COVID-19 and myositis - unique challenges for patients.

OBJECTIVE: The COVID-19 pandemic and the subsequent effects on healthcare systems is having a significant effect on the management of long-term autoimmune conditions. The aim of this study was to assess the problems faced by patients with idiopathic inflammatory myopathies (IIM). METHODS: An anonymized eSurvey was carried out with a focus on effects on disease control, continuity of medical care, drug procurance and prevalent fears in the patient population. RESULTS: Of the 608 participants (81.1% female, median (s.d.) age 57 (13.9) years), dermatomyositis was the most frequent subtype (247, 40.6%). Patients reported health-related problems attributable to the COVID-19 pandemic (n = 195, 32.1%); specifically 102 (52.3%) required increase in medicines, and 35 (18%) required hospitalization for disease-related complications. Over half (52.7%) of the surveyed patients were receiving glucocorticoids and/or had underlying cardiovascular risk factors (53.8%), placing them at higher risk for severe COVID-19. Almost one in four patients faced hurdles in procuring medicines. Physiotherapy, critical in the management of IIM, was disrupted in 214 (35.2%). One quarter (159, 26.1%) experienced difficulty in contacting their specialist, and 30 (4.9%) were unable to do so. Most (69.6%) were supportive of the increased use of remote consultations to maintain continuity of medical care during the pandemic. CONCLUSION: This large descriptive study suggests that the COVID-19 pandemic has incurred a detrimental effect on continuity of medical care for many patients with IIM. There is concern that delays and omissions in clinical care may potentially translate to poorer outcomes in the future.

Ventricular arrhythmia predicts poor outcome in polymyositis/dermatomyositis with myocardial involvement.

OBJECTIVE: Myocardial involvement (MCI) is known to increase morbidity and mortality in polymyositis (PM) and dermatomyositis (DM). This study aims to investigate whether complicating with ventricular arrhythmia (VA) predicts poor outcomes in patients with PM/DM-related myocardial involvement (PM/DM-MCI). METHODS: We reviewed all PM/DM-MCI patients admitted to Peking Union Medical College Hospital from October 1997 to April 2019. VA and the other possible risk factors for the composite endpoint, including death from any cause and rehospitalization for cardiac causes, were analyzed. RESULTS: A total of 75 PM/DM-MCI patients (44 PM and 31 DM) were enrolled, of which 27 (36%) met the composite endpoint during a median follow-up of 24 months. Independent prognostic factors for the composite endpoint include VA [HR 4.215, 95% CI (1.737, 10.230)], NT-proBNP > 3415 pg/ml [HR 2.606, 95% CI (1.203, 5.646)], interstitial lung disease [HR 2.688, 95% CI (1.209, 5.978)], and anti-cardiac remodelling therapy [HR 0.302, 95% CI (0.115, 0.792)]. The 3-year event-free survival rate of patients without VA was significantly higher than that of patients with VA (63.3% vs 40.7%, P = 0.034). Skin lesions [OR 0.163, 95% CI (0.051, 0.523)] and positive antimitochondrial antibody [OR 3.484, 95% CI (1.192, 10.183)] were independent predictors of VA. CONCLUSION: VA provides prognostic insights for PM/DM-MCI patients and predicts poor outcome. Polymyositis and positive antimitochondrial antibody are closely associated with the presence of VA in PM/DM-MCI.

Identification of a novel autoantigen eukaryotic initiation factor 3 associated with polymyositis.

OBJECTIVES: To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. METHODS: Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren's syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. RESULTS: IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. CONCLUSION: We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.

An exploratory study of contractile force production in muscle fibers from patients with inflammatory myopathies.

INTRODUCTION: The mechanism by which weakness develops in idiopathic inflammatory myopathies (IIMs) is still unclear. In this study we investigated the maximum force of single muscle fibers from patients with IIMs. METHODS: Permeabilized single muscle fibers from patients with IIMs and healthy controls were subjected to contractility measurements. Maximum force and specific force production (maximum force normalized to fiber size) and fiber type were determined for each isolated fiber. RESULTS: A total of 178 fibers were studied from five patients with IIMs and 95 fibers from four controls. Specific force production was significantly lower in the IIM group for all fiber types. DISCUSSION: The findings from this exploratory study suggest that weakness in IIMs may, in part, be caused by dysfunction of the contractile apparatus. These findings provide a basis for further studies into the mechanisms underlying weakness in IIMs.

Mitochondrial dysfunction and role of harakiri in the pathogenesis of myositis.

