Anti-signal Recognition Particle Antibodies Research Articles

Analytic and Clinical Validity of Myositis-Specific Antibodies by Line-Blot Immunoassay Is Essential.

This study assessed the concordance between line blot (LB) and immunoprecipitation (IP) assays for detecting myositis-specific antibodies (MSAs) in idiopathic inflammatory myopathies (IIMs) and their association with IIM subtypes. One hundred patients with IIM were enrolled, and MSA was detected using LB and IP. The IIM subtypes, including immune-mediated necrotizing myopathy-like, anti-tRNA synthetase syndrome-like, and clinically amyopathic dermatomyositis-like, were clinically diagnosed. The validity and reliability of the LB compared with the IP were evaluated. Optimal cutoff levels for LB were determined using various statistical methods including Cohen κ, Gwet's AC, diagnostic odds ratios, and receiver operating characteristic analysis. Line blot exhibited lower specificity and accuracy than IP in predicting IIM subtypes. Some MSAs performed better at higher LB cutoff values. Anti-signal recognition particle antibodies showed poor performance in predicting the immune-mediated necrotizing myopathy-like subtype using LB. Raising the cutoffs improved the reliability of anti-threonyl-tRNA synthetase and anti-signal recognition particle antibodies. Anti-histidyl-tRNA synthetase antibodies performed well at lower positivity, whereas diagnostic odds ratios increased for anti-transcription intermediary factor 1γ and anti-nuclear matrix protein 2 with higher cutoffs. Inconsistencies between LB and IP have been observed in patients with IIM. Individual optimal cutoffs for MSA by LB correlating with IP were determined. Rheumatologists should consider the differences between LB and IP results when classifying IIM subtypes.

What should we expect when two myositis-specific antibodies coexist in a patient

BackgroundThe coexistence of two myositis-specific autoantibodies (MSA) is considered extremely rare. We describe three patients with both anti-signal recognition particle (SRP) antibodies and another MSA in serum.MethodsWe performed a retrospective clinical data collection and follow-up studies of the clinical manifestations and treatment outcome of three patients positive with anti-SRP antibodies and other MSAs. IgG antibodies against MSAs were detected using commercial line immunoblot assay.ResultsThe tests of MSA showed positive result of anti-SRP antibodies and another one MSA including anti-TIF1-γ, anti-Jo1, or anti-EJ antibodies, respectively. The proximal muscle weakness appeared in 2 patients; interstitial lung disease presented in 2 patients. The serum CK level was elevated in 1 patient. The muscle biopsy showed necrotizing myopathy in 1 patient and deposition of membrane attack complex on scattered myofibers in the other one patient. One of the two patients with interstitial lung disease died because of respiratory failure. One patient had completely improved and the other one showed partial remission after immunosuppressive therapy.ConclusionsThe patients with anti-SRP antibodies co-occurred with the other MSA may have various clinical characteristics. The clinicopathological phenotypes of these patients seem to be mainly caused by one of the MSAs, namely the responsible antibody.

Gut microbiota dysbiosis characterized by abnormal elevation of Lactobacillus in patients with immune-mediated necrotizing myopathy.

