Autoimmune Myopathy Research Articles

Autoimmune Necrotizing Myopathies: Subtypes and Advances in Treatment

Purpose of Review Necrotizing autoimmune myopathies (NAM), or immune-mediated necrotizing myopathies (IMNM), are considered as a unique category of autoimmune myopathy given their distinctive histologic, serologic, and clinical features. The goals of this article are to review the subtypes of IMNM and to discuss treatment options that apply to these conditions.

Immune-mediated necrotizing myopathy associated with statins: history and recent developments.

The use of statins has increased exponentially over the last 2 decades. Consequently, side effects have also increased, with muscle-related side effects commonly reported. Although once thought to be only associated with self-limited direct myotoxicity, statins have recently been described in association with an autoimmune myopathy in association with antibodies directed against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis and the pharmacologic target of statins. Since this discovery, various cohorts have been identified worldwide and highlight both similarities and differences among them. Recent studies from different fields have revealed diverse aspects of anti-HMGCR-associated immune-mediated necrotizing myopathy (IMNM). HMGCR IMNM is a unique autoimmune disease characterized by a well defined environmental trigger (statins) and a strong association with a genetic risk factor (Human leukocyte antigen D related B 111 : 01). New diagnostic modalities have been established to confirm the presence of anti-HMGCR antibody and confirm the diagnosis of HMGCR IMNM. Clinical studies have shown that disease severity, as measured by muscle strength, as well as the rate of response to treatment have been associated with age at disease onset. Furthermore, a case series supported that intravenous immunoglobulin administration, perhaps even as monotherapy, may be a beneficial therapeutic intervention for selected patients.

Which nonautoimmune myopathies are most frequently misdiagnosed as myositis?

To discuss the spectrum of nonautoimmune myopathies that may be misdiagnosed as autoimmune myopathy. Inherited myopathies, such as dysferlinopathy, calpainopathy, and facioscapulohumeral dystrophy may be misdiagnosed as autoimmune myopathy, especially when they have inflammatory muscle biopsies. Inclusion body myositis is frequently misdiagnosed as polymyositis when rimmed vacuoles are absent on muscle biopsy, and a careful neuromuscular evaluation is not performed. Hypothyroid myopathy can be misdiagnosed as immune-mediated necrotizing myopathy if thyroid function tests, including a T4 level, are not obtained. Self-limited statin myopathy can be distinguished from statin-associated autoimmune myopathy because patients with the former do not have autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Autoimmune myopathies can usually be distinguished from nonautoimmune myopathies based on a combination of the patient history, neuromuscular exam, laboratory findings, and/or muscle biopsy features.

Multicenter Registry on Inflammatory Myositis From the Rheumatology Society in Madrid, Spain: Descriptive Analysis

ObjectiveTo analyze clinical characteristics, survival and causes of death of patients diagnosed with autoimmune inflammatory myositis in the REMICAM registry from the Society of Rheumatology in the Community of Madrid (SORCOM). MethodsMulticenter cohort of patients diagnosed with autoimmune inflammatory myopathy with follow-up between January 1980 and December 2014. A total of 313 variables concerning demographic, clinical and morbidity data were collected, and a comparison was performed between clinical subgroups. ResultsA total of 479 patients were recruited from 12 centers with 14% of patients lost to follow-up. Seventy-four percent of cases were women, age at diagnosis of 44±23 years and a mean follow-up period of 10±8 years. The most frequent clinical subgroups were primary myositis (PM 29%, DM 22%), followed by overlap myositis (20.5%), juvenile myositis (18%), myositis associated with cancer (8%), immune-mediated necrotizing myositis (1%) and inclusion body myositis (1%). During the follow-up period, a total of 114 deaths (28%) were registered, the main causes being cancer (24%), infections (23%) and cardiovascular events (21%). ConclusionsA total of 479 patients were recruited in the REMICAM registry of inflammatory myopathies. Including sociodemographic, clinical and prognostic information, it represents the largest Spanish multicenter registry to date in rheumatology, and constitutes an important source for conducting further substudies.

IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF–Producing γδ T Cells in the Muscle