The etiology of myositis is unknown. Although attempts to identify viruses in myositis skeletal muscle have failed, several studies have identified the presence of a viral signature in myositis patients. Here we postulate that in individuals with susceptible genetic backgrounds, viral infection alters the epigenome to activate the pathological pathways leading to disease onset. To identify epigenetic changes, methylation profiling of Coxsackie B infected human myotubes and muscle biopsies from polymyositis (PM) and dermatomyositis (DM) patients were compared to changes in global transcript expression induced by in vitro Coxsackie B infection. Gene and protein expression analysis and live cell imaging were performed to examine the mechanisms. Analysis of methylation and gene expression changes identified that a mitochondria-localized activator of apoptosis - harakiri (HRK) - is upregulated in myositis skeletal muscle cells. Muscle cells with higher HRK expression have reduced mitochondrial potential and poor ability to repair from injury as compared to controls. In cells from myositis patient toll-like receptor 7 (TLR7) activates and sustains high HRK expression. Forced over expression of HRK in healthy muscle cells is sufficient to compromise their membrane repair ability. Endurance exercise that is associated with improved muscle and mitochondrial function in PM and DM patients decreased TLR7 and HRK expression identifying these as therapeutic targets. Increased HRK and TLR7 expression causes mitochondrial damage leading to poor myofiber repair, myofiber death and muscle weakness in myositis patients and exercise induced reduction of HRK and TLR7 expression in patients is associated with disease amelioration. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Polymyositis with mitochondrial pathology or atypical form of sporadic inclusion body myositis: case series and review of the literature.

Polymyositis with mitochondrial pathology (PM-Mito) is a rare form of idiopathic inflammatory myopathy with no definite diagnostic criteria and similarities to both PM and sporadic inclusion body myositis (s-IBM). The aim of this study is to address the dilemma of whether PM-Mito is a subtype of inflammatory myopathy or represents a disease falling into the spectrum of s-IBM. Herein, we report four female patients diagnosed with PM-Mito, highlighting their rather atypical clinical and histopathological characteristics that seem to indicate a diagnosis away from s-IBM. Muscle weakness was rather proximal and symmetrical and lacked the selective pattern observed in s-IBM. Patients had large-scale deletions in mtDNA, reflecting the mitochondrial component in the pathology of the disease. Conclusively, our study adds to the limited data in the literature on whether PM-Mito is a distinct form of myositis or represents a prodromal stage of s-IBM. Although the latter seems to be supported by a substantial body of evidence, there are, however, important differences, such as the different patterns of muscle weakness, and the good response to treatment observed in some patients. Larger-scale studies are certainly needed to clarify pathogenesis and clinical characteristics of PM-Mito patients, especially in therapeutic and prognostic terms.

Musculoskeletal Manifestations of Non-RA Connective Tissue Diseases: Scleroderma, Systemic Lupus Erythematosus, Still's Disease, Dermatomyositis/Polymyositis, Sjögren's Syndrome, and Mixed Connective Tissue Disease.

The most common systemic rheumatologic conditions are connective tissue diseases (including rheumatoid arthritis [RA]) followed by spondyloarthropathy. With the advent of biotherapies and imaging biomarkers, development in the imaging of RA and spondyloarthropathies has received substantial attention in the literature. This article details the various musculoskeletal imaging features of the other connective tissue diseases such as scleroderma and progressive systemic sclerosis, systemic lupus erythematosus, Still's disease, dermatomyositis and polymyositis, Sjögren's syndrome, and mixed connective tissue disease.

Red blood cell distribution width and neutrophil to lymphocyte ratio are correlated with disease activity of dermatomyositis and polymyositis.

BACKGROUND: Previous studies indicated that both red blood cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR) were useful indices in assessing the disease activity of autoimmune diseases. However, the evidence for the association between RDW, NLR and dermatomyositis (DM) and polymyositis (PM) is limited. The aim of this study is to investigate the association between the disease activity of PM/DM and both RDW and NLR. METHODS: Medical records of 114 PM/DM patients and 114 healthy controls were retrospectively reviewed, and their RDW, NLR and myositis disease activity assessment visual analogue scale (MYOACT) on admission were extracted. The correlations between RDW, NLR and MYOACT were analyzed using the Spearman approach and multivariable model. RESULTS: PM/DM patients had significantly higher RDW and NLR. Increased RDW in PM/DM patients was not completely attributed to decreased hemoglobin or therapeutic agents. Both RDW and NLR are independently and positively correlated MYOACT. CONCLUSION: Both RDW and NLR are useful indices in assessing the disease activity of PM/DM.

Connective tissue diseases, multimorbidity and the ageing lung.

