No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Autoantibodies to cytosolic 5'-nucleotidase IA in inclusion body myositis.
Abstract
Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, myositis-specific autoantibodies had not been found in sIBM patients until recently. We used human skeletal muscle extracts as a source of antigens to detect autoantibodies in sIBM and to characterize the corresponding antigen.
Autoantibodies to skeletal muscle antigens were detected by immunoblotting. The target antigen was immunoaffinity-purified from skeletal muscle extracts and characterized by mass spectrometry. A cDNA encoding this protein was cloned and expressed in vitro, and its recognition by patient sera was analyzed in an immunoprecipitation assay. Epitopes were mapped using microarrays of overlapping peptides.
An Mr 44,000 polypeptide (Mup44) was frequently targeted by sIBM autoantibodies. The target protein was purified, and subsequent mass spectrometry analysis revealed that Mup44 is the cytosolic 5′-nucleotidase 1A (cN1A). By immunoprecipitation of recombinant cN1A, high concentrations of anti-Mup44 autoantibodies were detected in 33% of sIBM patient sera, whereas their prevalence in dermatomyositis, polymyositis, and other neuromuscular disorders appeared to be rare (4.2%, 4.5%, and 3.2%, respectively). Low concentrations of anti-Mup44 antibodies were found in myositis as well as other neuromuscular disorders, but not in healthy controls. Three major autoepitope regions of cN1A were mapped by using microarrays containing a set of overlapping peptides covering the complete cN1A amino acid sequence.
Anti-Mup44 autoantibodies, which are targeted to cN1A, represent the first serological biomarker for sIBM and may facilitate the diagnosis of this type of myositis. ANN NEUROL 2013;73:397–407
... Patients with IBM are clinically characterized by slow progressive muscle weakness that preferentially affects the finger flexors and quadriceps muscles. Although the primary pathogenic mechanism of IBM remains controversial, the pathologic findings of inclusions with autophagic vacuoles and lymphocytic infiltrations have suggested an immune-mediated pathway [5,6]. In 2013, autoantibodies against cytosolic 5'-nucleotidase 1A (NT5c1A) was identified in the serum of patients with IBM [6]. ...
... Although the primary pathogenic mechanism of IBM remains controversial, the pathologic findings of inclusions with autophagic vacuoles and lymphocytic infiltrations have suggested an immune-mediated pathway [5,6]. In 2013, autoantibodies against cytosolic 5'-nucleotidase 1A (NT5c1A) was identified in the serum of patients with IBM [6]. The NT5c1A is an enzyme that dephosphorylates adenosine monophosphate, which regulate energy balance and muscle contraction [5,6]. ...
... In 2013, autoantibodies against cytosolic 5'-nucleotidase 1A (NT5c1A) was identified in the serum of patients with IBM [6]. The NT5c1A is an enzyme that dephosphorylates adenosine monophosphate, which regulate energy balance and muscle contraction [5,6]. Autoantibodies were expected to serve as biomarkers for IBM diagnosis. ...
To explore the clinical significance of anti-cytosolic 5'-nucleoditase 1A (NT5c1A) antibody seropositivity in inflammatory myopathies, we measured anti-NT5c1A antibodies and analyzed their clinical features. Anti-NT5c1A antibodies were measured in the sera of 103 patients with inflammatory myopathies using an enzyme-linked immunosorbent assay. Positivity for anti-NT5c1A antibody was found in 13 (12.6%) of 103 patients with inflammatory myopathy. Anti-NT5c1A antibody was most frequently identified in patients with inclusion body myositis (IBM) (8/20, 40%), followed by dermatomyositis (2/13, 15.4%), immune-mediated necrotizing myopathy (2/28, 7.1%), and polymyositis (1/42, 2.4%). In eight patients with the anti-NT5c1A antibody-seropositive IBM, the median age at symptom onset was 54 years (interquartile range [IQR]: 48-57 years), and the median disease duration was 34 months (IQR: 24-50 months]. Knee extension weakness was greater than or equal to hip flexion weakness in eight (100%) patients, and finger flexion strength was less than shoulder abduction in three (38%) patients. Dysphagia symptoms were found in three (38%) patients. The median serum CK level was 581 IU/l (IQR: 434-868 IU/L]. Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment. Although anti-NT5c1A antibody is known to be associated with IBM, seropositivity has also been noted in non-IBM inflammatory myopathies, and is insufficient to have clinical significance by itself. These findings have important implications for interpreting anti-NT5c1A antibody test results as the first study in Korea.
... Electromyography reveals myopathic, neurological, or mixed patterns, while magnetic resonance imaging depicts the characteristic muscular involvement [8]. Additionally, antibodies to the cytosolic 5 -nucleotidase 1A (anti-cN1A or anti-NT51A/Mupp44) have been described in IBM [9]. ...
... Originally, IBM was considered to be a cytotoxic T cell-mediated disease with no humoral autoimmunity, until the finding of immunoglobulin transcripts in IBM muscle samples, and the finding of a 43-kD autoantibody, identified as being directed to cytosolic 5-nucleotidase 1A (anti-NT5c1A or anti-cN1A) [9,103,104]. About half of IBM patients (33-76%) are positive for this biomarker [71]. ...
... The IBM vacuoles contain intermediate filaments, extracellular matrix proteins, and the proteins involved in cell stress response, protein quality control, and protein degradation, among others [89]. The multi-protein congophilic aggregates in vacuoles include beta-amyloid, amyloid precursor protein, alphabeta crystalline, phosphorylated tau, alpha-synuclein, dysferlin, myostatin, heat shock protein 70, and others [3,9,11]. Nevertheless, the new histochemical markers p62 (SQSTM1), LC3, and TDP-43, involved in autophagy, unfolded protein response (UPR) and ER stress, could probably reflect better the degenerative changes in IBM [59,89]. ...
Abstract: Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed
to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated.
The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.
Keywords: inclusion body myositis; lymphocyte senescence; autophagy; mitochondria; cancer; interferon ; large granular lymphocytes leukemia (LGLL); paraneoplastic; lymphocyte exhaustion; antibodies to the cytosolic 50-nucleotidase 1A (anti-cN1A)
... In 2013, two groups confirmed the presence of an antibody against a 43 to 44 kilodalton protein, cytosolic 5′nucleotidase 1A (cN1A; synonyms: cN-1A, Mup44, NT5C1A, NT5c1A, NT5C1a) in patients with IBM (9,10). cN1A is an enzyme which is involved in the nucleic acid metabolism (11). ...
... This antibody was not present in the sera of 15 healthy volunteers and 25 autoimmune myositis (16). cN1A was identified to be this autoantigen in 2013 by two groups using mass spectrometry (9,10). Interestingly, immunohistochemistry illustrated the co-localisation of anti-cN1A antibodies to perinuclear regions, rimmed vacuoles and areas of myonuclear degeneration in muscle specimens from IBM patients (9). ...
... Three isotypes of the antibody have been identified; IgG, IgA and IgM isotypes of anti-cN1A antibodies (17). With regards to antibody binding, three peptide epitopes on the cN1A have been described in the literature thus far (9,10,18). Synthetic peptides derived from these immunodominant epitopes were used to develop initial Enzyme-Linked Immunosorbent Assays (ELISA) for detecting anti-cN1A antibodies (10,18). ...
Inclusion body myositis (IBM) is an acquired idiopathic inflammatory myopathy more commonly seen in individuals aged above 50. Unlike other idiopathic inflammatory myopathies, there is no response to immunosuppression/immunomodulation. The lack of response to such therapies led the focus away from considering IBM as a purely immune-mediated condition. However, the discovery of antibodies against cytosolic 5'-nucleotidase 1A (cN1A) in patients with IBM has reinvig-orated interest in autoimmunity as a key role in its pathogenesis. Over the last decade different methods have been developed to detect anti-cN1A antibodies. There has been an interest in whether these assays can be utilised in the diagnosis of IBM. Furthermore, there has been focus on whether anti-cN1A antibodies can be used to prognosticate and predict the clinical phenotype in IBM. Anti-cN1A antibodies appear to have a high specificity and moderate sensitivity for IBM. There have been some exploratory clinicopathological associations described in seropositive IBM patients, but sample sizes in most studies have been small so far. Antibody testing is yet to be standardised; which somewhat limits our ability to draw robust conclusions from current investi-gations. In this article we review the literature on anti-cN1A antibodies and discuss whether they have a role in clinical practice.
... 1 In 2013, anti-cytosolic 5 0 -nucleotidase 1A (NT5C1A) antibody was detected in the sera of patients with IBM and recognized as a potential diagnostic marker for IBM. 2,3 Subsequently, the antibody was detected in patients with dermatomyositis, Sj€ ogren's syndrome, and systemic lupus erythematosus. 4À10 This suggests that anti-NT5C1A antibody can be detected in autoimmune diseases other than IBM, however, seropositivity for anti-NT5C1A antibody in IIMs other than IBM has not been assessed within a large population. ...
... The P-values less than 0.05 are marked in bold. 2 The percentages of COX-negative and SDH-positive muscle fibers were determined by photographing a random field with a 10x objective and counting 200 fibers. We set cutoff value as 1.0% for qualitative analysis of COX-negative fibers. ...
... In adult patients with dermatomyositis, the seropositivity of anti-NT5C1A antibody was reported to be 0% to 15 %, whereas in this study it was 21%. 2,3,6,7,8,10 In clinical practice, myositis antibody panels are often ordered in patients with a suspected IIM. Indeed, more than 90% of the patients other than IBM were tested for anti-NT5C1A antibody through panel testing. ...
Objective:
To define the clinicopathologic features and diagnostic utility associated with anticytosolic 5'-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).
Methods:
Anti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.
Results:
Of 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti-NT5C1A antibody seropositive patients had more cytochrome oxidase-negative fibers compared with anti-NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti-NT5C1A antibody, three patients (21%) converted to positive. Anti-NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs.
Interpretation:
Anti-NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non-IBM IIMs and it does not correlate with any prognostic factors or survival.
... 1,3,8,9 It is usually seen in the over 50-year adult population, and tends to affect males more than females. 3,8,7,[10][11][12] The prevalence of IBM is varies from region to region e.g. due to factors like a tendency for the diagnosis to be missed or delayed, lack of awareness of this condition among generalist healthcare professionals, evolving diagnostic criteria, as well as incremental advances in molecular medicine and histopathology. ...
... In practice, IBM can be inaccurately or incorrectly diagnosed as polymyositis (e.g. if the presence of rimmed vacuoles is missed on muscle biopsy samples/specimens), or it may be clinically misdiagnosed as being a form of motor neuron disease (MND) (e.g. as may be the case without muscle biopsy/biopsies). 7,11,13,14 In the index case, polymyositis was deemed (clinically) unlikely due to the evolutionary timelines of her symptoms, and on account of the poor clinical response to a trial of steroid therapy. Some other relevant differential diagnoses that were considered, but deemed unlikely in this case, as guided by clinical and/or other histological grounds were: MND, a drug-associated myopathy, myasthenia gravis, Lambert-Eaton Myasthenic syndrome (LEMS), diabetic amyotrophy, thyrotoxic myopathy, post-viral myocarditis, muscular dystrophies (e.g. ...