The gut microbiota plays an important role in human health. In this study, we aimed to investigate whether and how gut microbiota communities are altered in patients with immune-mediated necrotizing myopathy (IMNM) and provide new ideas to further explore the pathogenesis of IMNM or screen for its clinical therapeutic targets in the future. The gut microbiota collected from 19 IMNM patients and 23 healthy controls (HCs) were examined by using 16S rRNA gene sequencing. Alpha and beta-diversity analyses were applied to examine the bacterial diversity and community structure. Welch's t test was performed to identify the significantly abundant taxa of bacteria between the two groups. Spearman correlation analysis was performed to analyze the correlation between gut microbiota and clinical indicators. A receiver operator characteristic (ROC) curve was used to reflect the sensitivity and specificity of microbial biomarker prediction of IMNM disease. P < 0.05 was considered statistically significant. Nineteen IMNM patients and 23 HCs were included in the analysis. Among IMNM patients, 94.74% (18/19) of them used glucocorticoids, while 57.89% (11/19) of them used disease-modifying antirheumatic drugs (DMARDs), and the disease was accessed by MITAX (18.26 ± 8.62) and MYOACT (20.68 ± 8.65) scores. Participants in the groups were matched for gender and age. The diversity of the gut microbiota of IMNM patients differed and decreased compared to that of HCs (Chao1, Shannon, and Simpson indexes: p < 0.05). In IMNM patients, the relative abundances of Bacteroides, Roseburia, and Coprococcus were decreased, while that of Lactobacillus and Streptococcus were relatively increased. Furthermore, in IMNM patients, Lactobacillus was positively correlated with the levels of anti-signal recognition particle (SRP) antibodies, anti-Ro52 antibodies, and erythrocyte sedimentation rate (ESR), while Streptococcus was positively correlated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies and C-reactive protein (CRP). Roseburia was negatively correlated with myoglobin (MYO), cardiac troponin T (cTnT), ESR, CRP, and the occurrence of interstitial lung disease (ILD). Bacteroides was negatively correlated with ESR and CRP, and Coprococcus was negatively correlated with ESR. Finally, the prediction model was built using the top five differential genera, which was verified using a ROC curve (area under the curve (AUC): 87%, 95% confidence interval: 73%-100%). We observed a characteristic compositional change in the gut microbiota with an abnormal elevation of Lactobacillus in IMNM patients, which was accompanied by changes in clinical indicators. This suggests that gut microbiota dysbiosis occurs in IMNM patients and is correlated with systemic autoimmune features.

COVID-19 Pneumonia Followed by Anti-signal Recognition Particle Antibody-positive Fibrosing Interstitial Lung Disease: A Case Report.

Coronavirus disease 2019 (COVID-19) pneumonia is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently accompanied by various sequelae. Interstitial lung diseases (ILDs) are observed in COVID-19 pneumonia patients after recovery, probably due to persistent inflammation in the lungs. We herein report a case of ILD with anti-signal recognition particle antibodies following severe COVID-19 pneumonia. The patient was diagnosed with ILD three months after COVID-19 pneumonia. Although the exact mechanism is unknown, the autoantibody-induced immune response might have been the pulmonary fibrosis trigger in this patient.

Immune-mediated necrotizing myopathy (NAM) related to SARS-Cov-2 infection: a case report

BackgroundThere is a growing body of evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 infection is associated with the development of autoimmune diseases. A recent systematic review reported that the new-onset autoimmune disorders during or after COVID-19 infection included inflammatory myopathies such as immune-mediated necrotizing myopathies.Case presentationWe described a 60-year-old man diagnosed with COVID-19 infection and later presented with a two-week history of myalgia, progressive limb weakness, and dysphagia. He had a Creatinine Kinase (CK) level of more than 10,000 U/L, was strongly positive for anti-signal recognition particle (SRP) and anti-Ro52 antibody, and a muscle biopsy revealed a paucity-inflammation necrotizing myopathy with randomly distributed necrotic fibers, which was consistent with necrotizing autoimmune myositis (NAM). He responded well clinically and biochemically to intravenous immunoglobulin, steroids and immunosuppressant and he was able to resume to his baseline.ConclusionSARS-CoV-2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis.