Abstract IL-21 is suggested to be involved in the development of some autoimmune diseases; however, the role of IL-21 in autoimmune inflammatory myopathies (IMs) remains unknown. In this study, we found that serum levels of IL-21 were significantly elevated in a subset of IM patients. Upon the induction of experimental autoimmune myositis (EAM), IL-21 was produced by CD4+ T cells in the muscle, and muscle weakness and muscle inflammation were less obvious in IL-21–deficient (IL-21−/−) mice compared with those in wild-type (WT) mice. Analysis of inflammatory cytokine production from draining lymph node cells of EAM-induced mice revealed that GM-CSF production was significantly decreased in IL-21−/− mice. Importantly, GM-CSF production from γδT cells, but not CD4+ T cells, was significantly reduced in EAM-induced IL-21−/− mice. In addition, the severity of EAM was attenuated by GM-CSF neutralization in WT mice or γδT cell deficiency. The majority of muscle-infiltrating GM-CSF–producing γδT cells expressed Vγ4+Vδ4+ TCR, and the number of Vγ4+Vδ4+ cells in the muscle was significantly decreased in EAM-induced IL-21−/− mice as compared with that in EAM-induced WT mice. Moreover, muscle-infiltrating Vγ4+Vδ4+ cells exhibited CX3CR1high phenotype, and the induction of Cx3cl1, a ligand for CX3CR1, in the muscle was reduced in EAM-induced IL-21−/− mice. Furthermore, reporter assays revealed that IL-21 activated the promoter of Cx3cl1. Consistent with these findings, serum levels of CX3CL1 were correlated with the levels of IL-21 in IM patients. Taken together, these results suggest that IL-21 facilitates autoimmune myositis through the accumulation of GM-CSF–producing Vγ4+Vδ4+ cells in the muscle possibly via CX3CR1-CX3CL1 pathways.

Evaluation for the clinical significance of cancer-association in anti-SRP antibody-positive myopathy

Background: Both anti-SRP and anti-HMGCR antibodies (Abs) are recognized as markers of necrotizing autoimmune myopathies. We recently identified that anti-HMGCR Ab was second most frequently detected in cancer-associated myositis (CAM) and that the synchronous occurrence of cancers and myopathies, advanced cancers and poor prognosis were frequently observed in HMGCR-CAM. Previous studies reported that cancers were detected in 5-17% of anti-SRP Ab+ myopathy, however, clinical features of SRP-CAM patients has not been well assessed and cancer-association in anti-SRP Ab+ myopathy remains controversial to date.

The cut-off levels of serum creatine kinase as a diagnostic marker for myopathy with anti-hmg-cr or anti-srp autoantibodies positive

Background: Patients with necrotizing autoimmune myopathy (NAM) are frequently refractory to treatments and early introduction of intensive treatment is necessary. Detection of anti-SRP or -HMGCR-Abs, which are usually seen in NAM patients, is not easily available in clinical setting.

Statin-induced Necrotizing Autoimmune Myopathy

Statin-induced Necrotizing Autoimmune Myopathy

Clinico-serologic features of statin-induced necrotising autoimmune myopathy in a single-centre cohort.

Statin-induced necrotising autoimmune myopathy (NAM) is a rare but disabling complication of statin therapy. Data regarding treatment and outcomes in these patients is sparse. We retrospectively identified those patients with a diagnosis of statin-induced NAM who were managed in a single-tertiary referral centre from January 2014 to January 2017. Data regarding clinical features, serology, antibody status and functional outcome was collected. We identified 16 patients diagnosed with statin-induced NAM. Truncal weakness was present in 9/16 patients, of which one patient presented with camptocormia. Following treatment, the mean improvement in the 8-point manual muscle test (MMT8) score was 11 points (range 1-25). Antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were detected in 8/14 patients tested. Of patients who were HMGCR positive, 7/8 had significant truncal weakness, compared with 1/6 who were anti-HMGCR negative. In 4/7 patients who had anti-HMGCR retested following treatment, these antibodies subsequently became undetectable. The disappearance of anti-HMGCR was accompanied by sustained clinical improvement in all four patients. The mean Karnofsky Performance Status (KPS) prior to diagnosis was 89/100, and at latest follow-up had fallen to 68/100. We report a novel association of anti-HMGCR antibodies with truncal weakness in patients with statin-induced NAM. Functional impairments persist despite normalisation of muscle strength. Anti-HMGCR antibodies may disappear with treatment, paralleled by clinical remission of disease. Further prospective clinical trials are needed to determine optimal management strategies for statin-induced NAM.

P.182 - Immunemediated necrotizing autoimmune myopathy: Dutch and Belgian experience

P.182 - Immunemediated necrotizing autoimmune myopathy: Dutch and Belgian experience

P.201 - Differential type I and type II interferon signatures in primary inflammatory/dysimmune myopathies