Inclusion body myositis (IBM) is a condition also referred to as sporadic IBM. It is a rare variant of a broader group of diseases described under the banner of inflammatory myositis. In general, myositis/myositides tend to present with a varying cluster of symptoms such as muscular weakness, aches and/or pain. Myositis has been linked to multiple causes or triggers, but generally share the common feature (present to a variable extent) of inflammatory changes within skeletal muscle tissue. In addition, some associations (e.g. Sjogren’s disease and systemic lupus erythematosus – SLE) have been reported for IBM. Some medication classes (e.g. statins and fibrates) may present a risk to certain individuals developing drug-associated myopathies. IBM can be challenging to diagnose, and may be mistaken for many other causes of muscle weakness e.g. polymyositis. Furthermore, IBM tends to affect muscles asymmetrically, and runs a typically progressive and chronic course. Consequently, over time IBM may result in significant functional impairment, activity limitation, and participation restriction. This case report describes an older woman with a clinical diagnosis of probable IBM complicated with oesophageal dysmotility. She presented to hospital with progressive dysphagia, breathlessness, and a productive cough for which treatment was started for aspiration pneumonia. The report considers some broader ‘principles of management’ of a chronic myositis. In the current absence of a definitive curative treatment, we also discuss some realistic and practical pharmacological treatment options that may be used for the selective care of patients presenting with an incurable chronic myositis such as IBM.
... 10,14,15 An autoimmune pathogenesis of IBM is indicated by the auto-invasion of inflammatory cytotoxic CD8+ T-cells in IBM muscle, 16 the strong association with the human leukocyte antigen (HLA)-DR3 haplotype 17 and a high prevalence of the autoantibody anti-cytosolic 5 0 -nucleotidase 1A (cN1A). [18][19][20][21] Other myositis-associated antibodies have not been shown to be increased. 22 An alternative hypothesis implying that IBM is a primary degenerative disorder is mainly based on the unresponsiveness to immunomodulating treatment and presence of protein aggregates in muscle fibers. ...
... 20 Anti-cN1A was positive in 40% of our patients with IBM, which is in line with previous studies showing an anti-cN1A frequency of 33% to 80% in IBM cohorts. [18][19][20][21]42,43 The frequency was higher in men than women. Although dysphagia was a more common presenting symptom in the group with anti-cN1A, there were no clear differences in symptom duration or frequency of ongoing immunomodulating treatment in patients with and without expression of anti-cN1A. ...
Objective:
We performed a population-based study on inclusion body myositis with the primary aims to define the prevalence, survival rate and incidence and to investigate the symptom profiles associated with disease duration and sex over a 33-year period.
Methods:
Patients diagnosed between 1985 and 2017 in Region Västra Götaland, Sweden were identified according to the European Neuromuscular Centre diagnostic criteria from 2011.
Results:
We identified 128 patients, 89 men and 39 women with the strict clinico-pathologically definition of inclusion body myositis. The prevalence was 32 per million inhabitants, 19 per million women and 45 per million men December 31st 2017. Mean incidence was 2.5 per million inhabitants and year. Mean age at symptom onset was 64.4 years with quadriceps weakness being the most common presenting symptom followed by finger flexor weakness. Dysphagia was a common presenting symptom being more frequent in women (23%) than men (10%) and was during the disease course reported in 74% of men and 84% of women. Seventy-three patients were deceased, with mean survival of 14 years from symptom onset. Survival rate from both diagnosis date and symptom onset was decreased compared to the matched population. Twenty-one percent of the patients had an additional autoimmune disease. A cross-sectional analysis of autoantibodies in 50 patients and 28 matched controls showed autoantibodies to cytosolic 5'-nucleotidase 1A in 40% of the patients and 3.6% of controls.
Interpretation:
Inclusion body myositis is an autoimmune disease with decreased survival rate and with marked sex differences in both prevalence and clinical manifestations. This article is protected by copyright. All rights reserved.
... CD8 + cytotoxic T-cells not only surround but also invade healthy, non-necrotic muscle fibers, which aberrantly express MHC-I, probably induced by T-cell-activated cytokines; the CD8/MHC-I complex is characteristic of IBM aiding in the histological diagnosis [1,[3][4][5][6][7][41][42][43][44]. Plasma cells and myeloid dendritic cells are also seen among the endomysial infiltrates, while nonspecific anti-cytosolic 5'-nucleotidase-1A (cN1A), detected in 33-51% of IBM patients, highlight the immune dysregulation and B-cell activation [1,[3][4][5][6][7][41][42][43][44][45]. The evidence of degeneration is highlighted by the presence of autophagic vacuoles with bluish-red material, proteinacious aggregates positive for ubiquitin, tau and TDP43 and congophilic amyloid deposits within the muscle fibers next to the vacuoles, visualized best with crystal violet or fluorescent optics as shown in Figure 4(a) [as modified from [1]]; chronic myopathic changes with atrophy and increased connective tissue as well as 'ragged-red' or cytochrome oxidase-negative fibers due to abnormal mitochondria, are also frequent [1,[3][4][5][6][7][41][42][43][44][45][46]. ...
... Plasma cells and myeloid dendritic cells are also seen among the endomysial infiltrates, while nonspecific anti-cytosolic 5'-nucleotidase-1A (cN1A), detected in 33-51% of IBM patients, highlight the immune dysregulation and B-cell activation [1,[3][4][5][6][7][41][42][43][44][45]. The evidence of degeneration is highlighted by the presence of autophagic vacuoles with bluish-red material, proteinacious aggregates positive for ubiquitin, tau and TDP43 and congophilic amyloid deposits within the muscle fibers next to the vacuoles, visualized best with crystal violet or fluorescent optics as shown in Figure 4(a) [as modified from [1]]; chronic myopathic changes with atrophy and increased connective tissue as well as 'ragged-red' or cytochrome oxidase-negative fibers due to abnormal mitochondria, are also frequent [1,[3][4][5][6][7][41][42][43][44][45][46]. The co-existence of degeneration and autoimmunity has been the impetus to study their interrelationship. ...
Introduction:
The inflammatory myopathies (IM) have now evolved into distinct subsets requiring clarification about their immunopathogenesis to guide applications of targeted therapies.
Areas covered:
Immunohistopathologic criteria of IM with focus on complement, anti-complement therapeutics and other biologic immunotherapies. The COVID19-triggered muscle autoimmunity along with the correct interpretation of muscle amyloid deposits are discussed.
Expert opinion:
The IM, unjustifiably referred as idiopathic, comprise Dermatomyositis (DM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). In DM, complement activation with MAC-mediated endomysial microvascular destruction and perifascicular atrophy is the fundamental process, while innate immunity activation factors, INF1 and MxA, sense and secondarily enhance inflammation. Complement participates in muscle fiber necrosis from any cause and may facilitate muscle-fiber necrosis in NAM but seems unlikely that myositis-associated antibodies participate in complement-fixing. Accordingly, anti-complement therapeutics should be prioritized for DM. SARS-CoV-2 can potentially trigger muscle autoimmunity but systematic studies are needed as the reported autopsy findings are not clinically relevant. In IBM, tiny amyloid deposits within muscle fibers are enhanced by inflammatory mediators contributing to myodegeneration; in contrast, spotty amyloid deposits in the endomysial connective tissue do not represent "amyloid myopathy" but only have diagnostic value for amyloidosis due to any cause.
... The presence of anti-cytosolic 5'-nucleotidase 1A (cN1A or NT5C1A) autoantibodies in IBM has been reported. 99,100 A passive immunization mouse model using anti-cN1A IBM patient IgG partially recapitulated pathological features such as sarcoplasmic p62 ...
... [102][103][104] The sensitivity for IBM varies, ranging from 33% to 76%, which is probably due to the different methods and cutoffs. 99,105 As a diagnostic marker, despite the high specificity, the diagnostic accuracy is limited. 106 ...
Over the recent decades, notable progress has been made in the understanding of the pathomechanism of autoimmune myositis. Dermatomyositis is considered a type I interferonopathy, distinctive from antisynthetase syndrome despite some common clinical features. Immune‐mediated necrotizing myopathy is related to complement‐mediated autoimmunity. In inclusion body myositis, myofiber invasion by highly differentiated cytotoxic T cells leads to myofiber damage. Based on the accumulated knowledge, targeted, more mechanism‐focused therapies are being developed.
... Despite the well-described histopathological and electrodiagnostic findings in IBM, there have been rare attempts to correlate these findings with clinical measures, as the previous studies were mainly focussed on delineating the clinical profile of patients with positive cN-1A antibodies [23][24][25][26]. Most studies showed no difference in the clinical phenotype between patients with cN-1a antibodies and seronegative patients [25,[27][28][29][30]. In one study, patients with cN-1a antibodies had more significant motor dysfunction, and were more likely to report difficulty swallowing and to have reduced vital capacity [26]. ...
... Based on previous reports, there is no clear difference in the clinical phenotype of IBM patients based on their cN-1A serological status [25,[27][28][29][30]. Likewise, none of the correlation analyses between various variables and clinical measures reached statistical significance in our study. ...
Objective
To determine whether histopathological, electromyographic and laboratory markers correlate with clinical measures in Inclusion Body Myositis (IBM)
Methods
We reviewed our electronic medical records to identify patients with IBM according to ENMC 2011 criteria, seen between 2015 and 2020. We only included patients who had a muscle biopsy and needle electromyography (EMG) performed on the same muscle (opposite or same side). We used a detailed grading system (0- normal to 4- severe) to score histopathological and EMG findings. Clinical severity was assessed by the modified Rankin scale (mRS), muscle strength sum score (SSS), quadriceps strength and severity of dysphagia on swallow evaluation. Serum markers of interest were creatine kinase level, and cN-1A antibodies.
Results
We included 50 IBM patients, with a median age of 69 years; 64% were males. Median disease duration at diagnosis was 51 months. On muscle biopsy, endomysial inflammation mainly correlated with dysphagia, and inversely correlated with mRS. Vacuoles and congophilic inclusions did not correlate with any of the clinical measures. On EMG, the shortness of motor unit potential (MUP) duration correlated with all clinical measures. Myotonic discharges, and not fibrillation potentials, correlated with the severity of inflammation. Serum markers did not have a statistically-significant correlation with any of the clinical measures.
Conclusions
Dysphagia was the main clinical feature of IBM correlating with endomysial inflammation. Otherwise, inclusion body myositis clinical measures had limited correlation with histopathological features in this study. The shortness of MUP duration correlated with all clinical measures.
... Therapeutic biomarkers, also called pharmacodynamic biomarkers, highlight responses to treatment and can be used to show whether a missing protein is restored after therapy. "NMDs" is a broad term including many diseases that can impair the functioning of a specific component of the neuromuscular unit: skeletal muscle [3][4][5][6][7][8] LGMDs CK miR-206 [9,10] DM1 miR-1, -133a, -133b, -206, -140, -454, -574 miR-1,-133a, -133b, -206 [11][12][13] IIMs CK MSA (anti-cN1A) MAA MSA (anti-cN1A) MAA CK [14][15][16][17][18][19][20] MG AChR Abs MuSK Abs LRP4 Abs miR150-5p, 21-5p, 27a3p ...
... Some Abs are considered alternately in MSA or in MAA group. An example is anti-cytosolic 5 -nucleotidase 1A Abs (anti-cN1A) in IBM [15]. The sensitivity of anti-cN1A in IBM significantly varies in different studies, ranging from 33% to 76%, mainly due to different detection methods and cut-off thresholds; specificity ranges from 87% to 100%, even though anti-cN1A Abs were also found in the sera of patients with other IIMs and other autoimmune diseases (mainly systemic lupus erythematosus and Sjögren syndrome) [101][102][103][104]. ...
The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less “time-consuming”. In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers.
... Last, the only currently available serum diagnostic biomarker for IBM is cytosolic 5'-nucleotidase 1A (cN-1A) antibody. It has a limited sensitivity ranging from 30% to 50% [34,35]. Although overall specificity was originally reported to be high (>90%), cN-1A antibodies can also been found in others diseases such as dermatomyositis, Sjogren's syndrome, antisynthetase syndrome, immune mediated necrotizing myopathy, and systemic lupus erythematous [36,37]. ...
Purpose of review:
This review provides an overview of the management and treatment landscape of inclusion body myositis (IBM), while highlighting the current challenges and future directions.
