Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist.
To ...develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria.
An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti-histidyl-ARN-t- synthetase (Jo1), anti-threonine-ARN-t-synthetase (PL7), anti-alanine-ARN-t-synthetase (PL12), anti-complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti-polymyositis/systemic scleroderma (PMScl), anti-topoisomerase 1 (Scl70), and anti-signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies).
Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups.
Among 260 participants (163 62.7% women; mean age, 59.7 years; median age range, 61.5 years 48-71 years), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients 93.5%; 95% CI, 85.5%-97.8%; P < .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti-SRP or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 58.2%; 95% CI, 47.4%-68.5%; P < .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti-melanoma differentiation-associated protein 5 (MDA5), or anti-transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 82.7%; 95% CI, 69.7%-91.8%; P < .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 90.0%; 95% CI, 76.3%-97.2%; P < .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9).
These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.
Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic ...tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.
Resident cells, such as fibroblast-like synoviocytes (FLS), play a crucial role in rheumatoid arthritis (RA). They are implicated in the inflammatory response and play a key role in osteoarticular ...destruction. Moreover, RA FLS spread RA to unaffected joints. Pathogen-associated molecular patterns and damage-associated molecular patterns have been found to activate RA FLS by interacting with pattern recognition receptors, such as TLR. RA FLS express a large number of TLR, and TLR2 was demonstrated to be involved in RA inflammation. Because microRNA have emerged as important controllers of TLR expression and signaling, the aim of this study was to evaluate their potential involvement in the control of TLR2 expression by RA FLS. We first showed that Tlr2 expression is strongly upregulated in RA FLS in response to TLR2 ligands. Using a microRNA microarray analysis, we identified one miRNA in activated RA FLS, miR-19b, which was downregulated and predicted to target Tlr2 mRNA. Downregulation of miR-19b and miR-19a, which belongs to the same cluster, was confirmed by real-time quantitative PCR. Transfection of RA FLS with miR-19a/b mimics decreased TLR2 protein expression. In parallel, we found that both IL-6 and matrix metalloproteinase 3 secretion was significantly downregulated in activated FLS transfected with either mimic. Moreover, using a luciferase assay, we showed that miR-19a/b directly target Tlr2 mRNA. Taken together, our data point toward an important role for miR-19a/b in the regulation of IL-6 and matrix metalloproteinase 3 release by controlling TLR2 expression, as well as provide evidence that miR-19a/b can act as negative regulators of inflammation in humans.
Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms ...that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.
Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an ...increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.
Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available ...treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.
Background
Patients with lower extremity peripheral arterial disease (PAD) and sarcopenia are a population at risk requiring specific and targeted care. The aim of this review is to gather all ...relevant studies associating sarcopenia and PAD and to identify the underlying pathophysiological mechanisms as well as potential therapeutic strategies to improve skeletal muscle function.
Methods
A systematic review was carried out following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA).
Results
Data extraction allowed the evaluation of 140 publications; 87 met the inclusion criteria; of which 79 were included in the final review, reporting sufficient data for epidemiological and diagnostic criteria, mechanical analysis, and therapeutic approaches. Epidemiological analysis and diagnostic criteria were based on 18 studies following 2362 PAD patients 31.39% (SD 7.61) women, aged 72.42 (SD 2.84); sarcopenia was present in 34.63% (SD 12.86) of the patients. Mechanical and pathway analysis were based on five animal studies and 29 clinical reports, showing significantly altered muscle strength and function in 1352 PAD patients 26.49% (SD 17.32) women, aged 67.67 (SD 5.14) years; impaired muscle histology in 192 PAD patients (9.2% (SD 11.22) women), aged 64.3 (SD 0.99) years; +58.63% (SD 25.48) of oxidative stress in 69 PAD patients 16.96% (SD 8.10) women, aged 63.17 (SD 1.43) years; mitochondriopathy in 153 PAD patients 29.39% (SD 28.27) women, aged 63.50 (SD 1.83) years; +15.58% (SD 7.41) of inflammation in 900 PAD patients 40.77% (SD 3.71) women, aged 74.88 (SD 2.76) years; and altered signalling pathways in 51 PAD patients 34.45% (SD 32.23) women, aged 72.25 (SD 5.25) years. Therapeutic approaches analysis was based on seven animal studies and 21 clinical reports. In total, 884 patients followed an exercise therapy, and 18 received an angiogenesis treatment; 30.84% (SD 17.74) were women. Mean ages of patients studied were 66.85 (SD 3.96).