Interstitial lung disease is not rare in immune-mediated necrotizing myopathy with anti-signal recognition particle antibodies

ObjectivesThe purpose was to clarify the characteristics of interstitial lung disease (ILD) in immune-mediated necrotizing myopathy (IMNM) patients with anti-signal recognition particle (SRP) antibodies.MethodsMedical records of IMNM patients with anti-SRP antibodies were reviewed retrospectively.ResultsA total of 60 patients were identified. Twenty-seven (45.0%) patients were diagnosed with ILD based on lung imaging: nonspecific interstitial pneumonia (NSIP) in 17 patients (63.0%) and organizing pneumonia in 9 patients (33.3%). Reticulation pattern was identified in 17 patients (63.0%) whereas 10 cases (37.0%) showed ground glass opacity and patchy shadows by high-resolution computed tomography (HRCT). Pulmonary function tests (PFTs) were available in 18 patients, 6 (33.3%) and 10 (55.6%) patients were included in the mild and moderate group, respectively. The average age at the time of ILD onset was significantly older than those without ILD (48.6 ± 14.4 years vs. 41.2 ± 15.4 years, p < 0.05), and the frequency of dysphagia in the ILD group was higher than the group without ILD (p < 0.05). Long-term follow-up was available on 9 patients. PFTs were stable in 8 (88.9%), and the HRCT remained stable in 6 (66.7%) patients.ConclusionsILD is not rare in IMNM patients with anti-SRP antibodies, most being characterized as mild to moderate in severity. NSIP is the principal radiologic pattern, and ILD typically remains stable following treatment.

AUTOIMMUNE & INFLAMMATORY NMD: EP.01 Autoimmune necrotizing myopathy with anti-signal recognition particle antibodies in the first year of life

Autoimmune necrotizing myopathy with anti-signal recognition particle antibodies (SRP ANM) has been rarely reported in childhood. Case Reports. We report 2 patients with onset in the first years of life. Both received corticosteroids, immunoglobulins, methotrexate, hydroxychloroquine and tacrolimus. Patient 1 has clearly improved. Patient 2 was misdiagnosed as muscular dystrophy for 15 years; nevertheless, after 4 months of therapy there was mild motor improvement. Patient 1. A 6-year-old girl presented with weakness, but her parents could not recall the beginning. She had axial as well as mild to moderate limb girdle weakness. There was no systemic/skin involvement. CK levels were 2.400 UI/l. The DMD MLPA test and next-generation sequencing (NGS) did not reveal any pathogenic mutation. Muscle weakness progressed quickly in the next 3 months, suggesting an acquired myopathy, and SRP antibodies were detected. Muscle biopsy was compatible with ANM. Patient 2. A 4-year-old girl presented with weakness in lower limbs for months. Her family was consanguineous. She achieved ambulation after 18 months. She had proximal limb weakness, as well as scapular winging and calf hypertrophy. Her cognitive capacity was borderline. CK levels were >5.000U/l. MRI disclosed posterior thig involvement and focal edema, but based on the rest of clinical findings, a muscular dystrophy was suspected. Muscle biopsy performed at 5 and 10 years of age showed a dystrophic pattern with necrotic fibers and endomysial connective infiltration. Immunochemistry study for muscular dystrophies was normal. Her clinical course has progressed very slowly. She showed rigid spine and maintains independent walking. At 19 year of age, due to the negativity of the all the genetic tests performed over the time (including NGS), myositis specific autoantibodies were tested and SRP antibodies were positive. Review of the second muscle biopsy disclosed C5b-9 expression in muscle fibers. SRP ANM is under-recognized and consequently undertreated in children. Early diagnosis is crucial to improve outcome.

Plasma exchange therapy in refractory inflammatory myopathy with anti-signal recognition particle antibody: a case series.

