, respectively. Four patients presented with slowly progressive weakness over 3-13 y, while weakness was subacute over ≤6mo in three patients. All patients responded to immunomodulatory therapy. Atypical clinical and histological features can occur in IMNM patients, causing delays in diagnosis and treatment. Clinicians should, therefore, consider IMNM in the differential diagnosis of unexplained proximal myopathies in spite of atypical clinical and myopathological findings.

SERONEGATIVE AUTOIMMUNE NECROTIZING MYOPATHY: ITS COURSE ACCELERATED BY COXSACKIE B INFECTION

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: We present a patient with necrotizing myopathy and rapid progression of muscle weakness, including respiratory muscles, leading to hypercapnic respiratory failure requiring mechanical ventilation following a myopericardial infection thought to be secondary to coxsackie B virus (CVB). This suggests that CVB accelerated the progression of the antibody-negative Immune mediated necrotizing myopathy (IMNM). CASE PRESENTATION: A 43 year old woman was hospitalized with proximal muscle weakness for 4 months with 2 weeks of substernal chest pain, which worsens when lying down and relieved when leaning forward. Progressive dyspnea on exertion and led to hypercapnic respiratory failure requiring mechanical ventilation. Laboratory and imaging findings were significant for creatinine kinase of 4,796, a troponin of 6.22, elevated antibody titers for CVB 1-6, and a pericardial effusion on echocardiogram. Pertinent negatives include acetylcholine receptor antibody (ab), antinuclear ab, skeletal muscle ab, Anti-signal recognition particle (SRP) and anti-hydroxy-3-methylglutarylCoA reductase (HMGCR) auto-ab. Due to a suspicion for inflammatory myopathy on MRI, a biopsy of quadriceps muscle showed predominant necrosis with minimal inflammation (monocytes, lymphocytes), myophagocytosis, and patchy MHC upregulation. Electromyogram (EMG) was negative for neuropathy or myasthenia gravis [4]. The constellation of findings was consistent with autoimmune necrotizing myopathy, its course complicated by myopericarditis thought to be secondary to CVB. The patient received IVIG, rituximab and high dose steroids, and was discharged to a long term acute care facility, where the patient's strength gradually improved. She was eventually weaned off of ventilator support. DISCUSSION: Necrotizing myopathy is a relatively recently defined form of autoimmune myopathy characterized by less inflammation and more necrosis in muscle tissue than seen in polymyositis [1]. Autoimmune myopathies are rare, with a prevalence of 9–14 cases per 100,000 people [5, 6]. Seronegative IMNM has not been characterized as well as seropositive IMNM [4]. While European Neuromuscular Centre criteria do not require muscle biopsy to diagnose seropositive IMNM, a muscle biopsy is essential/required for diagnosis of seronegative IMNM [3, 4]. CONCLUSIONS: In the setting of myocarditis likely secondary to CVB, the patient's myopathy rapidly worsened to include respiratory muscles and led to mechanical ventilation. This course of events strongly raises the possibility that coxsackie B infection led to acceleration of myopathy. REFERENCE #1: Adler BL, Christopher-Stine L. Triggers of inflammatory myopathy: insights into pathogenesis. Discov Med 2018;25:75–83. REFERENCE #2: Dalakas MC. Myositis: are autoantibodies pathogenic in necrotizing myopathy? Nat Rev Rheumatol 2018;14:251–2. REFERENCE #3: Khan NAJ, Khalid S, Ullah S, et al. Necrotizing autoimmune myopathy: a rare variant of idiopathic inflammatory myopathies. J Investig Med High Impact Case Rep 2017;5:232470961770903. DISCLOSURES: No relevant relationships by Erik Anderson, source=Web Response No relevant relationships by Amanda Eng, source=Web Response No relevant relationships by Padmanabhan Krishnan, source=Web Response

S2792 Marked Elevation in Serum Aminotransferases in Immune-Mediated Necrotizing Myopathy