Primary inflammatory/dysimmune myopathies (PIDM) include (i) polymyositis (PM)/inclusion body myositis (IBM), (ii) dermatomyositis (DM), (iii) necrotizing autoimmune myopathy, and (iv) overlap myositis (OM) . Type I α/β interferon signature was proposed as a characteristic feature of DM . Since OM and IBM differ from other PIDM by the presence of major histocompatibility complex (MHC)-2 expression by myofibers, we hypothesized that they are characterized by interferon (IFN)γ-mediated inflammation. To test this hypothesis, we evaluated by qPCR the expression of IFNγ, six IFNγ–induced genes (HLA-DM, -DO, -DP, -DR, CIITA, GBP2), and IFNα-induced gene ISG15 in muscle biopsy samples from patients with IBM (n = 10), DM (n = 10), NAM (n = 10), antisynthetase myositis (ASM, n = 10), and normal muscle (n = 10). Muscle IFNγ expression was found increased x50 in ASM and x80 in IBM compared to control, that of CIITA x4 and x3 (respectively) as well of HLA-DR (x5 and x8) and HLA-DM (x16 and x15). None of these genes were overexpressed in DM and NAM. ISG15 was increased x300 in DM, but not in other conditions. Our results confirmed that DM differed from other PIDM by its elective interferon α/β signature, while ASM and IBM were found associated with IFNγ signature.

051 Differences in the response of dermatologic symptoms and muscular strength after intravenous immunoglobulin therapy in dermatomyositis patients

Dermatomyositis (DM) is an auto-immune inflammatory myopathy characterized by muscle weakness and typical skin manifestations. Therapy includes systemic glucocorticoids, immunosuppressants and intravenous immunoglobulin (IVIG). Studies addressing the long-term efficacy of IVIG treatment are sparse. Particularly, studies investigating differences in response patterns of cutaneous and muscular symptoms are lacking. In this retrospective study we analyzed the clinical characteristics and outcomes of 20 DM patients treated between 2000-2017. The average age of patients was 62.5 (range 89-37) years. Six patients (30%) had paraneoplastic DM. Nineteen patients received glucocorticoids in addition to other immunomodulatory drugs: Fifteen patients (75%) were treated with IVIG at a dosage of 2g/kg bodyweight every 4 weeks. Four patients (20%) initially received azathioprine, and one patient was treated with glucocorticoid monotherapy. Response to treatment was individually assessed for cutaneous and muscular symptoms. Data revealed that muscular strength recovered to near baseline levels within the first 4 cycles of IVIG treatment, with the majority of patients experiencing marked improvement after the first cycle. Similarly, serum CK levels dropped from averageinitial=1138.7U/l to average4cycles=82.2U/l within the first 4 treatment cycles. In contrast, skin manifestations did not improve in the majority of DM patients. Regardless of the initial response to therapy, muscular and skin symptoms did not further improve during the course of treatment, but rather remained stable after cycle 4. None of the investigated clinical characteristics predicted a response to IVIG therapy. Similar findings were seen in patients receiving medication other than IVIG. We conclude that the initial response to treatment determines the success of therapy. Additionally, we found that muscular symptoms almost completely resolved in all patients, whereas skin symptoms were barely improved.

Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer.

Autoimmune myopathies (myositides) are strongly associated with malignancy. The link between myositis and cancer, originally noticed by Bohan and Peter in their classification in 1975 (1), has been evidenced by large population-based cohort studies and a recent meta-analysis. The numerous reports of cases in which the clinical course of myositis reflects that of cancer and the short delay between myositis and cancer onset support the notion that myositis may be an authentic paraneoplastic disorder. Thus, cancer-associated myositis raises the question of cancer as a cause rather than a consequence of autoimmunity. Among myositides, dermatomyositis and more recently, although to a lesser extent, immune-mediated necrotizing myopathies are the most documented forms associated with cancer. Interestingly, the current diagnostic approach for myositis is based on the identification of specific antibodies where each antibody determines specific clinical features and outcomes. Recent findings have shown that the autoantibodies anti-TIF1γ, anti-NXP2 and anti-HMGCR are associated with cancers in the course of myositis. Herein, we highlight the fact that the targets of these three autoantibodies involve cellular pathways that intervene in tumor promotion and we discuss the role of cancer mutations as autoimmunity triggers in adult myositis.

COULD ANTI-SYNTHETASE SYNDROME BE A GOOD PREDICTOR FACTOR FOR INTERSTITIAL LUNG DISEASE?

Anti-synthetase syndrome (SAS) is an autoimmune inflammatory myopathy, whose immune profile is dominated by anti-RNA synthetase antibodies (ARS), with a specific clinical phenotype. The major diagnostic criteria of SAS include the triad of myositis, arthritis and interstitial lung disease (ILD), on the background of positive anti-ARS antibodies. ILD in SAS, has a good evolution compared to the one in PM/DM, due to protective presence of anti Jo-1 antibodies.

Outcome measures in the idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune disorders that share some similarities, such as proximal predominant symmetric muscle weakness, also known as myopathy pattern 1,1 except for myopathy pattern 4 (distal arm and proximal leg weakness), in inclusion body myositis (IBM).1,2 Common features in IBM, dermatomyositis, polymyositis, and necrotizing autoimmune myopathy, frequently include serum creatine kinase (CK) elevation and myopathy with muscle membrane irritability on EMG. Muscle histopathology findings vary depending on the underlying disease, and may include inflammatory exudates of variable distribution, intact myofiber lymphocytic invasion, widespread necrosis and phagocytosis, or, in the case of IBM, rimmed vacuoles and protein aggregation.2,3

Necrotizing Autoimmune Myopathy: A Rare Variant of Idiopathic Inflammatory Myopathies.