Connective tissue diseases encompass a wide range of heterogeneous disorders characterised by immune-mediated chronic inflammation often leading to tissue damage, collagen deposition and possible loss of function of the target organ. Lung involvement is a common complication of connective tissue diseases. Depending on the underlying disease, various thoracic compartments can be involved but interstitial lung disease is a major contributor to morbidity and mortality. Interstitial lung disease, pulmonary hypertension or both are found most commonly in systemic sclerosis. In the elderly, the prevalence of connective tissue diseases continues to rise due to both longer life expectancy and more effective and better-tolerated treatments. In the geriatric population, connective tissue diseases are almost invariably accompanied by age-related comorbidities, and disease- and treatment-related complications, which contribute to the significant morbidity and mortality associated with these conditions, and complicate treatment decision-making. Connective tissue diseases in the elderly represent a growing concern for healthcare providers and an increasing burden of global health resources worldwide. A better understanding of the mechanisms involved in the regulation of the immune functions in the elderly and evidence-based guidelines specifically designed for this patient population are instrumental to improving the management of connective tissue diseases in elderly patients.

Risk of myocardial infarction and ischaemic stroke in adults with polymyositis and dermatomyositis: a general population-based study.

OBJECTIVE: Limited data are available on the risk of cardiovascular disease in DM and PM. The purpose of this study was to estimate the risk of incident myocardial infarction (MI) and ischaemic stroke in adults with incident PM/DM at the general population level. METHODS: We assembled a retrospective cohort of all adults with incident PM/DM in British Columbia, and we matched up to 10 adults randomly selected from the general population. We estimated the incidence rates (IRs) per 1000 person-years for MI and stroke. We calculated hazard ratios (HRs), adjusting for potential confounders. RESULTS: Among 774 new cases of inflammatory myopathies, 424 had PM (59% female, mean age 60 years) and 350 had DM (65% female, mean age 56 years). IRs for MI and stroke in PM were 22.52 and 10.15 events per 1000 person-years, respectively, vs 5.50 and 5.58 events in the comparison cohort, respectively. Fully adjusted HRs (95% CI) were 3.89 (95% CI: 2.28, 6.65) for MI and 1.76 (95% CI: 0.91, 3.40) for stroke. The age-, sex- and entry time-matched HRs for MI and stroke were highest in the first year after PM diagnosis (6.51, [95% CI: 3.15, 13.47] and 3.48 [95% CI: 1.26, 9.62], respectively). Similar trends were seen for DM. CONCLUSION: Our study demonstrates that PM and DM are both associated with an increased risk of MI but not ischaemic stroke. Our findings support increased vigilance in cardiovascular prevention, surveillance and risk modification in adults with PM and DM.

Immune Mediated Necrotizing Myopathy: a Cause of Isolated Myopathy of Neck Extensor Muscle.

Immune mediated necrotizing myopathy (IMNM) is a unique form of myositis that is characterized by distinct muscle biopsy features including abundant myofiber necrosis, degeneration, and regeneration with only minimal, if any, inflammation on muscle biopsy. IMNM is clinically similar to idiopathic inflammatory myopathy (IIM); hence, muscle biopsy is essential to diagnose IMNM. Herein we describe a case of neck extensor weakness due to necrotizing myopathy. Isolated weakness of the neck extensor muscles is uncommon in IIM and IMNM. This case describes the diagnostic work-up, treatments utilized, and 2 year follow-up course without involvement of other muscle groups and without progression of neck extensor muscle weakness. Advanced imaging using magnetic resonance imaging (MRI) facilitated the diagnosis by identifying the affected muscles and site for muscle biopsy.

ATOH8: a novel marker in human muscle fiber regeneration.

Regenerating muscle fibers emerge from quiescent satellite cells, which differentiate into mature multinuclear myofibers upon activation. It has recently been found that ATOH8, a bHLH transcription factor, is regulated during myogenic differentiation. In this study, expression and localization of ATOH8, the other well-described regeneration markers, vimentin, nestin and neonatal myosin, and the satellite cell marker Pax7 were analyzed on protein level in human myopathy samples by immunofluorescence studies. On mRNA level, expression levels of ATOH8 and vimentin were studied by quantitative real-time PCR. ATOH8 is expressed in activated satellite cells and proliferating myoblasts of human skeletal muscle tissue. Quantitative analyses of ATOH8+, Pax7+, vimentin+, nestin+ and neonatal myosin+ muscle fibers showed the highest amount of regenerating muscle fibers in inflammatory myopathies, followed by muscular dystrophy. The relative co-expression of ATOH8 with the above-mentioned markers did not vary among the disorders. These results show that the novel regeneration marker ATOH8 contributes to muscle cell differentiation in healthy and diseased human muscle tissue.

Activated IL-22 pathway occurs in the muscle tissues of patients with polymyositis or dermatomyositis and is correlated with disease activity.