Introduction: This is an elderly female diagnosed with immune-mediated necrotizing myopathy with marked elevations in serum aminotransaminases. Case Description/Methods: A 71 year old female was admitted for progressive proximal muscle weakness and lower extremity myalgia with an initial creatinine kinase (CK) of 10,520U/L concerning for rhabdomyolysis. Gastroenterology was consulted given an elevation in liver-associated enzymes in a hepatocellular injury pattern (AST 552U/L and ALT 653U/L) thought to be due to muscle breakdown. After a few days of intravenous fluids, the myalgias continued and her CK remained elevated. Rheumatology was consulted and an MRI of the extremities was pursued revealing T2 hyper-intensity and enhancement in multiple muscle segments concerning for an inflammatory myopathy. A muscle biopsy was obtained along the right thigh confirming an inflammatory change with necrotic muscle fibers. Furthermore, an anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) returned strongly positive ( >200U). Her atorvastatin 10mg PO qHS was discontinued. Chronic liver disease serologic evaluation resulted in a positive anti-smooth muscle antibody (ASMA) and an immunoglobulin G (IgG) level of 1218mg/dL. Given the concern for a concomitant autoimmune hepatitis, an EUS-guided liver biopsy was pursued which showed centrilobular hepatocyte drop-out with associated moderate mixed inflammation, increased iron deposition (2+ out of 4), with patchy mild fibrous portal expansion with rare periportal fibrosis without features consistent with autoimmune hepatitis and were thought to be due to the underlying immune-mediated necrotizing myopathy (IMNM). She was diagnosed with anti-HMGCR myopathy and was started on a course of prednisone. After 1 month of corticosteroid therapy and one week of azathioprine, her LAEs remained elevated (AST 577U/L and ALT 645U/L) and she continued to be symptomatic with worsening weakness. Rheumatology will be initiating a course of intravenous immunoglobulin G (IVIG) given the failure to respond to corticosteroid and thiopurine combination therapy. Discussion: This is a rare example of markedly elevated liver enzymes in a hepatocellular injury pattern of greater than 20 times the upper limit of normal mimicking autoimmune hepatitis in association with IMNM refractory to corticosteroid and thiopurine combination therapy. Salvage therapy with intravenous immunoglobulin G (IVIG) will be started by rheumatology. Liver enzyme levels are expected to downtrend with improvement in CK.Figure 1.: The top of the image illustrates centrilobular hepatocyte drop-out with associated inflammation including plasma cells and ceroid laden macrophages. Contrast these changes with the normal portal tract in the bottom portion of the image. (400X magnification).

Idiopathic inflammatory myopathies

The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (AS), and inclusion body myositis (IBM). I will discuss the clinical, laboratory, and histopathological features of these inflammatory myopathies and update the believed pathogenic basis for these disorders.

A CASE OF ANTI-SRP IMMUNE-MEDIATED NECROTIZING MYOPATHY WITH COEXISTING PULMONARY SARCOIDOSIS

A CASE OF ANTI-SRP IMMUNE-MEDIATED NECROTIZING MYOPATHY WITH COEXISTING PULMONARY SARCOIDOSIS

Role of Intravenous Immunoglobulin in Necrotizing Autoimmune Myopathy.

Immune-mediated necrotizing myopathy (IMNM) is a subtype of myositis that is associated with a refractory phenotype and poorer prognosis. The aim of the study was to provide single large center experience of outcomes of intravenous immunoglobulin (IVIg) for patients with IMNM using longitudinally collected data. This case series longitudinally evaluated 4 of the 6 myositis core set measures at baseline and at 3 and 6 months after IVIg on 20 adult IMNM patients from 2014 to 2019 at the University of Pittsburgh. We assessed patients for improvement in core set measures, prednisone dose, adverse effects, and by the "limited" ACR/EULAR 2016 myositis response criteria. The mean differences in CK and manual muscle testing (MMT-8) were compared using a paired t test. A clinically significant response was defined as a >10% absolute improvement in the MMT-8 and a >50% absolute reduction in serum CK at 6 months of IVIg. Intravenous immunoglobulin treatment was associated with marked improvement in IMNM patients, with 85% of patient meeting clinically significant response. The median (interquartile range) relative percent improvement in CK level was 96% (85%-98%) and in MMT was 29% (14%-36%) at 6 months.There was a significant reduction in the mean (SD) dose of prednisone at 6 months and had minimal adverse effects. In addition, with IVIg, most (13/14) patients had at least minimal improvement as per ACR/EULAR 2016 myositis response criteria. Based on objective, meaningful improvement in MMT-8 and CK as well as marked reduction in prednisone doses with acceptable tolerability, early implementation of IVIg should be considered in adult IMNM.