Conclusions
Sarcopenia and lower extremity PAD have musculoskeletal consequences that directly impair patients' quality of life and prognosis. Although PAD is primarily a vascular disease, all etiological factors of sarcopenia identified so far are present in PAD. Indeed, both sarcopenia and PAD are accompanied by oxidative stress, skeletal muscle mitochondrial impairments, inflammation, inhibition of specific pathways regulating muscle synthesis or protection (i.e. IGF‐1, RISK, and SAFE), and activation of molecules associated with muscle degradation. To date, besides revascularization, the best therapeutic strategy includes exercise, but approaches targeting the underlying mechanisms still deserve further studies.
To describe changes in the 2001–2014 mortality of 6 autoimmune systemic diseases (AISDs), namely Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies ...(IIM), Sjögren's Syndrome (SS), Mixed Connective Tissue Disease (MCTD) and ANCA-associated vasculitis (AAV) at the country-, continent-, and world-levels.
Mortality data were retrieved from the World Health Organization (WHO) mortality database for each disease, based on ICD-10 codes. We computed age-standardized mortality rate (ASMR) as the estimated number of deaths per million inhabitants and its 95% confidence interval (95%CI). The association between gender, geographical areas and disease-specific mortality was analyzed using multivariate Poisson regression. The 2001–2014 temporal trends were analyzed using Jointpoint software.
In 2014, the worldwide ASMR for SLE was 2.68 (95%CI: 2.62–2.75) deaths/millions inhabitants, 1.46 (1.42–1.51) for SSc, 0.47 (0.44–0.49) for IIM, 0.17 (0.15–0.18) for SS, 0.11 (0.10–0.13) for MCTD and 0.53 (0.50–0.56) for AAV, with ASMRs generally lower in Europe than in North America, Latin America and Asia. Between 2001 and 2014, the worldwide ASMR decreased significantly for SSc (−0.71%/year), IIM (−1.65%/year) and AAV (−1.01%/year; p < .001 for all) and increased for SS (+1.53%/year, p = .01). The worldwide ASMR of SLE decreased significantly between 2001 and 2003 (−6.37%, p < .05) before increasing slightly between 2004 and 2014 (+0.58%, p < .01).
We observed a strong heterogeneity of standardized mortality rates across all countries analyzed for 6 autoimmune diseases. Those results further highlight the impact of world-wide inequities and major gaps in access to care and strategies for diagnosis and management of rare diseases, a crucial finding for world-wide physicians, patient associations and policy makers.
•The age-standardized mortality rate (ASMR) of 6 auto-immune diseases was computed using the WHO mortality database.•The ASMR were generally lower in Europe than in North America, Latin America and Asia.•Between 2001 and 2014, there was a significant worldwide decrease of the ASMR of SSc, IIM & AAVs while it increased for SLE and Sjögren's
The post-COVID-19 condition, defined as COVID-19-related signs and symptoms lasting at least 2 months and persisting more than 3 months after infection, appears now as a public health issue in terms ...of frequency and quality of life alterations. Nevertheless, few data are available concerning long term evolution of malnutrition and sarcopenia, which deserve further attention.
Sarcopenia was investigated prospectively, together with weight evolution, at admission and at 3 and 6 months after hospital discharge in 139 COVID-19 patients, using the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria, associating both decreased muscle strength and muscle mass, assessed, respectively, with hand dynamometer and dual-energy X-ray absorptiometry.
Of the 139 patients, 22 presented with sarcopenia at 3 months; intensive care units (ICU) length of stay was the sole factor associated with sarcopenia after multivariate analysis. Although the entire group did not demonstrate significant weight change, weight decreased significantly in the sarcopenia group (Five and eight patients, showing, respectively, >5 or >10% weight decrease). Interestingly, at 6 months, 16 of the 22 patients recovered from sarcopenia and their weight returned toward baseline values.
Sarcopenia and malnutrition are frequently observed in patients hospitalized for COVID-19, even 3 months after infection occurrence, but can largely be reversed at 6 months after discharge. Enhanced patient care is needed in sarcopenic patients, particularly during long stays in an ICU.
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