OBJECTIVE: The aim of this study was to assess the expression of IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and p-STAT3 in muscle tissue from patients with PM and DM. METHODS: Levels of IL-22, IL-22R1, IL-22BP and STAT3 mRNA were quantified by RT-PCR. The expression of IL-22, IL-22R1, IL-22BP and p-STAT3 was also analysed using immunohistochemistry. RESULTS: Significant modulation of the IL-22 pathway was observed in inflammatory myopathic tissues. In particular, a significant overexpression of IL-22 at the protein but not the mRNA level was observed in PM/DM tissues and was correlated with myositis activity. IL-22R1 aberrant expression was also observed among infiltrating mononuclear cells and necrotic muscle cells. IL-22BP, which inhibits IL-22 signalling, was expressed only in some muscle fibres in PM/DM patients. CONCLUSION: Our findings indicate that the IL-22 pathway is activated in inflammatory myopathic tissues and may be involved in the induction of muscle inflammatory processes and muscle necrosis.

Pulmonary manifestations of polymyositis/dermatomyositis.

The idiopathic inflammatory myopathies are a group of connective tissue diseases marked by varying degrees of muscle inflammation and clinical involvement of multiple organs, most notably, the lung. Pulmonary manifestations consist primarily of interstitial lung disease (ILD), which is associated with significant morbidity and mortality in myositis patients. Several myositis-specific antibodies have been discovered, as well as antibodies targeting various aminoacyl-tRNA synthetase enzymes. These antibodies are associated with various clinical features and a risk for developing ILD, and their presence carries a prognostic value in myositis patients. Steroids remain the first-line treatment for myositis-associated ILD and the antisynthetase syndrome, though other traditional immunosuppressants have demonstrated efficacy in numerous studies. While a majority of patients experience either stabilization or improvement in lung imaging and function, fatal progression is still reported in a significant number of cases. Further research is needed to develop more effective and targeted therapies.

Exercise as an adjuvant treatment in persistent active polymyositis.

OBJECTIVES: A growing number of studies have suggested that exercise may promote therapeutic effects in patients with idiopathic inflammatory myopathy. This prospective case series study aimed to report on the effects of exercise in patients with persistent active myositis. METHODS: Three patients with persistent active polymyositis were submitted to a 12-week supervised exercise program comprising both aerobic and strength exercises. RESULTS: After the intervention, the patients presented improvements in selected parameters of muscle function and aerobic conditioning. In addition, an overall improvement was detected in the quality of life, as measured by both the 36-item Short-Form Health Survey and the Health Assessment Questionnaire questionnaires. Importantly, exercise did not increase serum levels of creatine kinase and aldolase. CONCLUSIONS: The findings herein suggest that a combined aerobic and strength training program may be tolerable and potentially effective in improving muscle function, aerobic conditioning, and quality of life in patients with persistent active polymyositis.

McArdle's disease: a clinical review and case report.

McArdle's Disease is a rare glycogen disease involving deficiency in muscle phosphorylase. This deficiency can lead to rhabdomyolysis and subsequently renal failure. McArdle's Disease has a similar presentation as several other metabolic myopathies with exercise-induced fatigue, myalgias, weakness or unexplained rhabdomyolysis. Suspicion should be raised in the presence of unexplained symptoms, and muscle biopsy can be done to confirm the diagnosis.

[Expression of Gphaq in peripheral blood T lymphocytes of patients with polymyositis and its correlation with disease activity].

OBJECTIVE: To analyze the expression of Gaq in peripheral blood T lymphocytes of the patients with polymyositis (PM) and its correlation with disease activity evaluated by the clinical markers [manual muscle test (MMT),myositis disease activity assessment (MDAA),creatine phosphokinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)]. METHODS: Blood samples were obtained from 30 patients with first onset PM and 30 healthy volunteers. Peripheral blood mononuclear cells (PBMCs) from these patients were collected and CD3+ T cells from PBMCs were sorted out with magnetic beans. The mRNA and protein expression levels of Galphaq in T cells were measured by RT-PCR and Western blot. Student's unpaired 2-tailed t-test was applied to identify Galphaq expression difference between PM patients and healthy controls. Pearson's correlation between Galphaq mRNA expression of PM and clinical evaluation markers MMT, MDAA, CK, ESR or CRP was determined. RESULTS: Compared to health control, PM patients had significantly lower expression levels of Galphaq protein and mRNA in peripheral blood CD3+ T cells (P<0. 001). Negative correlation was found between Galphaq mRNA level and MMT (r= -0. 704, P<0. 001), MDAA (r= -0. 793, P<0. 001) or CK (r= -0. 670, P<0. 001), and no correlation was found between Galphaq mRNA level and ESR or CRP. CONCLUSION: Galphaq expression in T cells of PM is lower than that in normal control and has negative correlation with PM disease activity.