Recent findings:
IBM is a slowly progressive myopathy that predominantly affects patients over the age of 40, leading to increased morbidity and mortality. Unfortunately, a definitive cure for IBM remains elusive. Various clinical trials targeting inflammatory and some of the noninflammatory pathways have failed. The search for effective disease-modifying treatments faces numerous hurdles including variability in presentation, diagnostic challenges, poor understanding of pathogenesis, scarcity of disease models, a lack of validated outcome measures, and challenges related to clinical trial design. Close monitoring of swallowing and respiratory function, adapting an exercise routine, and addressing mobility issues are the mainstay of management at this time.
Summary:
Patients with IBM and the medical community face numerous challenges in terms of clinical manifestations, diagnosis, and treatment. Overcoming these challenges necessitates the adoption of innovative research strategies. By understanding and addressing these hurdles, researchers and medical professionals can strive towards improving the management and treatment of IBM enhancing the quality of life for affected individuals.
... A laboratory evaluation for muscle weakness should include a comprehensive metabolic panel and testing for calcium, magnesium, phosphate, creatine kinase, aldolase, lactate dehydrogenase, and thyroid-stimulating hormone levels (7). Given the possibility of IBM, testing for anticytosolic 5:-nucleotidase 1A (anti-NT5C1A) antibodies is recommended (8)(9)(10). ...
... In the active phase of IMNM, anti-HMGCR seropositivity often shows ALT predominance, whereas in anti-SRP positive patients AST often predominates (20). An autoantibody associated with IBM has also been recognized, which is detected in up to 70% of patients and is directed against cytosolic 5′-nucleotidase 1A (NT5c1A) (21)(22)(23), and has quickly gained status as a diagnostic biomarker (24). Anti-NT5c1A has a moderate sensitivity, yet displays high specificity for IBM, although recent data showed presence of anti-NT5c1A also in other autoimmune conditions, particularly in systemic lupus erythematosus and Sjogren's syndrome (25). ...
Extensive diagnostic delays and deferred treatment impact the quality of life of patients suffering from an idiopathic inflammatory myopathy. In-depth subtyping of patients is a necessary effort to engage appropriate disease management and may require specialized and elaborate evaluation of the complex spectrum of clinical and pathological disease features. Blood samples are routinely taken for diagnostic purposes, with creatine kinase measurement and autoantibody typing representing standard diagnostic tools in the clinical setting. However, for many patients the diagnostic odyssey includes the invasive and time-consuming procedure of taking a muscle biopsy. It is proposed that further implementation of blood-based disease biomarkers represents a convenient alternative approach with the potential to reduce the need for diagnostic muscle biopsies substantially. Quantification of judicious combinations of circulating cytokines could be added to the diagnostic flowchart, and growth differentiation factor 15 and C-X-C motif chemokine ligand 10 come forward as particularly good candidates. These biomarkers can offer complementary information for diagnosis indicative of disease severity, therapeutic response and prognosis.
... Although VCP gene mutations are associated with hereditary IBM (hIBM), autoantibodies directed to VCP have not been reported in sIBM, whereas autoantibodies to cytosolic 5 0 -nucleotidase 1A (NT5c1A/cN1A/Mup44), although detected in other autoimmune diseases, are regarded as a biomarker for sIBM (5)(6)(7)(8). Anti-VCP autoantibodies were previously reported in primary biliary cholangitis (PBC) and autoimmune hepatitis sera (9,10). The goal of this study was to identify the frequency and performance of anti-VCP in sIBM, other IIMs, and control individuals. ...
Objective:
The rationale for this study was based on reports that valosin-containing protein (VCP) mutations are found in hereditary inclusion body myositis (IBM) and VCP was detected in rimmed vacuoles of sporadic IBM (sIBM) muscle biopsies. Autoantibodies to VCP have not been reported in sIBM or other inflammatory myopathies (IIMs). The aim of this study was to determine the frequency and clinical significance of anti-VCP antibodies in sIBM and other IIMs.
Methods:
Sera were collected from 73 patients with sIBM and 383 comparators or controls, including patients with IIM (n = 69), those with juvenile dermatomyositis (JDM) (n = 67), those with juvenile idiopathic arthritis (JIA) (n = 47), those with primary biliary cholangitis (PBC) (n = 105), controls that were age matched to patients with sIBM (similarly aged controls [SACs]) (n = 63), and healthy controls (HCs) (n = 32). Immunoglobulin G antibodies to VCP were detected by addressable laser bead immunoassay using a full-length recombinant human protein.
Results:
Among patients with sIBM, 26.0% (19/73) were positive for anti-VCP. The frequency in disease controls was 15.0% (48/320). Among SACs, the frequency was 1.6% (1/63), and in HCs 0% (0/32). Frequencies were 17.5% (11/63) for IIM, 25.7% (27/105) for PBC, 3.0% (2/67) for JDM, and 17.0% (8/47) for JIA. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-VCP for sIBM were 26.0%, 87.2%, 28.4%, and 85.9%, respectively. Of patients with sIBM, 15.1% (11/73) were positive for both anti-VCP and anti-cytosolic 5'-nucleotidase 1A (NT5c1A). Eleven percent of patients (8/73) were positive for anti-VCP, but negative for anti-NT5c1A.
Conclusion:
Anti-VCP has low sensitivity and moderate specificity for sIBM but may help fill the seronegative gap in sIBM. Further studies are needed to determine whether anti-VCP is a biomarker for a clinical phenotype that may have clinical value.
... In contrast to other inflammatory myopathies, until recently myositis-specific autoantibodies had not been found in sIBM patients. Autoantibodies directed against major epitopes of cN-1A (also known as Mup-44, NT5c1A) are found in 30-50% of patients with sIBM, which has helped distinguish sIBM patients within the context of inflammatory myopathy [204]. Anti-cN1A has moderate sensitivity and high specificity for sIBM. ...
Personalized medicine (PM) aims individualized approach to prevention, diagnosis, and treatment. Precision Medicine applies the paradigm of PM by defining groups of individuals with akin characteristics. Often the two terms have been used interchangeably. The quest for PM has been advancing for centuries as traditional nosology classification defines groups of clinical conditions with relatively similar prognoses and treatment options. However, any individual is characterized by a unique set of multiple characteristics and therefore the achievement of PM implies the determination of myriad demographic, epidemiological, clinical, laboratory, and imaging parameters. The accelerated identification of numerous biological variables associated with diverse health conditions contributes to the fulfillment of one of the pre-requisites for PM. The advent of multiplex analytical platforms contributes to the determination of thousands of biological parameters using minute amounts of serum or other biological matrixes. Finally, big data analysis and machine learning contribute to the processing and integration of the multiplexed data at the individual level, allowing for the personalized definition of susceptibility, diagnosis, prognosis, prevention, and treatment. Autoantibodies are traditional biomarkers for autoimmune diseases and can contribute to PM in many aspects, including identification of individuals at risk, early diagnosis, disease sub-phenotyping, definition of prognosis, and treatment, as well as monitoring disease activity. Herein we address how autoantibodies can promote PM in autoimmune diseases using the examples of systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, idiopathic inflammatory myopathies, autoimmune hepatitis, primary biliary cholangitis, and autoimmune neurologic diseases.
... Immune attack and possible mechanisms of protein aggregation in IBM IBM muscle is infiltrated by CD8 + Tcells, but cytotoxic CD4 + CD28 null Tcells, dendritic cells and plasma cells can also be found (1). The only known antigen for this immune response is Cytosolic 5'-nucleotidase 1A (cN1A) protein, with antibodies against this protein found in 33-76% of patients with IBM (15,16). Antigen presentation to T-cells results from cleavage of proteins by the proteasome, immunoproteasome (17) (Fig. 1) and/or other proteases into peptides, which are then loaded onto MHC Class I and/or MHC Class II for transportation to the cell membrane (18,19). ...
Inclusion body myositis (IBM) is characterised by infiltration of CD8+ T-cells and signs of protein aggregation such as rimmed vacuoles and inclusion bodies. Aggregated proteins include those present in neurodegenerative diseases, and also those involved in protein homeostasis. The aim of this review is to discuss the pathological effects of protein aggregates and the process of aggregation following immune attack in IBM. Immune attack is likely to cause protein aggregation by impairing endoplasmic reticulum (ER) and mitochondrial function. Apoptotic and necrotic pathways are activated, possibly leading to nucleo-cytoplasmic coagulation. Overexpression of nuclear and ribosomal proteins in rimmed vacuoles suggests that the vacuoles develop from the collapse of myonuclei and the surrounding ER. Aggregated proteins can activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome or provoke a humoral immune response. Heat shock proteins, ribosomal proteins and protein fragments may provoke interferon-gamma and cytotoxic T-cell responses in a similar manner to Mycobacterium tuberculosis antigens. Persistent provocation can lead to T-cell large granular lymphocytic leukaemia which is resistant to immunosuppression, and would explain the progression from polymyositis to IBM. Protein aggregates may impair the cellular machinery, and proteins may propagate along a myocyte in a prion-like manner. These pathological mechanisms may prevent myocyte regeneration following damage from eccentric muscle contraction, causing weakness and atrophy in a characteristic pattern. Further understanding of the mechanisms of protein aggregation in IBM may lead to additional therapies as well as novel muscle and blood biomarkers. Earlier diagnosis and treatment may result in improved outcomes when effective therapies are available.
... Il n'existe pour le moment pas d'anticorps réellement spécifique associé avec la myosite à inclusions. Néanmoins, la présence d'anticorps anti-cN1a se retrouve dans environ un tiers des cas chez des patients atteints de MI, et est absent dans les autres MII [10]. Aussi, la présence de ces anticorps pourrait permettre de différencier une MI d'expression inhabituelle (touchant préférentiellement les ceintures, ou chez le sujet jeune) d'une autre MII avant même la réalisation d'une biopsie musculaire. ...
... The combination of inflammatory and degenerative pathological features has led to considerable debate as to the primary cause of the disease (2,(6)(7)(8). The presence of major histocompatibility complex class I (MHC-I) up-regulation within myofibers that are invaded by highly differentiated cytotoxic CD8 + T cells, the association of IBM with other autoimmune disorders and specific human leukocyte antigen haplotypes, and the presence of autoantibodies in sera from subjects with IBM support an autoimmune trigger for the disease (9)(10)(11)(12). The lack of clinical efficacy of immunosuppression therapies, however, suggests that endomysial inflammation may not be required for disease progression. ...
Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell–mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43–mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR–mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8 ⁺ T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.
... Anti-cN1A antibodies. An antibody targeting the cytosolic 5'-nucleotidase 1A (anti-cN1A) has been reported in roughly one third of cases of IBM (70). ...
Background:
Interstitial lung disease (ILD) comprises a heterogeneous group of inflammatory and fibrotic conditions, often resulting in progressive lung function decline and increased mortality. Connective tissue disease (CTD) should be considered in all patients with ILD, as distinguishing between CTD-ILD and other forms of fibrotic lung disease has important therapeutic and prognostic implications. The idiopathic inflammatory myopathies (IIM) represent a CTD subtype of growing interest to ILD experts. The expansion and availability of myositis-specific and myositis-associated antibody testing has allowed for improved disease detection and characterization.
Content:
In this review, we highlight the relationship between myositis antibodies and ILD. Select forms of IIM, such as the antisynthetase syndrome and clinically amyopathic dermatomyositis can present with rapidly progressive ILD, warranting timely disease diagnosis and management. Disease phenotypes, prevalence, laboratory testing, prognosis, and management strategies are described according to select myositis antibodies.
Summary:
Myositis antibodies provide valuable information for clinicians managing patients with ILD. This review aims to increase awareness of their role in disease detection, pathophysiology, and possibly therapeutics.
... Patients with IBM have finger flexor and quadriceps weakness and are easily to be misdiagnosed as chronic PM and receive multiple immunotherapy. Thus, the discovery of autoantibodies against cytosolic 5'-nucleotidase 1A (cN1A or NT5C1A) brought insights into the immunopathogenic mechanisms of IBM (93). Anti-cN1A autoantibodies were detected in 30-50% of patients with IBM (94), who were more likely to be older than age 60 years at disease onset (95). ...
