Objective
We undertook this study to 1) determine the sensitivity of the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for ...idiopathic inflammatory myopathies (IIMs) to properly classify myositis‐specific autoantibody (MSA)–positive myositis patients, 2) describe the phenotype and muscle involvement over time in different MSA‐positive patients, and 3) compare MSA subgroups to EULAR/ACR criteria–defined myositis subgroups for their capacity to predict clinical phenotypes in patients with IIMs.
Methods
The study included 524 MSA‐positive myositis patients from the Johns Hopkins Myositis Center. Each patient was classified using the EULAR/ACR classification criteria. Patient phenotypes were summarized using factor analysis of mixed data (FAMD). We compared the ability of MSAs to that of the EULAR/ACR classification subgroups to predict the phenotype of patients by applying the Akaike information criterion (AIC) and the Bayesian information criteria (BIC) to the linear regression models.
Results
Overall, 91% of MSA‐positive patients met the EULAR/ACR criteria to be classified as having myositis. However, 20% of patients with anti–hydroxymethylglutaryl‐coenzyme A reductase (anti‐HMGCR) and 50% of patients with anti–PL‐7 were incorrectly classified as not having myositis. Furthermore, ~10% of patients with anti–signal recognition particle (anti‐SRP) and patients with anti‐HMGCR were misclassified as having inclusion body myositis. FAMD demonstrated that patients within each MSA‐defined subgroup had similar phenotypes. Application of both the AIC and BIC to the linear regression models revealed that MSAs were better predictors of myositis phenotypes than the subgroups defined by the EULAR/ACR criteria.
Conclusion
Although the EULAR/ACR criteria successfully classified 91% of MSA‐positive myositis patients, certain MSA‐defined subgroups, including those with autoantibodies against HMGCR, SRP, and PL‐7, are frequently misclassified. In myositis patients with MSAs, autoantibodies outperform the EULAR/ACR‐defined myositis subgroups in predicting the clinical phenotypes of patients. These findings underscore the need to include MSAs in a revised myositis classification scheme.
Objective
Although more than a dozen myositis‐specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given ...myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis.
Methods
In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA‐positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells.
Results
Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl‐coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo‐1 (n = 18), nuclear matrix protein 2 (n = 12), Mi‐2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation–associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells.
Conclusion
Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.
Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 ...pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies.
The expression of IFN1- and IFN2-inducible genes was compared between the different groups.
The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note,
expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies.
IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.
The aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to ...compare patients with IMNM with different autoantibodies.
All Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies.
The study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p<0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM.
Compared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients.
The microbial compositions from concurrent peri-implant and periodontal lesions were compared, since the results reported in the literature on the etiological relationship between these oral ...pathologies are contradictory. Microbial compositions from nine patients were evaluated using Illumina MiSeq sequencing of 16S rRNA gene amplicons and Principal Components Analysis. Comparisons between the use of curettes or paper points as collection methods and between bacterial composition in both pathologies were performed. Paper points allowed the recovery of a higher number of bacterial genera. A higher bacterial diversity was found in peri-implantitis compared to periodontal samples from the same patient, while a greater number of operational taxonomic units (OTUs) were present in the corresponding periodontal samples. A higher abundance of oral pathogens, such as
or
, was found in peri-implantitis sites. The opposite trend was observed for
abundance, which was higher in periodontal than in peri-implantitis lesions, suggesting that both oral pathologies could be considered different but related diseases. Although the analysis of a higher number of samples would be needed, the differences regarding the microbial composition provide a basis for further understating the pathogenesis of peri-implant infections.
Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. ...In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFNγ)-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFNγ-induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFNγ upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFNγ coordinates the local overexpression of complement genes that occurs in several cell types.
Immune-Mediated Necrotizing Myopathy Pinal-Fernandez, Iago; Casal-Dominguez, Maria; Mammen, Andrew L.
Current rheumatology reports,
04/2018, Letnik:
20, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Purpose of Review
Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune myopathy characterized by relatively severe proximal weakness, myofiber necrosis with minimal inflammatory cell ...infiltrate on muscle biopsy, and infrequent extra-muscular involvement. Here, we will review the characteristics of patients with IMNM.
Recent Findings
Anti-signal recognition particle (SRP) and anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies are closely associated with IMNM and define unique subtypes of patients. Importantly, the new European Neuromuscular Centre criteria recognize anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM as three distinct subtypes of IMNM. Anti-SRP myopathy patients have more severe muscle involvement, have more common extra-muscular features, and may respond best to immunosuppressive regimens that include rituximab. In contrast, anti-HMGCR myopathy is often associated with statin exposure and intravenous immunoglobulin treatment may be an effective treatment, even as monotherapy. Both anti-SRP and anti-HMGCR myopathy tend to be most severe in younger patients. Furthermore, children with these forms of IMNM may present with dystrophy-like features which are potentially reversible with immunosuppressant treatment. IMNM patients with either autoantibody may experience fatty replacement of muscle soon after disease onset, suggesting that intense and early immunosuppressant therapy may provide the best chance to avoid long-term disability.
Summary
IMNM is composed of anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative IMNM. Both anti-SRP and anti-HMGCR myopathy can cause severe weakness, especially in younger patients. Anti-SRP myopathy patients tend to have the most severe weakness and most prevalent extra-muscular features. Autoantibody-negative IMNM remains poorly described.
•Long outcomes of a large sample of hospitalized CPVID-19 patients were analyzed.•A large proportion of hospitalized COVID-19 patients had a reduced functional status six months after ...hospitalization.•ICU patients referred a large decrease of their functional status compared with not ICU patients six months after hospitalization.•Female sex, age, length of hospital stay, mechanical ventilation, and ICU admission were associated with limitations in everyday life .
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