To explore the efficacy of plasma exchange (PE) therapy in refractory idiopathic inflammatory myopathy (IIM) patients with positive anti-signal recognition particle (SRP) antibody. Nine refractory IIM patients with positive anti-SRP antibody were enrolled, who received PE therapy at Ruijin Hospital from October 2017 to December 2020. The clinical manifestations, laboratory tests, chest CT and lower extremity MRI images before and after PE therapy were compared. The treatment response was evaluated by the 2016 ACR/EULAR myositis response criteria. A total of 88.9% (8/9) of subjects had achieved improvement by 3 weeks after PE therapy, with 55.6% (5/9) minimal improvement and 33.3% (3/9) moderate improvement. There were statistically significant improvements between baseline and after PE therapy at 3 weeks on the core set measures: physician global activity, patient global activity, HAQ, manual muscle testing (MMT), extramuscular disease activity, and muscle enzymes activity including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), except for alanine transaminase (ALT). Moreover, the chest CT showed regression of ground glass opacities and irregular linear opacities after PE therapy in four patients with interstitial lung disease. The MRI images of lower extremity in four patients showed reduction of muscle oedema after the therapy. PE therapy is effective for refractory IIM patients with positive anti-SRP antibody. It should be considered as an alternative treatment for those patients who are resistant to the combined therapy of glucocorticoids and immunosuppressive agents.

Rituximab in the treatment of immune-mediated necrotizing myopathy: a review of case reports and case series.

Immune-mediated necrotizing myopathy (IMNM) is a group of immune-related myopathies characterized by progressive proximal muscle weakness, extremely high serum creatine kinase (CK) levels, and necrotic muscle fibers with a relative lack of inflammation. Treatment of IMNM is challenging, with most cases refractory to high-dose steroids in combination with multiple immunotherapies. The role of rituximab (RTX) for IMNM has been explored in isolated case reports and small series. The aim of this article was to perform a literature review of patients with IMNM treated with RTX and to evaluate RTX efficacy and safety. A total of 34 patients with IMNM were reviewed: 52.9% (18/34) with anti-signal recognition particle (SRP) antibodies and 47.1% (16/34) with anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies. Patient age at onset varied from 11 years to 81 years (mean 41 years). The majority of patients presented as a severe proximal muscle weakness and the peak level of CK varied from 3900 IU/L to 56,000 IU/L (mean 18,440 IU/L). Prior to RTX administration, all patients were treated with high-dose steroids and most were treated with multiple immunotherapies. The reason for initiating RTX was that 64.7% (22/34) of patients showed no improvement after previous treatments, and 35.3% (12/34) of patients relapsed when attempting to wean steroids or other immunosuppressive agents. With regard to RTX efficacy, 61.8% (21/34) of patients presented a response to RTX.Our data may support the use of RTX as an effective treatment strategy against IMNM resistant to steroids and multiple immunotherapies. Meanwhile, RTX as a first-line therapy could be a choice in IMNM, particularly in African Americans with anti-SRP antibody-positive subsets. ANA, antinuclear antibody; CK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; IMNM, immune-mediated necrotizing myopathy; MAC, membrane attack complex; MHC-I, major histocompatibility complex-I; RTX, rituximab; SRP, signal recognition particle.

Factors associated with refractory autoimmune necrotizing myopathy with anti-signal recognition particle antibodies

BackgroundAutoimmune necrotizing myopathy with anti-signal recognition particle antibodies (ANM-SRP) is regarded as refractory myositis, whereby some patients respond poorly to conventional immunosuppression and require B cell depletion treatment. This study aimed to evaluate factors associated with refractory ANM-SRP.ResultsClinical and pathological data from 48 patients with ANM-SRP were collected. We followed up clinical symptoms and image changes over 12 months. Univariate and multivariate analyses were undertaken to determine the associations between variables of interest and poor response to therapy. Refractory ANM-SRP appeared in 32.5% of patients who showed no or minimal improvement after 12 months of steroid therapy. The clinical risk factors for refractory patients were being male (OR, 19.57; P < 0.001), severe muscle weakness (OR, 7.51; P < 0.001) and concurrent interstitial lung disease (OR, 39.70; P < 0.001). The imaging refractory-related factor was the fatty infiltration rate of thigh muscles over 3 months (P = 0.022) and the pathological factor associated with refractory ANM-SRP was the high expression of B cell activating factor receptor (BAFF-R) in muscle (P = 0.036).ConclusionBeing male, severe muscle weakness, concurrent interstitial lung disease, quick development of muscle fatty infiltration and more BAFF-R and B lymphocyte infiltration in muscle indicate a poor response to immunosuppressive therapy in patients with ANM-SRP.