Objective:
To discuss the characteristics of autoantigens, detection methods and roles of myositis associated autoantibodies (MAAs) and myositis specific autoantibodies (MSAs), as well as the clinical features of disease subgroups defined by MAAs/MSAs.
Background:
Autoantibodies in patients with idiopathic inflammatory myopathies (IIMs) are conventionally divided into MAAs and MSAs. MAAs usually refer to autoantibodies which are also available in systematic autoimmune diseases (anti-PM/SCL, anti-Ku, anti-Ro52 and anti-U1RNP antibodies). MSAs refer to autoantibodies which were distinctive for IIM (anti-Mi-2, anti-MDA5, anti-TIF1gammma, anti-NXP2, anti-SAE, anti-synthetase, anti-SRP, anti-HMGCR and anti-cN1A antibodies). The discovery and identification of novel autoantigens is a long and complicated process, which brought light in immunopathogenesis of IIMs. Detection methods of MAAs/MSAs mainly consist of monospecific methods [immunoprecipitation, enzyme-linked immune sorbent assay (ELISA) and indirect immunofluorescence] and multispecific methods [line immunoassay (LIA), dot immunoassay (DIA) and addressable laser bead assay (ALBIA)]. Patients with different MAAs/MSAs have different clinical features and require different clinical management.
Methods:
The search engine PubMed (https://www.ncbi.nlm.nih.gov/pmc/) was used to research the keywords "autoantibodies", "idiopathic inflammatory myopathies", "detection methods" and "clinical features". A narrative review was conducted to literature findings from 1975 to 2020.
Conclusions:
Development and validation of efficient detection methods of MAAs and MSAs help clinicians for diagnosis, classification and management of IIMs. The exploration of clinical features associated with different autoantibodies that facilitate the creation of diagnostic and classification guidelines and further clinical decision-making is of high value.
... When there was no evidence of other underlying diseases, additional diagnostic procedures were carried out with a focus on IIM: Whole-body muscle MRI and electromyography (EMG) were performed and creatine kinase (CK), lactate dehydrogenase, glutamate oxalacetate transaminase and glutamate pyruvate transferase blood level, as well as an antibody panel with myositis-specific and myositis-associated antibodies including ANA, pANCA, cANCA, Anti-SSA-Ro, Anti-SSB/La, Anti-U1-RNP, Anti-U2RNP, Anti-U3RNP, Anti-PmScl, Anti-Ku, Anti-EJ, Anti-OJ, Anti-TIF1-Gamma, Anti-SRP, Anti-SAE, Anti-Jo-1. Anti-Mi-2, Anti-PL-7, Anti-PL-12, Anti-Scl70, Anti-MDA5, Anti-HMG-CoA-reductase, and Anti-cN1A, as commonly tested autoantibodies in suspected IIM [31,32] were determined. If diagnostic uncertainty remained after these diagnostic procedures or if patients explicitly requested it, a muscle biopsy was recommended as the final diagnostic step. ...
Background:
Idiopathic Inflammatory Myopathy (IIM) can present with dysphagia as leading or only symptom. In such cases, diagnostic evaluation may be difficult, especially if serological and electromyographical findings are unsuspicious. In this observational study we propose and evaluate a diagnostic algorithm to identify IIM as a cause of unexplained dysphagia.
Methods:
Over a period of 4 years, patients with unexplained dysphagia were offered diagnostic evaluation according to a specific algorithm: The pattern of dysphagia was characterized by instrumental assessment (swallowing-endoscopy, videofluoroscopy, high-resolution manometry). Patients with an IIM compatible dysphagia pattern were subjected to further IIM-focused diagnostic procedures, including whole body muscle MRI, electromyography, CK blood level, IIM antibody panel and, as a final diagnostic step, muscle biopsy. Muscle biopsies were taken from affected muscles. In cases were no other muscles showed abnormalities, the cricopharyngeal muscle was targeted.
Results:
Seventy-two patients presented with IIM compatible dysphagia as leading or only symptom. As a result of the specific diagnostic approach, nineteen of these patients were diagnosed with IIM according to the European League Against Rheumatism (EULAR) criteria. Eighteen patients received immunomodulatory therapy as a result of the diagnosis. Of 10 patients with follow-up swallowing examination, dysphagia improved in 3 patients after therapy, while it remained at least stable in 6 patients.
Conclusions:
IIM constitutes a potentially treatable etiology in patients with unexplained dysphagia. The diagnostic algorithm presented in this study helps to identify patients with IIM compatible dysphagia pattern and to assign those patients for further IIM-focused diagnostic and therapeutic procedures.
... Thorough biochemical and immunological testing should be performed for two reasons, to exclude other causes of muscle weakness (electrolytes, thyroid hormones, infections, etc.) and to differentiate sIBM from other clinical conditions such as monoclonal gammopathy, Sjogren's syndrome, systemic lupus erythematosus, sarcoidosis, human immunodeficiency virus, HTLV-1, hepatitis C, and lymphocytic leukemia, which would require investigation if present [104][105][106][107][108]. Recently, a new tool was added to the diagnostic armamentarium of the clinician. Although the serum autoantibody, anti-5 0 -nucleotidase cytosolic IA (anti-NT5C1A), is not specific for sIBM, it is present in 40-60% of sIBM cases and can support the diagnostic investigation [109][110][111]. ...
Idiopathic inflammatory myopathies (IIMs) are rare autoimmune disorders affecting primarily muscles, but other organs can be involved. This review describes the clinical features, diagnosis and treatment for IIMs, namely polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), immune-mediated necrotizing myopathy (IMNM), and myositis associated with antisynthetase syndrome (ASS). The diagnostic approach has been updated recently based on the discovery of circulating autoantibodies, which has enhanced the management of patients. Currently, validated classification criteria for IIMs allow clinical studies with well-defined sets of patients but diagnostic criteria to guide the care of individual patients in routine clinical practice are still missing. This review analyzes the clinical manifestations and laboratory findings of IIMs, discusses the efficiency of modern and standard methods employed in their workup, and delineates optimal practice for clinical care. Α multidisciplinary diagnostic approach that combines clinical, neurologic and rheumatologic examination, evaluation of electrophysiologic and morphologic muscle characteristics, and assessment of autoantibody immunoassays has been determined to be the preferred approach for effective management of patients with suspected IIMs.
... Anti-cytosolic 5′-nucleotidase 1A (anti-cN1A) antibody is present in the sera of 27-52% of sIBM patients [8,9]. Seropositivity can be seen in other autoimmune disorders such as Sjogren's syndrome and systemic lupus erythematosus [10] as well as in amyotrophic lateral sclerosis [11], dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, and VCP myopathy. ...
Purpose of the review
The purpose of this paper is to review the recent findings that pertain to the diagnosis and treatment of sporadic inclusion body myositis.
Recent findings
New evidence highlighting lack of correlation between the presence of cytosolic 5′-nucleotidase 1A antibody with any of the clinical features, or laboratory findings in inclusion body myositis. New studies emphasizing heterogeneity and showing separation of inclusion body myositis patients into separate trajectories. The failure of bimagrumab and arimoclomol as potential treatments of inclusion body myositis and the mixed results of the sirolimus trial in sporadic inclusion body myositis.
Summary
A significant gap exists in understanding the heterogeneity of sporadic inclusion body myositis. Recent evidence suggests that cytosolic 5′-nucleotidase 1A antibody does not provide significant clinical or laboratory differentiation between antibody-positive and negative patients. Despite recent failures in the clinical trials of arimoclomol and bimagrumab, sirolimus showed mixed results, and a larger definitive trial is needed.
... In sporadic inclusion body myositis (IBM), a neuromuscular disorder that together with dermatomyositis (DM) and polymyositis (PM) belongs to the idiopathic inflammatory myopathy (IIM) family, the use of muscle tissue as antigenic material allowed us to identify specific autoantibodies to skeletal muscle antigens such as cytosolic 5'-nucleotidase 1A (cN1A) [13]. Although FSHD is not categorized as an inflammatory myopathy, inflammatory features are described in about 40% of FSHD muscle biopsies [14,15]. ...
Background:
FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells.
Objective:
This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated.
Methods:
FSHD sera (N = 138, 48±16 years, 48%male) and healthy control sera (N = 20, 47±14 years, 50%male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera.
Results:
The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera.
Conclusion:
Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.
... In 2011, an autoantibody directed against a 43 kD protein was identified in the sera of s-IBM patients [6]. Two years later, the target antigen was identified in the 5 -citosolic nucleotidase 1A (cN1A) [7,8]. The sensitivity of anti-cN1A antibodies in s-IBM significantly varies in different studies, ranging from 33% to 76%, mainly due to different detection methods and cut-off thresholds [9][10][11][12][13][14][15][16][17]. ...
In recent years, an autoantibody directed against the 5′-citosolic nucleotidase1A (cN1A) was identified in the sera of sporadic inclusion body myositis (s-IBM) patients with widely variable sensitivity (33%–76%) and specificity (87%–100%). We assessed the sensitivity/specificity of anti-cN1A antibodies in an Italian cohort of s-IBM patients, searching for a potential correlation with clinical data. We collected clinical data and sera from 62 consecutive s-IBM patients and 62 other inflammatory myopathies patients. Testing for anti-cN1A antibodies was performed using a commercial ELISA. Anti-cN1A antibodies were detected in 23 s-IBM patients, resulting in a sensitivity of 37.1% with a specificity of 96.8%. Positive and negative predictive values were 92.0% and 60.6%, respectively. We did not find significant difference regarding demographic variables, nor quadriceps or finger flexor weakness. Nevertheless, we found that anti-cN1A-positive patients presented significantly lower scores in IBMFRS item 1 (swallowing, p = 0.045) and more frequently reported more severe swallowing problems, expressed as an IBMFRS item 1 score ≤ 2 (p < 0.001). We confirmed the low sensitivity and high specificity of anti-cN1A Ab in s-IBM patients with a high positive predictive value. The presence of anti-CN1A antibodies identified patients with a greater risk of more severe dysphagia.
Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin–proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.
Introduction
We aimed to identify B-cell-mediated immunomechanisms in inclusion body myositis (IBM) and polymyositis (PM) as part of the complex pathophysiology.
Materials and methods
Human primary myotube cultures were derived from orthopedic surgery. Diagnostic biopsy specimens from patients with IBM (n=9) and PM (n=9) were analyzed for markers of B cell activation (BAFF and APRIL) and for chemokines that control the recruitment of B cells (CXCL-12 and CXCL-13). Results were compared to biopsy specimens without myopathic changes (n=9) and hereditary muscular dystrophy (n=9).
Results
The mRNA expression of BAFF, APRIL, and CXCL-13 was significantly higher in IBM and PM compared to controls. Patients with IBM displayed the highest number of double positive muscle fibers for BAFF and CXCL-12 (48%) compared to PM (25%), muscular dystrophy (3%), and non-myopathic controls (0%). In vitro , exposure of human myotubes to pro-inflammatory cytokines led to a significant upregulation of BAFF and CXCL-12, but APRIL and CXCL-13 remained unchanged.
Conclusion
The results substantiate the hypothesis of an involvement of B cell-associated mechanisms in the pathophysiology of IBM and PM. Muscle fibers themselves seem to contribute to the recruitment of B cells and sustain inflammation.
