Purpose of Review
The purpose of this review is to critically discuss the use of ultrasound in the evaluation of muscle disorders with a particular focus on the emerging use in inflammatory ...myopathies.
Recent Findings
In myopathies, pathologic muscle shows an increase in echogenicity. Muscle echogenicity can be assessed visually, semi-quantitatively, or quantitatively using grayscale analysis. The involvement of specific muscle groups and the pattern of increase in echogenicity can further point to specific diseases. In pediatric neuromuscular disorders, the value of muscle ultrasound for screening and diagnosis is well-established. It has also been found to be a responsive measure of disease change in muscular dystrophies. In chronic forms of myositis like inclusion body myositis, ultrasound is very suitable for detecting markedly increased echogenicity and atrophy in affected muscles. Acute cases of muscle edema show only a mild increase in echogenicity, which can also reverse with successful treatment.
Summary
Muscle ultrasound is an important imaging modality that is highly adaptable to study various muscle conditions. Although its diagnostic value for neuromuscular disorders is high, the evidence in myositis has only begun to accrue in earnest. Further systematic studies are needed, especially in its role for detecting muscle edema.
To evaluate the use of ultrasound coupled with machine learning (ML) and deep learning (DL) techniques for automated or semi-automated classification of myositis.
Eighty subjects comprised of 19 with ...inclusion body myositis (IBM), 14 with polymyositis (PM), 14 with dermatomyositis (DM), and 33 normal (N) subjects were included in this study, where 3214 muscle ultrasound images of 7 muscles (observed bilaterally) were acquired. We considered three problems of classification including (A) normal vs. affected (DM, PM, IBM); (B) normal vs. IBM patients; and (C) IBM vs. other types of myositis (DM or PM). We studied the use of an automated DL method using deep convolutional neural networks (DL-DCNNs) for diagnostic classification and compared it with a semi-automated conventional ML method based on random forests (ML-RF) and "engineered" features. We used the known clinical diagnosis as the gold standard for evaluating performance of muscle classification.
The performance of the DL-DCNN method resulted in accuracies ± standard deviation of 76.2% ± 3.1% for problem (A), 86.6% ± 2.4% for (B) and 74.8% ± 3.9% for (C), while the ML-RF method led to accuracies of 72.3% ± 3.3% for problem (A), 84.3% ± 2.3% for (B) and 68.9% ± 2.5% for (C).
This study demonstrates the application of machine learning methods for automatically or semi-automatically classifying inflammatory muscle disease using muscle ultrasound. Compared to the conventional random forest machine learning method used here, which has the drawback of requiring manual delineation of muscle/fat boundaries, DCNN-based classification by and large improved the accuracies in all classification problems while providing a fully automated approach to classification.
Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in ...multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.
We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.
We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.
As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
Objective
This open‐label 12‐week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment‐refractory active dermatomyositis (DM).
Methods
Tofacitinib in ...extended‐release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid‐sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety.
Results
At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin.
Conclusion
This is the first prospective, open‐label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan‐JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.
Objective
Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with ...autoantibodies recognizing the nuclear matrix protein NXP‐2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti–NXP‐2 autoantibodies.
Methods
There were 235 DM patients who underwent testing for anti–NXP‐2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti–NXP‐2‐positive subjects was compared with the number expected in the general population.
Results
Of the DM patients, 56 (23.8%) were anti–NXP‐2‐positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti–NXP‐2. In contrast, anti–NXP‐2‐positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti–NXP‐2‐positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti–NXP‐2‐negative patients. Five anti–NXP‐2‐positive subjects (9%) had cancer‐associated myositis, representing a 3.68‐fold increased risk (95% confidence interval 1.2–8.6) compared to the expected prevalence in the general population.
Conclusion
In DM, anti–NXP‐2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti–NXP‐2‐positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.
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.
Abstract Objective In the context of clinical evaluations performed on our prospective myositis cohort, we noted a striking association of severe cardiac disease in myositis patients with ...anti-mitochondrial antibodies. We sought to review all cases of anti-mitochondrial antibody (AMA) associated myositis in our cohort to describe the clinical features of this disease subset. Methods We identified 7 patients with confirmed anti-mitochondrial antibodies who presented as an inflammatory myopathy. A retrospective chart review was completed to assess their clinical presentation, laboratory, imaging, electrophysiologic and histopathologic features. Results One patient presented with dermatomyositis, and six were classified as polymyositis using Bohan and Peter criteria 1,2. In all but one patient, a chronic course of muscle involvement was appreciated with an average of 6.5 years of weakness prior to presentation. Muscle atrophy was often noted, as well as atypical findings of scapular winging in 2 of the patients. Muscle biopsies were consistent with immune-mediated necrotizing myopathy in four patients, dermatomyositis in one, polymyositis in one and non-specific or granulomatous myositis in one patient. Cardiac involvement (including myocarditis, atrial and ventricular arrhythmias and cardiomyopathy), was seen in 5 out of 7 (71%) of the patients, and usually preceded the muscle involvement. Coexisting autoimmune conditions were seen in 3/7of the patients and included primary biliary cirrhosis, autoimmune hepatitis, psoriasis, and Hashimoto′s thyroiditis. Conclusions Anti-mitochondrial antibodies identify a distinct inflammatory myopathy phenotype that is frequently associated with chronic skeletal muscle disease and severe cardiac involvement. Early recognition of this rare entity as an immune-mediated process is important due to implications for treatment. We propose that anti-mitochondrial antibody status should be determined in patients with a compatible clinical picture.
Dermatomyositis (DM) and alopecia areata are two diseases characterised by aberrant interferon signalling. While patchy alopecia of the scalp is a known feature of DM, alopecia universalis, which ...involves hair loss over the entire body, has rarely been reported in conjunction with DM. Herein, we report the case of a 30-year-old female with DM who developed refractory cutaneous disease and alopecia universalis that were successfully treated with tofacitinib. This could suggest that concomitant severe alopecia and refractory cutaneous DM may reflect a strong baseline interferon gene signature that may predict responsiveness to janus kinase inhibitors.
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