Coexistence of Anti-SRP and Anti-SS-A/Ro Antibodies in Inflammatory Myopathy: Does the Association Occur by Chance? A Case Report

Specific autoantibodies are often reported as occurring in autoimmune diseases, with some autoantibodies believed to be myositis-related. These autoantibodies are placed into two groups according to their diagnostic accuracy: myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs). Of the MSAs, anti-signal recognition particle (SRP) antibodies occur in idiopathic inflammatory myopathy (anti-SRP myopathy), an immune-mediated necrotizing myopathy. This case report concerns a 65-year-old Japanese man who was diagnosed as having anti-SRP myopathy associated with anti-Sjogren’s syndrome-related antigens A/Ro (SS-A/Ro) antibody. Given my experience with anti-SRP myopathy with typical clinical features and a coexistence with anti-SS-A/Ro antibody, a literature review to evaluate this autoantibody combination in inflammatory myopathy was performed. Coexistence of anti-SRP antibody with anti-SS-A/Ro antibody was not unique, but this combination may be not by chance but one subset occurring in inflammatory myopathy. It may mean that the disease condition is more severe and may be an indication of risk. Clarification of the MSA-MAA association in inflammatory myopathy may contribute to improved comprehensive clinical management and understanding of disease subsets. The severity of anti-SRP myopathy progresses in general, and intensive immunosuppressive maintenance treatments with human intravenous immunoglobulin will be required, as in the present case.

Acute Overlap Syndrome with Myopathy Associated with Anti-signal Recognition Particle Antibodies and Sarcoidosis (5078)

Acute Overlap Syndrome with Myopathy Associated with Anti-signal Recognition Particle Antibodies and Sarcoidosis (5078)

Anti-HMGCR Antibody-Positive Myopathy Shows Bcl-2-Positive Inflammation and Lymphocytic Accumulations.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and antisignal recognition particle (SRP) antibodies are frequently associated with immune-mediated necrotizing myopathy (IMNM). However, the difference in clinical manifestations between anti-HMGCR and anti-SRP antibodies is unclear. HMGCR is an essential enzyme for cholesterol biosynthesis and is inhibited by statins that regulate apoptosis of Bcl-2-positive and beta chemokine receptor 4 (CCR4)-positive lymphoma cells. In this study, we aimed to clarify Bcl-2 and CCR4 expressions of lymphocytes in anti-HMGCR antibody-positive IMNM and explore the difference between anti-HMGCR antibody-positive myopathy and other inflammatory myopathies. We retrospectively examined Bcl-2- and CCR4-positive lymphocyte infiltrations in muscle and skin biopsy specimens from 19 anti-HMGCR antibody-positive patients and 75 other idiopathic inflammatory myopathies (IIMs) patients. A higher incidence of Bcl-2- and CCR4-positive lymphocytes was detected in the muscle and skin of anti-HMGCR antibody-positive IMNM patients (p < 0.001). In 5 patients with anti-HMGCR antibodies, Bcl-2-positive lymphocytes formed lymphocytic accumulations, which were not observed in other IIMs. Low-density lipoprotein cholesterol levels were not increased except for patients with Bcl-2-positive lymphocytic accumulations (p = 0.010). Bcl-2 and CCR4 lymphocyte infiltrations could be a pathological characteristic of anti-HMGCR antibody-positive IMNM.