The autoimmune inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation and moderate to severe muscle weakness. Based on currently evolved distinct clinical, histologic, immunopathologic, and autoantibody features, these disorders can be best classified as dermatomyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis. Although polymyositis is no longer considered a distinct subset but rather an extinct entity, it is herein described because its clinicopathologic information has provided over many years fundamental information on T-cell-mediated myocytotoxicity, especially in reference to inclusion body myositis. Each inflammatory myopathy subset has distinct immunopathogenesis, prognosis, and response to immunotherapies, necessitating the need to correctly diagnose each subtype from the outset and avoid disease mimics. The paper describes the main clinical characteristics that aid in the diagnosis of each myositis subtype, highlights the distinct features on muscle morphology and immunopathology, elaborates on the potential role of autoantibodies in pathogenesis or diagnosis , and clarifies common uncertainties in reference to putative triggering factors such as statins and viruses including the 2019-coronavirus-2 pandemic. It extensively describes the main autoimmune markers related to autoinvasive myocytotoxic T-cells, activated B-cells, complement, cytokines, and the possible role of innate immunity. The concomitant myodegenerative features seen in inclusion body myositis along with their interrelationship between inflammation and degeneration are specifically emphasized. Finally, practical guidelines on the best therapeutic approaches are summarized based on up-to-date knowledge and controlled studies, highlighting the prospects of future immunotherapies and ongoing controversies.
Background
Sporadic inclusion body myositis (sIBM) is an intractable muscle disease that frequently affects elderly people. Autoantibodies recognising cytosolic 5’-nucleotidase 1A (cN1A) were found in the sera of patients with sIBM. However, the pathogenic role of the autoantibodies remained unknown. This study investigated the pathogenic properties of the autoantibodies using active cN1A peptides immunisation.
Methods
Wild-type C57BL6 mice were injected with three different mouse cN1A peptides corresponding to the previously reported epitope sequences of human cN1A. After confirming the production of autoantibodies to the corresponding cN1A peptides in each group, changes in body weight, exercise capacity by treadmill test and histological changes in mice injected with cN1A peptides or controls were investigated.
Results
Autoantibodies against cN1A were detected in serum samples from mice injected with cN1A peptide. Some groups of mice injected with cN1A peptide showed significant weight loss and decreased motor activity. The number of myofibres with internal nuclei increased in all the peptide-injected groups, with surrounding or invading CD8-positive T cells into myofibres, abnormal protein aggregates and overexpression of p62 and LC3.
Conclusions
Active cN1A peptide immunisation partially reproduced the clinical and histological aspects of sIBM in wild-type mice. The murine model demonstrates the pathogenic properties of anti-cN1A autoantibodies to cause sIBM-like histological changes.
Sporadic inclusion body myositis (s-IBM) represents a unique disease within idiopathic inflammatory myopathies with a dual myodegenerative-autoimmune physiopathology and a lack of an efficacious treatment. Circulating miRNA expression could expand our knowledge of s-IBM patho-mechanisms and provide new potential disease biomarkers. To evaluate the expression of selected pre-amplified miRNAs in the serum of s-IBM patients compared to those of a sex- and age-matched healthy control group, we enrolled 14 consecutive s-IBM patients and 8 sex- and age-matched healthy controls. By using two different normalization approaches, we found one downregulated and three upregulated miRNAs. hsa-miR-192-5p was significantly downregulated, while hsa-miR-372-3p was found to be upregulated more in the s-IBM patients compared to the level of the controls. The other two miRNAs had a very low expression levels (raw Ct data > 29). hsa-miR-192-5p and hsa-miR-372-3p were found to be significantly dysregulated in the serum of s-IBM patients. These miRNAs are involved in differentiation and regeneration processes, thus possibly reflecting pathological mechanisms in s-IBM muscles and potentially representing disease biomarkers.
Introduction/aims:
Cytosolic 5'-nucleotidase 1A (cN-1A) autoantibodies have been recognized as myositis-related autoantibodies. However, their correlations with clinical characteristics and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) are still unclear. We aimed to establish the prevalence and clinical and laboratory associations of cN-1A autoantibodies in a cohort of patients with connective tissue diseases.
Methods:
A total of 567 participants (182 idiopathic inflammatory myopathies [IIM], 164 systemic lupus erythematosus [SLE], 121 systemic sclerosis [SSc], and 100 blood donors [BD]) were tested for the presence of cN-1A autoantibodies and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs). Clinical and laboratory characteristics were compared between anti-cN-1A positive and negative patients with sporadic inclusion body myositis (sIBM) and between anti-cN-1A positive and negative patients with non-IBM IIM.
Results:
In the sIBM cohort, 30 patients (46.9%) were anti-cN-1A positive vs. 18 (15.2%) in the non-IBM IIM cohort, 17 (10%) were anti-cN-1A positive in the SLE cohort and none in the SSc or the BD cohorts. Anti-cN-1A positivity had an overall sensitivity of 46.9% and a specificity of 93.2% for sIBM. Dysphagia was more frequent in the anti-cN-1A positive vs. negative sIBM patients (p = .04). In the non-IBM IIM group, being anti-cN-1A antibody positive was associated with the diagnosis polymyositis (p = .04) and overlap-myositis (p = .04) and less disease damage evaluated by physician global damage score (p < .001).
Discussion:
cN-1A autoantibodies were predominantly found in IIM patients and was associated with dysphagia in sIBM patients. Notably, anti-cN-1A appears to identify a distinct phenotype of anti-cN-1A positive non-IBM IIM patients with a milder disease course.
Purpose of review:
This article highlights the clinical and diagnostic features of inclusion body myositis (IBM) and provides recent insights into the pathomechanisms and therapeutic strategies of the disease.
Recent findings:
IBM is an often-misdiagnosed myopathy subtype. Due to the insidious onset and slow progression of muscle weakness, it can often be dismissed as a sign of aging as it commonly presents in older adults. While challenging to recognize upon initial clinical evaluation, the recent recognition of specialized stains highlighting features seen on muscle pathology, the use of diagnostic tools such as the anti-cytosolic 5'-nucleotidase 1A antibody biomarker, and the ability of muscle imaging to detect patterns of preferential muscle involvement seen in IBM has allowed for earlier diagnosis of the disease than was previously possible. While the pathogenesis of IBM has historically been poorly understood, several ongoing studies point toward mechanisms of autophagy and highly differentiated cytotoxic T cells that are postulated to be pathogenic in IBM.
Summary:
Overall advancements in our understanding of IBM have resulted in improvements in the management of the disease and are the foundation of several strategies for current and upcoming novel therapeutic drug trials in IBM.
The inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common progressive muscle weakness associated with muscle autoimmunity. Based on currently evolved distinct clinical, histological and autoantibody features, these disorders are best classified in five subsets: Dermatomyositis (DM), Polymyositis (PM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). Polymyosiitis is very rare-if it exists as a single entity-but it is included for historical reasons on classic muscle immunopathology. Because prognosis and response to immunotherapies is variable according to each subtype, correct identification is fundamental from the outset to avoid disease mimics. The paper describes the main clinicopathologic characteristics of each subset highlighting the need for careful neurological examination, precise reading of muscle pathology and careful interpretation of the various autoantibodies and immunopathologic findings to avoid erroneous diagnoses and initiate the correct therapeutic schemes.KeywordsInterstitial lung diseaseInclusion-body myositisMixed connective tissue diseaseInflammatory myopathyMuscle involvement
Purpose of review:
To discuss recent developments in our understanding of epidemiology, diagnostics, biomarkers, pathology, pathogenesis, outcome measures, and therapeutics in inclusion body myositis (IBM).
Recent findings:
Recent epidemiology data confirms a relatively higher prevalence in the population aged above 50 years and the reduced life expectancy. Association with cancer and other systemic disorders is better defined. The role of magnetic resonance imaging (MRI) and ultrasound in diagnosis as well as in following disease progression has been elucidated. There are new blood and imaging biomarkers that show tremendous promise for diagnosis and as outcome measures in therapeutic trials. Improved understanding of the pathogenesis of the disease will lead to better therapeutic interventions, but also highlights the importance to have sensitive and responsive outcome measures that accurately quantitate change.
Summary:
There are exciting new developments in our understanding of IBM which should lead to improved management and therapeutic options.
Inclusion body myositis (IBM) is a progressive muscle disease affecting patients over the age of 40, with distinctive clinical and histopathological features. The typical clinical phenotype is characterized by prominent involvement of deep finger flexors and quadriceps muscles. Less common presentations include isolated dysphagia, asymptomatic hyper-CKemia, and axial or limb weakness beyond the typical pattern. IBM is associated with marked morbidity as majority of patients eventually become wheelchair dependent with limited use of their hands and marked dysphagia. Furthermore, IBM mildly affects longevity with aspiration pneumonia and respiratory complications being the most common cause of death. On muscle biopsy, IBM is characterized by a peculiar combination of endomysial inflammation, rimmed vacuoles, and protein aggregation. These histopathological features are reflective of the complexity of underlying disease mechanisms. No pharmacological treatment is yet available for IBM. Monitoring for swallowing and respiratory complications, exercise, and addressing mobility issues are the mainstay of management. Further research is needed to better understand disease pathogenesis and identify novel therapeutic targets.
Accumulating evidence has shown that Tau aggregates not only seed further tau aggregation within neurons but may also spread to neighboring cells and functionally connected brain regions. This process is referred to as “Tau propagation” and may explain the stereotypic progression of Tau pathology in the brains of Alzheimer’s disease (AD) patients. Tau filaments have distinct cellular and neuroanatomical distributions with morphological and biochemical differences, suggesting the ability to adopt disease-specific molecular conformations. These conformers may give rise to different neuropathological phenotypes, reminiscent of prion strains (strain hypothesis). Autophagy is one of the surveillance systems that contribute to protein homeostasis (proteostasis) through their degradation in lysosomes. The loss of proteostasis occurs with age and in neurodegenerative diseases, such as AD. Defective autophagy has been proposed to contribute to the accumulation of protein aggregates in the elderly brain and as well as the brains of patients with neurodegenerative conditions. In this chapter, we discuss the different Tau propagation mechanisms that may be involved in the cell-to-cell transmission of AD and related tauopathies. The mechanisms by which deficits in autophagic degradative pathways may contribute to the abnormal accumulation of tau in AD are also considered. Furthermore, the issue of pharmacological agents targeting specific tau species to promote the autophagic clearance of Tau from cells will be addressed. We propose our hypothesis that strain-specific autophagic degradation may contribute to the pathogenesis of tauopathies.
Autophagic vacuolar myopathy is a subgroup of muscle diseases defined as a condition in which autophagic vacuoles are present as a muscle pathological feature and is caused by abnormality of autophagy in skeletal muscles. In patients with inclusion body myositis (IBM), refractory slowly progressive muscular weakness in the extremities develops. In IBM, many autophagic vacuoles called rimmed vacuoles are present in muscle cells with deposition of Alzheimer’s disease (AD)-related proteins such as amyloid beta and phosphorylated tau, suggesting homology between IBM and AD. Danon disease is a hereditary disease associated with primary deficiency of lysosomal-associated membrane protein 2 in which cardiomyopathy and myopathy develop. This disease is characterized by the presence of specific autophagic vacuoles called autophagic vacuoles with sarcolemmal features (AVSF). The pathomechanism of Danon disease is considered to be caused by abnormality of autophagy resulting from primary lysosomal dysfunction.
This eighth edition of Dr Reichel's formative text remains the go-to guide for practicing physicians and allied health staff confronted with the unique problems of an increasing elderly population. Fully updated and revised, it provides a practical guide for all health specialists, emphasizing the clinical management of the elderly patient with simple to complex problems. Featuring four new chapters and the incorporation of geriatric emergency medicine into chapters. The book begins with a general approach to the management of older adults, followed by a review of common geriatric syndromes, and proceeding to an organ-based review of care. The final section addresses principles of care, including care in special situations, psychosocial aspects of our aging society, and organization of care. Particular emphasis is placed on cost-effective, patient-centered care, including a discussion of the Choosing Wisely campaign. A must-read for all practitioners seeking practical and relevant information in a comprehensive format.