AUTOIMMUNE & INFLAMMATORY NMD: EP.12 ER-stress and UPR-activation in immune-mediated necrotizing myopathy

Immune mediated necrotizing myopathies (IMNM) are part of the idiopathic inflammatory myopathies, precisely defined by international consensus recently. The main characteristics include proximal muscle weakness, substantially increased serum CK levels and detection of the myositis-specific auto-antibodies -SPR54 or -HMGCR in many patients, while 1/3 of IMNM patients do not present those. Notably, both antibodies target proteins of the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) and are involved in protein processing.

Differential diagnosis of necrotizing myopathy

Necrotizing myopathy is a broad term. It includes patients with the recently described immune-mediated necrotizing myopathies (IMNM) who have specific antibodies, such as anti-hydroxy-3-methylglutaryl-CoA reductase or anti-signal recognition particle, seronegative phenotypes that can be associated with cancer, and other types of myositis and connective tissue diseases involving necrotic muscle fibers as a characteristic pathologic feature. Necrotizing myopathies that are not immune-mediated, such as those caused by drugs, dystrophies, infections, or even hypothyroidism are also included. The purpose of this review is to address the differential diagnosis of these disorders. New IMNM have been described over the last few years, some of them related with checkpoint inhibitors, drugs that are being increasingly used in cancer treatment. Necrotizing myopathy has also been reported in association with specific phenotypes and autoantibodies (e.g. anti-Mi2 dermatomyositis, antisynthetase syndrome, and myositis associated with antimitochondrial antibodies). Rarer cases associated with graft-versus-host disease and severe acute respiratory syndrome coronavirus 2 infection are also emerging. Differentiation between patients with IMNM and those without the superimposed autoimmune phenomena helps clinicians determine the best individualized approach to use and the appropriate immunosuppressive therapy, whenever needed.

Miopatía necrotizante autoinmune. Presentación de un caso clínico

Inflammatory myopathies (IM) or myositis are a heterogeneous group of muscle diseases of rare occurrence. Such diseases are characterized by inflammation of the different components of muscle tissue, which can occur either in isolation or, more commonly, as part of a systemic disorder. Immune-mediated necrotizing myopathies (IMNM) are a type of autoimmune myopathy characterized by proximal muscle weakness, myofiber necrosis with minimal inflammatory cell infiltrate on muscle biopsy and infrequent extramuscular involvement. Even though there are clinical and histopathological similarities. The spectrum of inflammatory myopathies is considerably variable. Therefore, the performance of complementary studies is essential for the proper identification of the IM subtype to contribute accurately on treatment so determine the better prognosis). The present article shows the case of a young 29 years old, with no personal and family history background of autoimmune disease and no relevant pathological back-ground. The patient consulted the medical ward of the Institution with pain, functional impairment of upper and lower extremities, muscle weakness mainly located in the pectoral girdle area and, although to a lesser degree, in the pelvic girdle area. It was also associated with asthenia, tendency to drowsiness and hyporeactivity.

Clinical Course, Myopathology and Challenge of Therapeutic Intervention in Pediatric Patients with Autoimmune-Mediated Necrotizing Myopathy.