Idiopathic inflammatory myopathies are an unusual group of myopathies with annual incidence of 1 in 100 000 people in the United States. Necrotizing autoimmune myopathy comprises only 16% of this group. It usually presents with severe proximal weakness, lower extremity weakness, and severe fatigue while very rarely does it present with dysphagia and respiratory muscle weakness. Statin use, cancer, and connective tissue disorder are the usual associated risk factors. Anti-signal recognition particle and 3-hydroxy-3-methylglutaryl-coenzyme A reductase are the 2 most common autoantibodies associated with necrotizing autoimmune myopathy. In this article, we present a very rare case of a 66-year-old male who presented with shortness of breath and dysphagia requiring intubation and ventilator support. Creatine kinase was 23 000, myoglobin was 7000, and ANA was positive. All other autoimmune and infectious workup including Lyme disease was unremarkable. Muscle biopsy turned out remarkable for necrotizing myopathy. No evidence of statin use, active malignancy, or connective tissue disease was found. He was treated with high-dose corticosteroids and a short course of intravenous immunoglobulin with very mild improvement in symptoms. Anti-signal recognition particle and 3-hydroxy-3-methylglutaryl-coenzyme A reductase could not be performed as the patient refused to pursue further medical testing. This is a very rare case of idiopathic inflammatory myopathy presenting with bulbar and respiratory muscle weakness requiring ventilator support.

Statin-Associated Autoimmune Myopathy: A Systematic Review of 100 Cases.

Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. About 2-20% patients on statins develop toxic myopathies, which usually resolve on discontinuation of statin. More recently, an immune-mediated necrotizing myopathy has been found to be associated with statin use which in most cases requires treatment with immunosuppressants. To perform a systematic review on published case reports and case series of statin-associated autoimmune myopathy. A comprehensive search of PUBMED, EMBASE, Cochrane library and ClinicalTrials.gov databases was performed for relevant articles from inception until March 19, 2016 to identify cases of statin-associated necrotizing myopathy and characterize their symptoms, evaluation and response to treatment. A total of 16 articles describing 100 patients with statin-associated autoimmune myopathy were identified. The mean age of presentation was 64.72 years, and 54.44% were males. The main presenting clinical feature was proximal muscle weakness, which was symmetric in 83.33% of patients. The mean creatine kinase (CK) was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases tested (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Most (83.82%) patients received two or more immunosuppressants to induce remission. Ninety-one percent had resolution of symptoms after treatment. Statin-associated necrotizing myopathy is a symmetric proximal muscle weakness associated with extreme elevations of CK. It is common in males and can occur after months of statin use. It is associated with necrosis on muscle biopsy and the presence of anti-HMG-CoA reductase antibodies. It usually requires discontinuation and immune suppression for resolution. Rechallenge with statin is unsuccessful in most cases.

Statin-associated immune-mediated myopathy: biology and clinical implications.

In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Pathogenic role of anti-signal recognition protein and anti-3-Hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies.

Immune-mediated necrotizing myopathies (IMNM) may be associated with either anti-signal recognition protein (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies (Abs), and the titer of these Abs is correlated with disease activity. We investigated whether anti-SRP and anti-HMGCR Abs could be involved in muscle damage. Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles. In muscle biopsies of patients with anti-SRP+ and anti-HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)-6, and reactive oxygen species. In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity. These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538-548.

The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent

Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL−/− NOD mice show stronger protection from insulitis than their ICOS−/− counterparts. Also, the ICOSL−/− NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS−/− NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL−/− NOD model. The phenotype observed in ICOSL−/− NOD mice is globally similar to that observed in ICOS−/− and ICOS−/−ICOSL−/− double-knockout NOD mice, manifested by a progressive locomotor disability first affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myofiber necrosis/regeneration and an inflammatory infiltrate composed of CD4+ T-cells, CD8+ T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopathy can be transferred to NOD.scid recipients by CD4+ but not by CD8+ T-cells isolated from 40-week-old female ICOSL−/− NOD mice. The predominant role of CD4+ T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA−/−ICOSL−/− NOD in contrast to β2microglobulin−/−ICOSL−/− NOD mice. Also, the cytokine profile of CD4+ T-cells infiltrating muscle and nerve of ICOSL−/− NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4+ T-cells, leads to myofiber necrosis and regeneration. It provides the first mouse model of spontaneous autoimmune myopathy akin to human myositis.