Résumé
Les myosites à inclusions (MI) font partie du groupe des myopathies inflammatoires ou myosites. Le diagnostic de ces maladies, caractérisées par un processus inflammatoire dégénératif et progressif des muscles squelettiques, repose notamment sur des signes cliniques spécifiques et des signes histopathologiques à la biopsie musculaire. La recherche de marqueurs biologiques comme les anticorps dirigés contre la 5’-nucléotidase 1A cytosolique (cN1A) peut s’avérer très utile comme élément de diagnostic complémentaire. La prévalence de ces anticorps pour les MI est de l’ordre de 40 % à 70 % en fonction des techniques de détection et leur spécificité de 80 %.
We present a patient presented with new onset progressive proximal weakness. On examination noted to have proximal weakness on upper and lower limbs, with preserved reflexes, without sensory involvement. Blood work revealed to have elevated creatine kinase. On electromyography testing shows myopathic features and also noted to have myotonic discharges. Muscle biopsy was obtained next which showed many vacuolization, marked increase in all fat content noted. These findings led us to checking carnitine levels which were noted to be significantly reduced with elevated carnitine palmitoyltransferase levels. These findings highly suggestive of systemic carnitine deficiency. Secondary causes of systemic Carnitine deficiency not identified in this patient and presumed to have primary systemic carnitine deficiency. Patient improved on oral supplementation of L- Carnitine.
Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that IIM are systemic inflammatory disorders. Different myositis-specific auto-antibodies have been identified and, on the basis of clinical, histopathological and serological features, IIM can be classified into several subgroups — dermatomyositis (including amyopathic dermatomyositis), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis and overlap myositis. The prognoses, treatment responses and organ manifestations vary among these groups, implicating different pathophysiological mechanisms in each subtype. A deeper understanding of the molecular pathways underlying the pathogenesis and identifying the auto-antigens of the immune reactions in these subgroups is crucial to improving outcomes. New, more homogeneous subgroups defined by auto-antibodies may help define disease mechanisms and will also be important in future clinical trials for the development of targeted therapies and in identifying biomarkers to guide treatment decisions for the individual patient.
Sporadic inclusion body myositis (IBM) is an acquired muscle disease and the most common idiopathic inflammatory myopathy over the age of 50. It is characterized by male predominance, with a prevalence rate between 1 and 71 cases per million, reaching 139 cases per million over the age of 50 globally. The diagnosis of IBM is based on clinical presentation and muscle biopsy findings. However, there is increasing evidence for the role of genetics and serum biomarkers in supporting a diagnosis. Antibodies against the cytosolic 5'-nucleotidase 1A (Anti-CN1A), an enzyme catalyzing the conversion of adenosine monophosphate into adenosine and phosphate and is abundant in skeletal muscle, has been reported to be present in IBM and could be of crucial significance in the diagnosis of the disease. In this study, we investigated the diagnostic accuracy of anti-CN1A antibodies for sporadic IBM in comparison with other inflammatory myopathies, autoimmune disorders, motor neurone disease, using a hierarchical bivariate approach, and a Bayesian model taking into account the variable prevalence. The results of the present analysis show that anti-CN1A antibodies have moderate sensitivity, and despite having high specificity, they are not useful biomarkers for the diagnosis of IBM, polymyositis or dermatomyositis, other autoimmune conditions, or neuromuscular disorders. Neither the hierarchical bivariate nor the Bayesian analysis showed any significant usefulness of anti-CN1A antibodies in the diagnosis of IBM.
The group of inflammatory myopathies constitutes a heterogeneous group of acquired autoimmune myopathies that have in common the presence of endomysial inflammation. Based on currently evolved distinct clinical, histological, and autoantibody features, these disorders can be best classified in five subsets: dermatomyositis, polymyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis (IBM). Because each inflammatory myopathy subset has distinct immunopathogenesis, prognosis, and response to immunotherapies, correct identification of each subtype and distinction from disease mimics are fundamental for early therapy initiation and better clinical outcome. With these issues in mind, this article describes the main clinicopathologic characteristics of each subset, emphasizing how best to avoid erroneous diagnoses; highlights the main autoimmune markers related to immunopathogenesis, including the role of autoreactive T cells, B cells, autoantibodies, and cytokines; describes the myodegenerative features prominent in IBM; addresses controversial issues related to pathogenic role of autoantibodies or statins as putative triggering factors; and provides practical guidelines on the best therapeutic approaches.
Immune and inflammatory myopathies (IIM) are characterized by weakness with muscle inflammation and are frequently accompanied by extra-muscular manifestations. Previously, patients were diagnosed with dermatomyositis if a characteristic rash accompanied muscle involvement or polymyositis if no rash was present. The discovery of unique clinical features, autoantibodies, and histopathological patterns that associate with specific clinical phenotypes has been instrumental in understanding IIM and predicting treatment response and prognosis. While numerous classification systems exist, the most commonly agreed-upon criteria recognize four main categories: dermatomyositis, sporadic inclusion body myositis, antisynthetase syndrome, and immune-mediated necrotizing myopathy. Treatment still largely relies on expert opinion and empirical use of corticosteroids and steroid-sparing agents. A deeper understanding of the molecular pathways that drive pathogenesis and accurate disease classification will aid clinical research and the development of more precision therapies. This chapter discusses current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of IIM.
Sporadic inclusion body myositis (sIBM) is considered to be the most common acquired muscle disease associated with aging. It is a disabling disorder still without effective treatment. sIBM causes weakness and atrophy of the distal and proximal muscles. Involvement of quadriceps and deep finger flexors are clues to early diagnosis. Dysphagia in the course of the disease is common. Muscle biopsy shows chronic myopathic features, lymphocytic infiltration invading non-necrotic fibbers, rimmed vacuoles and accumulation of amyloid-related proteins. It remains uncertain whether sIBM is primarily an immune-mediated inflammatory myopathy or a degenerative myopathy with an associated inflammatory component. This review describes the epidemiology and clinical features of the disease as well as the current genetic and pathogenic concepts and therapeutic approaches. Despite recent clues, in many respects sIBM remains an unsolved mystery.
Inclusion body myositis (IBM) is a poorly understood and refractory autoimmune muscle disease. Though widely believed to have no significant humoral autoimmunity, we sought to identify novel autoantibodies with high specificity for this disease.
Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein.
Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.
To determine the prevalence of myositis specific autoantibodies (MSAs) and several myositis associated autoantibodies (MAAs) in a large group of patients with myositis.
A total of 417 patients with myositis from 11 European countries (198 patients with polymyositis (PM), 181 with dermatomyositis (DM), and 38 with inclusion body myositis (IBM)) were serologically analysed by immunoblot, enzyme linked immunosorbent assay (ELISA) and/or immunoprecipitation.
Autoantibodies were found in 232 sera (56%), including 157 samples (38%) which contained MSAs. The most commonly detected MSA was anti-Jo-1 (18%). Other anti-synthetase, anti-Mi-2, and anti-SRP autoantibodies were found in 3%, 14%, and 5% of the sera, respectively. A relatively high number of anti-Mi-2 positive PM sera were found (9% of PM sera). The most commonly detected MAA was anti-Ro52 (25%). Anti-PM/Scl-100, anti-PM/Scl-75, anti-Mas, anti-Ro60, anti-La, and anti-U1 snRNP autoantibodies were present in 6%, 3%, 2%, 4%, 5%, and 6% of the sera, respectively. Remarkable associations were noticed between anti-Ro52 and anti-Jo-1 autoantibodies and, in a few sera, also between anti-Jo-1 and anti-SRP or anti-Mi-2 autoantibodies.
The incidence of most of the tested autoantibody activities in this large group of European patients is in agreement with similar studies of Japanese and American patients. The relatively high number of PM sera with anti-Mi-2 reactivity may be explained by the use of multiple recombinant fragments spanning the complete antigen. Furthermore, our data show that some sera may contain more than one type of MSA and confirm the strong association of anti-Ro52 with anti-Jo-1 reactivity.
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease
entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies
which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed
by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the
anti-Jo-1 autoantibody (20 %), followed by anti-tRNAHis (6 %), anti-Mi-2 (6 %), and anti-SRP (4 %). The presence of certain MSAs was clearly associated with specific clinical characteristics.
Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response
to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently
present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated
a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within
the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders
by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.
Myositis specific autoantibodies (MSAs) are proven to be specific for myositis compared with other inflammatory connective tissue diseases. Their specificity compared, however, with other neuromuscular disorders, which are included in the differential diagnosis of patients in whom the diagnosis myositis is under consideration, is unknown. We prospectively screened sera from 107 patients with various neuromuscular disorders for the most common MSAs and compared the results with the findings in a group of 97 myositis patients, published previously. Special attention was paid to patients with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant muscle disease with marked inflammation in skeletal muscle tissue.
Only one patient in the neuromuscular disorders group tested positive for an MSA, compared with 41 in the myositis group, resulting in a specificity of 99%. None of the FSHD patients tested positive. We conclude that the tested MSAs are highly specific for myositis and that they are not merely associated with muscle inflammation.
The inflammatory myopathies are putative autoimmune disorders characterized by muscle weakness and the presence of intramuscular inflammatory infiltrates. Although inclusion body myositis and polymyositis have been characterized as cytotoxic CD8(+) T cell-mediated diseases, we recently demonstrated high frequencies of CD138(+) plasma cells in the inflamed muscle tissue of patients with these diseases. To gain a deeper understanding of the role these B cell family members play in the disease pathology, we examined the molecular characteristics of the H chain portion of the Ag receptor. Biopsies of muscle tissue were sectioned and tissue regions and individual cells were isolated through laser capture microdissection. Ig H chain gene transcripts isolated from the sections, regions, and cells were used to determine the variable region gene sequences. Analysis of these sequences revealed clear evidence of affinity maturation in that significant somatic mutation, isotype switching, receptor revision, codon insertion/deletion, and oligoclonal expansion had occurred within the B and plasma cell populations. Moreover, analysis of tissue regions isolated by laser capture microdissection revealed both clonal expansion and variation, suggesting that local B cell maturation occurs within muscle. In contrast, sequences from control muscle tissues and peripheral blood revealed none of these characteristics found in inflammatory myopathy muscle tissue. Collectively, these data demonstrate that Ag drives a B cell Ag-specific response in muscle in patients with dermatomyositis, inclusion body myositis, and polymyositis. These findings highlight the need for a revision of the current paradigm of exclusively T cell-mediated intramuscular Ag-specific autoimmunity in inclusion body myositis and polymyositis.
Idiopathic inflammatory myopathies (IIMs), comprising polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by inflammatory cell infiltrates in skeletal muscle tissue, muscle weakness, and muscle fatigue. The cellular infiltrates often consist of T lymphocytes and macrophages but also, in some cases, B lymphocytes. Emerging data have led to improved phenotypic characterization of the inflammatory cells, including their effector molecules, in skeletal muscle, peripheral blood, and other organs that are frequently involved, such as skin and lungs. In this review we summarize the latest findings concerning the role of T lymphocytes, B lymphocytes, dendritic cells, and other antigen-presenting cells in the pathophysiology of IIMs.
We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, −0.2% for methotrexate and −3.4% for placebo (95% confidence interval = −2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.
We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective. The HLA-DRB1*03:01 and HLA-DRB1*13:01 alleles also appear to have an influence on the age at onset of the disease and severity of muscle weakness. Our findings indicate that the influence of HLA-DRB1 in s-IBM is complex and that epistatic interactions at the HLA-DRB1 locus contribute both to disease susceptibility and to the clinical phenotype.