(1) Background: Immune–mediated necrotizing myopathy (IMNM) is a rare form of inflammatory muscle disease which is even more rare in pediatric patients. To increase the knowledge of juvenile IMNM, we here present the clinical findings on long-term follow-up, myopathological changes, and therapeutic strategies in two juvenile patients. (2) Methods: Investigations included phenotyping, determination of antibody status, microscopy on muscle biopsies, MRI, and response to therapeutic interventions. (3) Results: Anti-signal recognition particle (anti-SRP54) and anti- 3-hydroxy-3-methylglutarly coenzyme A reductase (anti-HMGCR) antibodies (Ab) were detected in the patients. Limb girdle presentation, very high CK-levels, and a lack of skin rash at disease-manifestation and an absence of prominent inflammatory signs accompanied by an abnormal distribution of α-dystroglycan in muscle biopsies initially hinted toward a genetically caused muscle dystrophy. Further immunostaining studies revealed an increase of proteins involved in chaperone-assisted autophagy (CASA), a finding already described in adult IMNM-patients. Asymmetrical muscular weakness was present in the anti-SRP54 positive Ab patient. After initial stabilization under therapy with intravenous immunoglobulins and methotrexate, both patients experienced a worsening of their symptoms and despite further therapy escalation, developed a permanent reduction of their muscle strength and muscular atrophy. (4) Conclusions: Diagnosis of juvenile IMNM might be complicated by asymmetric muscle weakness, lack of cutaneous features, absence of prominent inflammatory changes in the biopsy, and altered α-dystroglycan.

Cutaneous involvement in anti-HMGCR positive necrotizing myopathy

ObjectiveAnti-3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive immune-mediated necrotizing myopathy (IMNM) is a rare disease. It is induced by exogenous substances, most often by statins. Little is known about cutaneous manifestations of HMGCR positive IMNM and about HMGCR antibody positivity in other diseases. MethodsThe characteristics of patients with anti-HMGCR autoantibodies measured at our laboratory between January 2012 and September 2020 were studied. Characteristics of patients with IMNM were compared to those patients with positive antibodies but without muscle involvement. Associations of IMNM with other organ involvements were searched for. ResultsOf the 32 patients studied, 23 showed characteristics of IMNM, 9 did not fulfill current classification criteria but most showed signs of connective tissue diseases. Patients with IMNM were older (66 and 35 years, respectively; 0.92 (0.73–0.98); p < 0.001), had more frequent statin exposure (87% and 33%, respectively; 0.84 (0.61–0.94); p = 0.005) and higher mean peak CK (8717U/l and 329U/l, respectively; 1.0 (0.85–1.0); p < 0.001). 13/23 (56%) of IMNM patients showed cutaneous lesions; none of the patients suffered from cancer; only three IMNM patients showed drug-free complete remission. Incidence of IMNM in the catchment area of our center is at least 2.7/Mio/year. ConclusionCutaneous lesions were found to be more frequent in anti-HMRCR positive IMNM than previously reported. Titer of anti-HMGCR antibodies and CK levels were significantly higher in IMNM than in other autoimmune connective tissue diseases. The data support the hypothesis of an antigen-driven response in IMNM, and suggests an activation of autoreactive B-lymphocytes in non-IMNM patients.

The Clinicopathological Distinction Between Seropositive and Seronegative Immune-Mediated Necrotizing Myopathy in China.

Objectives: The present study aimed to compare the clinicopathological features of patients with seronegative immune-mediated necrotizing myopathy (IMNM) and those positive for anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme-a reductase (HMGCR) antibodies.Methods: We retrospectively analyzed the data of patients with IMNM treated in the Neurology Department of Tongji Hospital from January 1, 2013, to December 31, 2019.Results: Among the 117 patients with IMNM, 30.8% (36/117) were positive for anti-SRP antibodies, 6.0% (7/117) were positive for anti-HMGCR antibodies, and 13.7% (16/117) were seronegative. Myalgia at presentation (62.5 vs. 23.3%, p = 0.0114) was more commonly observed in patients with seronegative IMNM than in those with seropositive IMNM. Subclinical cardiac involvement was more frequently detected in seronegative IMNM than in seropositive IMNM (6/13 vs. 5/33, p = 0.0509, echocardiogram; 7/7 vs. 12/24, p = 0.0261, cardiac MRI). Deposition of membrane attack complex (MAC) on the sarcolemma of myofibers in biopsied muscle was less commonly observed in patients with seronegative IMNM than in patients with seropositive IMNM (16.7 vs. 68.2%, p = 0.0104). The rate of marked improvement following immunotherapy tended to be higher in patients with seronegative IMNM than in those with seropositive IMNM (87.5 vs. 61%, p = 0.0641).Conclusions: Patients with seronegative IMNM more frequently present with myalgia at onset, exhibit more subclinical cardiac involvement and uncommon MAC deposition on myofibers, and experience better outcomes than those with seropositive IMNM.