Myopathy associated with anti-signal recognition peptide antibodies: Five case reports

Five patients with myopathy associated with anti-signal recognition peptide antibodies, admitted to our hospital from December 2015 to June 2018, were chosen in our study, and their clinical and pathological manifestations and treatments were retrospectively analyzed. Five patients showed subacute or chronic onset and proximal limb muscle weakness. Serum creatine kinase level was significantly elevated. Immunoblotting assay confirmed the positive anti-signal recognition particle antibody. EMG prompted myogenic damage. Pathological features included muscle degeneration, necrosis with regeneration, visible atrophy and hypertrophic of muscle fiber, connective tissue hyperplasia and a small amount of inflammatory cell infiltration. Immunohistochemical staining showed necrotizing muscle fiber infiltrated with CD4-positive and CD8-positive lymphocytes and CD68-positive macrophages, and no CD20-positive lymphocytes and CD303-positive dendritic cells were observed. Two patients had expressed a bit of c5b-9 positive capillary. Anti-sarcoglycans staining, anti-dysferlin staining and dystrophin staining showed continuous strong positive expression. Follow-up study found that all patients were response to glucocorticoid, and a combination therapy of immunoglobulin and immunosuppression were necessary for some patients.

Pembrolizumab-related systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report

BackgroundPembrolizumab is an immune-checkpoints inhibitor that enhances the immune response against cancer cells and therefore is useful for the treatment of several carcinomas. However, pembrolizumab sometimes perturbs the immune system resulting in various autoimmune neurological complications. In this situation, autoimmune myositis due to pembrolizumab is a rare but not-negligible complication. Here, we report two cases of autoimmune myositis due to pembrolizumab, with systemic myositis involving levator palpebrae superioris, extraocular and hindneck muscles.Case presentationCase 1 was a 78-year-old man with advanced urinary cancer referred to the neurological ward presenting with bilateral ptosis, restriction of eye movements, dropped head and weakness in the lower extremities after pembrolizumab administration. His blood examination showed elevated serum levels of creatine kinase with positive anti-PM-Scl 75 and anti-signal recognition particle antibodies. Needle electromyography and MRI suggested systemic inflammatory myopathy. There were no findings to indicate myocardial involvement on electrocardiogram or echocardiogram. Administration of intravenous methylprednisolone following plasma exchange ameliorated creatine kinase levels and inhibited the progression of clinical symptoms. Case 2 was a 72-year-old female with lung cancer and multiple metastasis, including lymph nodes and brain. She presented with back pain, right-sided ptosis, weakness of her neck extensors and flexors and elevated serum creatine kinase after receiving pembrolizumab. Although myositis specific autoantibodies were negative, needle electromyography and MRI suggested systemic inflammatory myopathy and muscle biopsy indicated necrotizing myopathy. There were no signs indicating heart dysfunction and her electrocardiogram was normal. Clinical symptoms and serum creatine kinase levels were ameliorated after the administration of intravenous methylprednisolone.ConclusionsBoth cases showed atypical extensive inflammatory myositis including levator palpebrae superioris, extraocular and hindneck muscles, resembling myasthenia gravis (MG), but they did not have MG-related antibodies. Edrophonium test was negative and showed no daily fluctuation. Two previously reported cases also presented with systemic necrotizing systemic myositis involving extraocular and facial muscles caused by pembrolizumab. Idiopathic inflammatory myositis evolving levator palpebrae superioris and ocular muscles is quite rare; however, myositis due to immune-checkpoint inhibitors may preferentially involve these muscles. This case report will alert physicians to the possibility of systemic inflammatory myopathy evolving levator palpebrae superioris, extraocular and hindneck muscles mimicking MG due to pembrolizumab.

Difficult case: rituximab in anti-SRP antibody myositis in pregnancy

A 30-year-old nulliparous woman presented at 15-week gestation with severe skeletal and respiratory muscle weakness, having been diagnosed with anti-signal recognition particle antibody myositis 3 years before. Remission had previously...