Accumulation of amyloid-β (Aβ) within muscle fibers has been considered an upstream step in the development of the s-IBM pathologic phenotype. Aβ42, which is considered more cytotoxic than Aβ40 and has a higher propensity to oligomerize, is preferentially increased in s-IBM muscle fibers. In Alzheimer disease (AD), low-molecular weight Aβ oligomers and toxic oligomers, also referred to as "Aβ-Derived Diffusible Ligands" (ADDLs), are considered strongly cytotoxic and proposed to play an important pathogenic role. ADDLs have been shown to be increased in AD brain. We now report for the first time that in s-IBM muscle biopsies Aβ-dimer, -trimer, and -tetramer are identifiable by immunoblots. While all the s-IBM samples we studied had Aβ-oligomers, their molecular weights and intensity varied between the patient samples. None of the control muscle biopsies had Aβ oligomers. Dot-immunoblots using highly specific anti-ADDL monoclonal antibodies also showed highly increased ADDLs in all s-IBM biopsies studied, while controls were negative. By immunofluorescence, in some of the abnormal s-IBM muscle fibers ADDLs were accumulated in the form of plaque-like inclusions, and were often increased diffusely in very small fibers. Normal and disease-controls were negative. By gold-immuno-electron microscopy, ADDL-immunoreactivities were in close proximity to 6-10 nm amyloid-like fibrils, and also were immunodecorating amorphous and floccular material. In cultured human muscle fibers, we found that inhibition of autophagy led to the accumulation of Aβ oligomers. This novel demonstration of Aβ42 oligomers in s-IBM muscle biopsy provides additional evidence that intra-muscle fiber accumulation of Aβ42 oligomers in s-IBM may contribute importantly to s-IBM pathogenic cascade.
The relevance of proteins that accumulate and aggregate in the muscle fibers of patients with sporadic inclusion body myositis (sIBM) is unknown. Many of these proteins also aggregate in other disorders, including Alzheimer's disease, leading to speculation that sIBM pathogenesis has similarities to neurodegenerative disorders. Our review will discuss current studies on these protein biomarkers and their utility in sIBM diagnosis.
Two 'classical' components of sIBM aggregates (amyloid beta and phospho-tau) have been re-evaluated. Three additional components of aggregates (TDP-43, p62, and LC3) have been identified. The sensitivity and specificity of these biomarkers has been explored. Two studies suggest that TDP-43 may have clinical utility in distinguishing sIBM from other inflammatory myopathies.
The fact that sIBM muscle accumulates multiple protein aggregates with no single protein appearing in every sIBM patient biopsy suggests that it is not presently possible to place pathogenic blame on any single protein (i.e. amyloid beta or TDP-43). Instead changes in protein homeostasis may lead to the accumulation of different proteins that have a propensity to aggregate in skeletal muscle. Therapies aimed at improving protein homeostasis, instead of targeting a specific protein that may or may not accumulate in all sIBM patients, could be useful future strategies for this devastating and enigmatic disorder.
Sporadic inclusion body myositis (IBM) is characterized by T cell infiltrates in muscle tissue, but their functional role is unclear. Systemic signs of inflammation are lacking, and the absence of beneficial effects following immunosuppression has challenged the notion of a role for the immune system. This study was undertaken to investigate the phenotype and functionality of T cells, specifically a subset of proinflammatory, cytotoxic, and apoptosis-resistant T cells defined as CD28(null) T cells, in the pathogenesis of sporadic IBM.
A cohort of 27 patients with sporadic IBM was analyzed for the frequency of circulating and muscle-infiltrating CD28(null) T cells. The T cell receptor (TCR) V(β) usage was determined using flow cytometry and immunohistochemistry. Anti-CD3-stimulated peripheral blood mononuclear cells were analyzed for intracellular interferon-γ and cytotoxic potential by flow cytometry.
We found striking accumulations of both CD8+CD28(null) and CD4+CD28(null) T cells, which represented the TCR V(β) -expanded T cells in sporadic IBM. Such CD28(null) T cells were abundant both in the inflamed muscle tissue and in the circulation. Although the specific TCR V(β) expansions varied between patients, both CD8+CD28(null) and CD4+CD28(null) T cells consistently displayed a highly proinflammatory and cytotoxic potential.
Our results suggest that CD28null T cell expansions represent the previously described expanded T cell subsets in sporadic IBM, and their proinflammatory capacity and presence in both muscle tissue and the circulation may imply a role of immune activation in sporadic IBM. In addition, CD4+CD28(null) T cells may exert cytotoxic effects directly on muscle fibers due to a cytotoxic potential similar to that in CD8+ T cells.
Inclusion body myositis is a progressive disease of the skeletal muscle. Here, specific theories of its pathogenesis are reviewed and general considerations pertaining to modeling of this disease discussed. Understanding of inclusion body myositis disease mechanism remains extremely poor. Current published animal models do not represent the disease. Future studies need to consider the critical role of biomarkers and methodologic issues in their discovery.
Based on unique clinicopathological criteria, the most common immune inflammatory muscle disorders include Dermatomyositis (DM), Polymyositis (PM), Necrotizing Myositis (NM), and sporadic Inclusion Body Myositis (sIBM). DM is an undeniably a complement-mediated microangiopathy with destruction of capillaries, hypoperfusion, and inflammatory cell stress on the perifascicular regions. Necrotizing Myopathy is a poorly studied subacute myopathy triggered by toxic, viral, or autoimmune factors with macrophages as the final effector cells. In PM and IBM cytotoxic CD8-positive T-cells clonally expand in situ and invade MHC-I-expressing muscle fibers. In sIBM, in addition to autoimmune inflammation, there are degenerative features characterized by vacuolization and accumulation of stressor and amyloid-related molecules. Advances in the immunobiology of these disorders are discussed including the interaction between pro-inflammatory and beta-amyloid or stressor proteins. A critical review regarding tissue biomarkers and strategies for more effective treatments are presented.
Dermatomyositis (DM) and polymyositis (PM) are autoimmune myopathies characterized clinically by proximal muscle weakness, muscle inflammation, extramuscular manifestations, and frequently, the presence of autoantibodies. Although there is some overlap, DM and PM are separate diseases with different pathophysiological mechanisms. Furthermore, unique clinical phenotypes are associated with each of the myositis-specific autoantibodies (MSAs) associated with these disorders. This review will focus on the clinical features, pathology, and immunogenetics of PM and DM with an emphasis on the importance of autoantibodies in defining unique phenotypes and, perhaps, as clues to help elucidate the mechanisms of disease.
The main inflammatory myopathies within the myositis group include polymyositis, dermatomyositis and inclusion-body myositis (IBM). Although potentially treatable, various practical issues have an impact on the response of these conditions to therapy. The most common reason for therapeutic failure is that the treatment targets the wrong disease, often owing to poor distinction of polymyositis from difficult-to-treat mimics such as sporadic IBM, necrotizing myopathies and inflammatory dystrophies. Evidence from uncontrolled studies suggests that polymyositis and dermatomyositis respond to treatment with prednisone at least to some degree. Empirically, adding an immunosuppressive drug might offer a 'steroid-sparing' effect or perhaps additional benefit. Intravenous immunoglobulin is proven effective as a second-line agent in patients with dermatomyositis and also seems to be effective for those with polymyositis, but offers only minimal and transient benefit to a small proportion of patients with IBM. Small, uncontrolled series suggest other agents such as rituximab or tacrolimus might offer some benefit in disease refractory to the aforementioned therapies, although IBM is resistant to most therapies. Novel agents are emerging as potential treatment options for all forms of myositis. This Review highlights common pitfalls in therapy, discusses emerging new therapies, and provides a practical therapeutic algorithm.
Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy occurring in patients over the age of 50 years and probably accounts for about 30% of all inflammatory myopathies. Muscle biopsy characteristically reveals endomysial inflammation, small groups of atrophic fibres, eosinophilic cytoplasmic inclusions and muscle fibres with one or more rimmed vacuoles. However, any given biopsy may lack these histopathological abnormalities; the clinical examination is often the key to diagnosis. Early and often asymmetrical weakness and atrophy of the quadriceps and flexor forearm muscles (ie, wrist and finger flexors) are the clinical hallmarks of IBM. The pathogenesis of IBM is unknown. It may be autoimmune inflammatory myopathy or a primary degenerative myopathy with a secondary inflammatory. A prevailing theory is that there is an overproduction of beta-amyloid precursor protein in muscle fibres that is somehow cleaved into abnormal beta-amyloid, and the accumulation of the latter is somehow toxic to muscle fibres. However, there are many problems with this theory and more work needs to be done. Unfortunately, IBM is generally refractory to therapy. Further research into the pathogenesis, along with both preliminary small pilot trials and larger double blind, placebo controlled efficacy trials, are needed to make progress in our understanding and therapeutic approach for this disorder.
Recent literature in inflammatory myopathies suggests that both immune (cell-mediated and humoral) and nonimmune [endoplasmic reticulum (ER) stress and autophagy] mechanisms play a role in muscle fiber damage and dysfunction. This review describes these findings and discusses their relevance to disease pathogenesis and therapy.
Recent studies highlight the role of ER stress response, especially the roles of hexose-6-phosphate dehydrogenase and ER-anchored RING finger E3 ligase in the activation of unfolded protein response and the formation of vacuoles and inclusions in myopathies. Several studies investigated the link between inflammation and the beta-amyloid-associated muscle fiber degeneration and loss of muscle function. Likewise, the roles of ER stress and autophagy in skeletal muscle damage have been explored in multiple muscle diseases.
Current data indicate that the ER stress, nuclear factor-kappaB pathway and autophagy are active in the skeletal muscle of myositis patients, and the proinflammatory nuclear factor-kappaB pathway connects the immune and nonimmune pathways of muscle damage. The relative contributions of each of these pathways to muscle fiber damage are currently unclear. Therefore, further defining the role of these pathways in disease pathogenesis should help to design effective therapeutic agents for these diseases.
Sporadic inclusion body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause, and there is no enduring treatment. Abnormal accumulation of intracellular multi-protein inclusions is a characteristic feature of the s-IBM phenotype, and as such s-IBM can be considered a “conformational disorder,” caused by protein unfolding/misfolding combined with the formation of inclusion bodies. Abnormal intracellular accumulation of unfolded proteins may lead to their aggregation and inclusion body formation.
The present article is focusing on the multiple proteins that are accumulated in the form of aggregates within s-IBM muscle fibers, and it explores the most recent research advances directed toward a better understanding of mechanisms causing their impaired degradation and abnormal aggregation. We illustrate that, among other factors, abnormal misfolding, accumulation and aggregation of proteins are associated with their inadequate disposal—and these factors are combined with, and perhaps provoked by, an aging intracellular milieu. Other concurrent and possibly provocative phenomena known within s-IBM muscle fibers are: endoplasmic reticulum stress and unfolded protein response, mitochondrial abnormalities, proteasome inhibition, lysosome abnormality and endodissolution. Together, these appear to lead to the s-IBM-specific vacuolar degeneration, and muscle fiber atrophy, concluding with muscle fiber death.
The inflammatory myopathies are a heterogeneous group of diseases including dermatomyositis, polymyositis, and inclusion body myositis. Clinical trials in myositis are rare, making it difficult to make clear recommendations on the treatment of these rare disorders.
To give an overview of treatment options and strategies and to provide the clinician with a framework that can be used in treating patients with myositis.
Results of clinical trials in myositis, case series and important case reports are presented and discussed.
Most patients with dermatomyositis or polymyositis require treatment with oral high-dose prednisone combined with azathioprine or methotrexate to facilitate early tapering of prednisone. In case of treatment failure, intravenous immunoglobulin can be tried, followed by rituximab, mycophenolate mofetil, or tacrolimus depending on the specific clinical situation. A treatment trial with oral prednisone combined with methotrexate is advised in a subgroup of patients with inclusion body myositis.
To evaluate the clinical utility of a commercial immunoblot assay for the detection of myositis-specific autoantibodies.
Serum samples from 153 myositis patients and 77 disease controls were investigated. The commercial Euroline assay with seven autoantigens (Mi-2, Ku, PM-Scl, Jo-1, Pl-7, Pl-12 and SSA/Ro-52) was used according to the manufacturer s instructions, and supplemented with an anti-SRP strip. In a separate experiment analyses were performed at different temperatures. Results were recorded with densitometry.