A Case of Statin-Associated Immune-Mediated Necrotizing Myopathy, Successfully Treated With Intravenous Immunoglobulin

Statins have become the commonest lipid-lowering agent worldwide and have significantly reduced morbidity and mortality associated with cardiovascular diseases. Overall, statins are very well tolerated. However, in clinical practice, a wide variety of skeletal myopathic effects have been observed, ranging from asymptomatic patients with high creatine phosphokinase (CPK) to fatal cases of acute rhabdomyolysis. Recent reports suggest that statins are associated with immune-mediated necrotizing myopathy (IMNM), a unique autoimmune myopathy. Unlike other drug reactions, this can occur months to years after initiation of statin. It is a distinctive autoimmune myopathy where symptoms persist or even progress after statin discontinuation and requires immunosuppressive therapy. The presence of anti-hydroxy-methyl-glutaryl coenzyme-A reductase (HMGCR) antibody in serum strengthens the diagnosis of statin-associated necrotizing myopathy. Here we present a case of statin-associated IMNM in a 43-year-old Caucasian female who had statin-induced progressive deterioration of proximal muscle weakness with poor response to high-dose steroids and required further immunosuppressive therapy.

Muscle pathological features and extra-muscle involvement in idiopathic inflammatory myopathies with anti-mitochondrial antibody

ObjectiveAnti-mitochondrial antibodies (AMAs) can be detected in some idiopathic inflammatory myopathy (IIM) patients. We aimed to investigate the clinical features of IIM patients with AMAs. MethodsWe retrospectively analysed 1,167 consecutive patients with IIM for AMA-associated myositis and compared them to age- and gender-matched AMA-negative IIM patients. ResultsTwenty-nine patients (2.5%) were identified with AMA-positive myositis; eight of them had primary biliary cholangitis (PBC). There were no significant differences in skin rash, dysphagia, interstitial lung disease, and muscle strength between AMA-positive patients and AMA-negative patients. Of 23 cases, 12 (52.2%) showed immune-mediated necrotizing myopathy (IMNM)-like pathological features. amongst AMA-positive patients, 11 of 16 patients with isolated anti-AMAs were classified as IMNM which was significantly higher than that of patients with coexistent anti-AMAs and myositis-specific antibodies (p = 0.026). Moreover, subclinical cardiac involvement was significantly more common in AMA-positive patients than in AMA-negative patients (21/29 VS 33/116, p<0.001). In addition, patients without PBC had a significantly higher incidence of abnormal echocardiography findings than that of patients with PBC (p = 0.009). Patients without heart abnormalities took significantly less time to achieve disease remission and prednisone tapering to <10 mg than patients with heart abnormalities (p = 0.000 and p = 0.001, respectively). ConclusionsIMNM was a major histopathological finding in IIM patients with isolated AMAs. AMAs were significantly associated with subclinical cardiac involvement in IIM. PBC seemed to be a protective factor for abnormal echocardiography findings in AMA-positive patients. Patients without heart involvement took less time to achieve disease remission and prednisone tapering off.

High-intensity strength training in patients with idiopathic inflammatory myopathies: a randomised controlled trial protocol

IntroductionIdiopathic inflammatory myopathies (IIMs) are rare diseases characterised by non-suppurative inflammation of skeletal muscles and muscle weakness. Additionally, IIM is associated with a reduced quality of life. Strength training is...