Inflammatory myopathy associated with PD-1 inhibitors

ObjectiveTo characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). MethodsWe studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. ResultsIn regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. ConclusionsBased on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Statins and Immune-Mediated Necrotizing Myopathy

Statins are a well-recognized cause of a variety of skeletal myopathic effects, which generally resolve when discontinuing the treatment. Among autoimmune manifestations associated with statins, there is immune-mediated necrotizing myopathy (IMNM).The present article summarizes the main features of statin-related IMNM, describing diagnosis, classification, epidemiology, treatment, and the main autoantibodies detected.Statins are a well-recognized cause of a variety of skeletal myopathic effects, which generally resolve when discontinuing the treatment. Among autoimmune manifestations associated with statins, there is immune-mediated necrotizing myopathy (IMNM).The present article summarizes the main features of statin-related IMNM, describing diagnosis, classification, epidemiology, treatment, and the main autoantibodies detected.Although it is impossible to define the precise number, it evident that more than 550 statin-related IMNM cases have been described in the literature. Among IMNM, two forms must be distinguished: with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and with anti-signal recognition particle (SRP) antibodies. The differential diagnosis should be made between the IMNM and self-limited statin-related myopathy, drug-induced rhabdomyolysis, and nonautoimmune myopathies.Patients who have failed to normalize high creatine phosphokinase (CPK) after statin withdrawal should be tested for anti-HMGCR antibodies and, if these are positive, undergo muscle biopsy to confirm the diagnosis of IMNM. Pharmacological therapy of IMNM, not yet based on evidence, involves the use of high-dose corticosteroids, immunosuppressant drugs used alone or in combination, intravenous immunoglobulins (IVIg) or plasmapheresis.

Development of a New Classification System for Idiopathic Inflammatory Myopathies Based on Clinical Manifestations and Myositis-Specific Autoantibodies

Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist. To develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria. An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti-histidyl-ARN-t- synthetase (Jo1), anti-threonine-ARN-t-synthetase (PL7), anti-alanine-ARN-t-synthetase (PL12), anti-complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti-polymyositis/systemic scleroderma (PMScl), anti-topoisomerase 1 (Scl70), and anti-signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies). Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups. Among 260 participants (163 [62.7%] women; mean age, 59.7 years; median age [range], 61.5 years [48-71 years]), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients [93.5%]; 95% CI, 85.5%-97.8%; P < .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti-SRP or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 [58.2%]; 95% CI, 47.4%-68.5%; P < .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti-melanoma differentiation-associated protein 5 (MDA5), or anti-transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 [82.7%]; 95% CI, 69.7%-91.8%; P < .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 [90.0%]; 95% CI, 76.3%-97.2%; P < .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9). These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.

Statin-naïve anti-HMGCR antibody-mediated necrotizing myopathy in China

This study aimed to clarify the phenotypes and therapeutic responses of statin-naïve anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-mediated necrotizing myopathy. Anti-HMGCR antibodies were tested with ELISA methodology in the sera sample of 98 patients meeting the idiopathic inflammatory myopathy criteria and with negative anti-signal recognition particle (SRP) antibody. Twenty-one statin-naïve patients with anti-HMGCR antibody were detected (21.4%), with onset age from 6 to 67 years old. Proximal weakness and neck flexion weakness was the core neurological feature. The average maximal creatine kinase (CK) level was 7968.6 ± 4408.7U/L. Muscle MR imaging showed edema (88.2%), moderate or severe fatty replacement (70.6%) and muscle atrophy (88.2%) in lower limbs. Fatty replacement was significantly more prominent in the medial and posterior musculature than the anterior musculature (p = 0.0013). Seven (33.3%) patients were treated with mono-glucocorticoid, and thirteen (61.9%) patients needed adjuvant immunosuppressant. Eight (38.1%) patients experienced symptom relapse. The early-onset patients (<50 years old) were found with higher CK levels, shorter duration course, poorer response to adjuvant immunosuppressant and more recurrent weakness than the late-onset patients (≥50 years old). As a conclusion, Statin-naïve anti-HMGCR antibody-mediated necrotizing myopathy may not be rare. Compared with late-onset statin-naïve patients with anti-HMGCR antibody-mediated necrotizing myopathy, early-onset patients presented severer clinical features and worse therapeutic responses.