Anti-Jo-1 was found in 18 myositis and one systemic sclerosis patient. Antibodies against Mi-2 were found in 5 myositis patients, and eleven myositis patients had antibodies against PM-Scl. Four myositis patients showed anti-Pl-7 reactivity, whereas no patients had antibodies against Pl-12. Anti-Ku antibodies were found in 4 myositis and 2 primary Sjögren's syndrome patients. Anti-SRP was found in 8 myositis patients as well as in two disease controls. Antibodies against SSA/Ro52 ranged between 23-62% in all groups except juvenile dermatomyositis patients. Most autoantibody reactivities were clearly positive, only 11% (14/127) were borderline positive. Higher assay temperature increased antibody reactivities.
Except for anti-SSA/Ro-52 and anti-Ku the antibody reactivities were rather myositis-specific, supporting the use of this immunoblot assay. However, assay validation needs to be determined against other methods.
The idiopathic inflammatory myopathies are chronic autoimmune disorders sharing the clinical symptom of muscle weakness and, in typical cases, inflammatory cell infiltrates in muscle tissue. During the last decade, novel information has accumulated supporting a role of both the innate and adaptive immune systems in myositis and suggesting that different molecular pathways predominate in different subsets of myositis. The type I interferon activity is one such novel pathway identified in some subsets of myositis. Furthermore, nonimmunological pathways have been identified, suggesting that factors other than direct T cell-mediated muscle fibre necrosis could have a role in the development of muscle weakness.
We applied a simple lead salt-based stain for interstitial and vascular 5'-nucleotidase to 150 muscle biopsy specimens. No reaction was obtained with 2'- or 3'-adenosine monophosphate, indicating that the stain was specific, and distinct from phosphatases. Staining was not inhibited by alpha, beta-methylene adenosine 5'-diphosphate, but was prevented by formaldehyde fixation or by brief immersion in octoxynol 9 (Triton X-100). Nucleotidase stains the following specific histologic sites that distinguish it from alkaline phosphatase: the intima and adventitia of medium-sized and large arteries, perineural and muscle spindle sheaths, and tendon insertions. Aside from these structures, normal muscle shows little reaction, as the sarcoplasm and sarcolemma do not stain. Neither of these enzymes shows a compensatory increase, histochemically, in myo-adenylate deaminase deficiency. In Duchenne's muscular dystrophy, however, and particularly in inflammatory myopathy, interstitial staining of 5'-nucleotidase is increased, leading to investment of most muscle fibers in the affected area. The stain rarely identifies regenerating fibers. Although alkaline phosphatase commonly shows a corresponding increase in interstitial staining, we encountered six cases of inflammatory myopathy in which this was absent, despite pronounced endomysial staining in the 5'-nucleotidase reaction. 5'-Nucleotidase thus appears to provide a valuable adjunct in the diagnosis of inflammatory myopathy.
The establishment of classification criteria for polymyositis (PM) and dermatomyositis (DM).
Questionnaires inquiring about patients with DM, PM, systemic lupus erythematosus, progressive systemic sclerosis and noninflammatory neuromuscular diseases were distributed to the main medical institutes in Japan. Data were collected and analyzed by computer.
Among skin lesions of DM, heliotrope rash, Gottron's sign and erythema or purpura on the extensor surfaces of the extremity joints were shown to be distinguishing criteria. In both DM and PM, proximal muscle weakness, muscle grasping and spontaneous pain, nondestructive arthritis or arthralgia, elevated CK or aldolase level, presence of systemic inflammatory signs, myogenic changes on EMG, positive and anti Jo-1 antibody and pathologic findings compatible with inflammatory myositis were distinguishing criteria items.
When a patient satisfies one of 3 skin lesion items and at least 4 other items, he or she shall be classified as having DM, sensitivity 94.1%. When a patient satisfies at least 4 items other than skin lesion items, he or she shall be classified as having PM, sensitivity 98.9%. Specificity of DM and PM is 95.2%.
Serum from 70 patients with sporadic inclusion body myositis (IBM) was subjected to agarose gel immunofixation electrophoresis. The IgG extracted from 9 patients with monoclonal proteins, 3 without, and 2 control subjects and was purified, biotinylated, and applied to muscle biopsy sections for immunocytochemistry and to purified muscle protein fractions for immunoblots. Sixteen of 70 (22.8%) patients with IBM, compared with 2% of age-matched controls, had a monoclonal gammopathy characterized as IgG lambda in 9 patients, IgG kappa in 4, IgM kappa in 2, and IgA lambda in 1. The mean age of IBM patients with gammopathy was 60.6 years (range, 35-77 years), compared with 66.1 years (range, 42-80 years) of the IBM patients without gammopathy. The IgG of the patients, more often than that of the control subjects, immunostained myonuclei and recognized various muscle proteins of 35 to 145 kd. We conclude that IBM, regardless of age, is frequently associated with monoclonal gammopathies, which often recognize various muscle components, especially myonuclei, suggesting disturbed immunoregulation.
heterogeneous group of systemic diseases characterized by a progressive mus- cle weakness, elevated levels of creatinine kinase, characteristic electromyographic abnormalities, and inflammatory infiltrates in skeletal muscles.’ The three major categories of this disorder are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). The clinical differentiation between DM/PM and IBM can be difficult to make, even histological- ly.’ Yet it is of extreme importance, as IBM, unlike DM and I’M, lacks
To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis.
Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal.
Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immune-related genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton genes is also identified.
The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified.
The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders. Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases.
Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs. Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.
Previous immunohistochemical studies of muscle from patients with inclusion body myositis and polymyositis found many more T cells than B cells, suggesting a role for intramuscular cell-mediated immune mechanisms rather than humoral mechanisms.
Microarray studies were performed on muscle biopsy specimens from 40 patients with inclusion body myositis (IBM; n = 23), polymyositis (PM; n = 6), and without neuromuscular disease (n = 11). Reverse transcription PCR of selected immunoglobulin gene transcripts was performed on two patient samples. Qualitative immunohistochemical studies for B-cell lineage cell surface markers were performed on 28 muscle specimens and quantitative studies performed on a subset of 19 untreated patients with IBM or PM. CD138+ cells were isolated from muscle using laser capture microdissection, and immunoglobulin transcripts were PCR amplified to determine the presence or absence of immunoglobulin gene rearrangements unique to the B-cell lineage.
Immunoglobulin gene transcripts accounted for 59% in IBM and 33% in PM of the most stringently defined highest differentially expressed muscle transcripts compared with normal. Plasma cells, terminally differentiated B cells expressing CD138 but not CD19 or CD20, are present in IBM and PM muscle in numbers several times higher than B cells.
There are differentiated B cells in the form of CD138+ plasma cells within the muscle of patients with inclusion body myositis and polymyositis. The principle of linked recognition of B-cell activation predicts several strategies for autoantigen discovery that could not otherwise be pursued through the study of the infiltrating T-cell population alone.
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and there is no successful treatment. We summarize our most recent findings, which provide a better understanding of the steps in the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer disease, the most common neurodegenerative disease of older persons. In s-IBM, abnormal accumulation of the amyloid-beta (Abeta) precursor protein and its proteolytic fragment, Abeta, associated with the aging intracellular milieu of the muscle fiber, appear to be key upstream pathogenic events. We propose that the identified abnormal accumulation, misfolding, and aggregation of proteins, perhaps provoked by the aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and atrophy of muscle fibers.
Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.
Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-beta-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFkappaB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.
To correlate muscle biopsy findings with prebiopsy and postbiopsy clinical course and response to therapy in polymyositis (PM) and sporadic inclusion body myositis (IBM).
Existence of pure PM has recently been questioned; subsequently, the definition and criteria for diagnosing PM were debated.
Patient records, follow-up information, and muscle biopsies were analyzed in 107 patients whose biopsies were initially read as PM and IBM.
The patients fell into three groups by combined biopsy and clinical criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy diagnosis of PM but clinical features of IBM. For the three groups, the respective mean periods from disease onset to end of follow-up were 5.9, 8.5, and 9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM, and 1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of each group. Nineteen PM patients had no associated autoimmune disease or marker. Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27 PM, and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy improved 22 of 27 PM patients but had only transient beneficial effects in 2 of 32 IBM and 1 of 14 PM/IBM patients.
1) Sixteen of 43 patients (37%) with biopsy features of polymyositis (PM) had clinical features of inclusion body myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically affected muscles of IBM patients challenges biopsy criteria for IBM, or the IBM markers appear late in some patients, or their distribution in muscle is patchy and restricted compared with that of the inflammatory exudate. 3) The muscle biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85% of the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced by combined evaluation of the clinical and pathologic findings.
There is now compelling evidence that sporadic inclusion body myositis (sIBM) is a muscle-specific autoimmune disease in which both T and B-cells play a part and in which both cytotoxic muscle fibre necrosis and degeneration occur. However the factors responsible for breakdown of immune tolerance and the nature of the target antigens expressed by muscle fibres remain unknown. Genetic factors are known to contribute to susceptibility, in particular MHC haplotyes which may influence antigenic presentation, and could also operate through genetic variations in muscle fibre constituents or immune effector mechanisms. Viral infection may act as a trigger mechanism, as in cases of HIV-associated sIBM. Our understanding of the mechanisms leading to the degenerative changes in muscle fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather than defective transcriptional control is likely to underlie the abnormal accumulation of multiple proteins in the muscle fibre inclusions. However, aberrant transcription is thought to be the basis for the accumulation of potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple clonally expanded somatic mtDNA mutations in COX-negative segments of muscle fibres remains uncertain but may be linked to the effects of oxidative stress. It is proposed that the disproportionate involvement of certain muscles in sIBM may be due to the existence of muscle group-specific transcriptomes which are differentially affected by the disease process and that the male predominance of the disease may indicate the influence of genes preferentially expressed in males. There is a need to develop better animal models of sIBM in which the relationship between the inflammatory and degenerative components of the disease as well as the gender difference in susceptibility and differential vulnerability of different muscle groups can be more critically investigated.
Inclusion body myositis Diagnostic criteria for neuro-muscular disorders
- Verschuuren Jj
- Badrising
- Ua
- B Van Engelen
Verschuuren JJ, Badrising UA, van Engelen B, et al. Inclusion body myositis. In: Emery AEH, ed. Diagnostic criteria for neuro-muscular disorders. London, UK: Royal Society of Medicine Press, 1997:81–84.
05% NP-40) overnight at 4 C. Beads were washed 3Â with IPP500 and once with IPP150 (150mM NaCl, 10mM Tris-HCl
- Nacl
NaCl, 10mM Tris-HCl, pH 8.0, 0.05% NP-40) overnight at 4 C. Beads were washed 3Â with IPP500 and once with IPP150 (150mM NaCl, 10mM Tris-HCl, pH 8.0, 0.05% NP-40). In vitro translated References
Immunotherapy of myositis: issues, concerns and future prospects
- Dalakas
Dalakas MC. Immunotherapy of myositis: issues, concerns and
future prospects. Nat Rev Rheumatol 2010;6:129-137.
Novel demonstration of amyloid-beta oligomers in sporadic inclusion-body myositis muscle fibers
- A Nogalska
- C Agostino
- W K Engel
Nogalska A, D'Agostino C, Engel WK, et al. Novel demonstration
of amyloid-beta oligomers in sporadic inclusion-body myositis
muscle fibers. Acta Neuropathol 2010;120:661-666.
Diagnostic criteria for neuromuscular disorders
- J J Verschuuren
- U A Badrising
- B Van Engelen
Verschuuren JJ, Badrising UA, van Engelen B, et al. Inclusion
body myositis. In: Emery AEH, ed. Diagnostic criteria for neuromuscular disorders. London, UK: Royal Society of Medicine Press,
1997:81-84.