The role of interferons type I, II and III in myositis: A review.

The classification of idiopathic inflammatory myopathies (IIM) is based on clinical, serological and histological criteria. The identification of myositis‐specific antibodies has helped to define more homogeneous groups of myositis into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), sporadic inclusion body myositis (sIBM) and immune‐mediated necrotising myopathy (IMNM). sIBM and IMNM patients present predominantly with muscle involvement, whereas DM and ASyS patients present additionally with other extramuscular features, such as skin, lung and joints manifestations. Moreover, the pathophysiological mechanisms are distinct between each myositis subsets. Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In DM, the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in muscle, blood and skin of DM patients. In addition, DM‐specific antibodies are targeting antigens involved in the IFN signalling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signalling pathways induces systemic manifestations such as interstitial lung disease, myositis and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signalling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in ASyS, available data suggest a role of type II IFN in blood, muscle and lung. Indeed, transcriptomic analyses highlighted a type II IFN gene expression in ASyS muscle tissue. In sIBM, type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to myodegenerative features. For IMNM, currently published data are scarce, suggesting a minor implication of type II IFN. This review highlights the involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset.

Miopatías inflamatorias idiopáticas

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of immune-mediated disorders, characterised by inflammation of the skeletal muscle. The 8 groups defined histologically and clinically are as follows: polymyositis (PM), adult dermatomyositis (DM), juvenile DM, amyopathic DM, inclusion-body myositis (IBM), immune-mediated necrotising myopathy (IMNM), myopathies associated with neoplasia and myopathies associated with other systemic autoimmune rheumatic conditions in the context of overlap syndromes. In addition to muscle weakness, there may be other extramuscular manifestations such as cutaneous, joint, lung, digestive and cardiac conditions. Up to 60% of the patients with IIM have antibodies that can be divided into 2 large groups: myositis-specific antibodies and myositis-associated antibodies that can be present overlapping with other systemic diseases. Muscle biopsy is essential for their diagnosis, given that the histopathological study defines the type of myositis. Treatment consists of high doses of glucocorticoids that, most of the time, requires immunosuppressive therapy as well.

The phenotype of myositis patients with anti-Ku autoantibodies

ObjectivesTo define the clinical features of anti-Ku-positive myositis patients and to determine the reliability of the Euroline assay to detect anti-Ku autoantibodies. MethodsSerum samples were screened for anti-Ku autoantibodies by Euroline and positive samples were confirmed by ELISA. The prevalence and severity of clinical features at onset and during follow-up in patients with anti-Ku-positive myositis were compared to those with dermatomyositis, immune-mediated necrotizing myopathy (IMNM), the antisynthetase syndrome (AS), inclusion body myositis (IBM), anti-U1-RNP-positive myositis, and anti-PM/Scl-positive myositis. Results72 (2.9%) of 2475 samples were anti-Ku positive by Euroline using the manufacturer's recommended cutoff of >15. Just 17 (23.6%) of these were confirmed by ELISA and considered anti-Ku-positive for the analysis. Comparators included 169 IMNM, 168 AS, 387 IBM, 20 anti-U1-RNP-positive, and 47 anti-PM/Scl-positive patients. Muscle weakness was a presenting feature in 38% of anti-Ku-positive patients; 81% developed weakness during follow-up. Anti-Ku-positive patients had increased distal weakness compared to the non-IBM comparators. Interstitial lung disease (ILD) was present in 19% of anti-Ku-positive patients at the first visit and eventually developed in 56% of them. Throughout the course of disease, Gottron's papules and/or heliotrope rashes were less common in anti-Ku-positive patients (19%) compared to those with dermatomyositis (94%) or anti-PM/Scl-positive myositis (89%). Anti-Ku-positive patients never developed calcinosis. ConclusionsThe phenotype of anti-Ku positive myositis is distinguished by distal weakness, frequent ILD, infrequent rash, and no calcinosis. When used according to the current manufacturer's instructions, the Euroline assay has a high false-positive rate for anti-Ku autoantibodies.