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Background: Antibodies against Ku have been described in patients with various connective tissue diseases. The objective of this study was to describe the clinical, functional, and imaging characteristics of interstitial lung disease in patients with anti-Ku antibodies. Methods : This single-center, retrospective observational study was conducted at a tertiary referral institution. Patients with positive anti-Ku antibodies and interstitial lung disease identified between 2007 and 2022 were included. Clinical, immunological, functional, and imaging data were systematically reviewed. Results : Nineteen patients (ten females) with a mean age of 59 ± 12.6 years were included. The most frequent associated diagnosis was systemic sclerosis (42%), followed by rheumatoid arthritis (26%), Sjögren syndrome, undifferentiated connective tissue disease, and overlap between systemic sclerosis and idiopathic inflammatory myopathy (scleromyositis). Imaging revealed frequent septal and intralobular reticulations and ground-glass opacities, with nonspecific interstitial pneumonia as the predominant pattern (53%). The mean forced vital capacity was 82% ± 26 of the predicted value, and the mean diffusing capacity for carbon monoxide was 55% ± 21. Over the first year of follow-up, the mean annual forced vital capacity decline was 140 mL/year (range: 0-1610 mL/year). The overall survival rate was 82% at 5 years and 67% at 10 years. Conclusions : Most patients with interstitial lung disease and anti-Ku antibodies presented with dyspnea, a mild-to-moderate restrictive ventilatory pattern, and reduced diffusing capacity for carbon monoxide. The CT pattern was heterogeneous but was consistent with nonspecific interstitial pneumonia in half of the patients.

A medication error is an inadvertent failure in the drug therapy process that can cause serious harm to patients by increasing morbidity and mortality and are associated with significant economic costs to the healthcare system. Medication reconciliation is the most cost-effective intervention and can result in a 66% reduction in medication errors. To improve patient safety, we developed a machine learning-based tool that prioritizes patients at risk of medication errors upon admission to the hospital to ensure that they undergo medication reconciliation by clinical pharmacists. The data were collected from the electronic health records of patients admitted to Reims University Hospital who underwent medication reconciliation between 2017 and 2023. The data from 7200 patients were used to train four machine learning-based models based on 52 variables in the development dataset. These models were used to prioritize admitted patients according to their likelihood of being exposed to a medication error. Our models, particularly the voting classifier model, demonstrated good performance (a recall of 0.75, precision of 0.65, F1 score of 0.70, AUROC of 0.74 and AUCPR of 0.75). In a retrospective evaluation simulating real-life use, the voting classifier model successfully identified 45% of the total patients selected who were found to have at least one unintended discrepancy compared to 21% when using the existing tool. The positive experimental results of this tool showed a superior improvement of 113% over the existing tool by targeting patients at risk of medication errors upon admission to Reims University Hospital., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The Institut d’Intelligence Artificielle en Santé (IIAS) Research Ethics Committee has confirmed. We confirmed that all experiments in this study were performed in accordance with the relevant guidelines and regulations. Informed consent: The informed consent was waived by the IIAS research., (© 2024. The Author(s).)

Idiopathic inflammatory myopathies (IIM) are rare, acquired muscle diseases; their diagnosis of is based on clinical, serological, and histological criteria. MHC-I-positive immunostaining, although non-specific, is used as a marker for IIM diagnosis; however, the significance of major histocompatibility complex (MHC)-II immunostaining in IIM remains debated. We investigated patterns of MHC-II immunostaining in myofibers and capillaries in muscle biopsies from 103 patients with dermatomyositis ([DM], n = 31), inclusion body myositis ([IBM], n = 24), anti-synthetase syndrome ([ASyS], n = 10), immune-mediated necrotizing myopathy ([IMNM], n = 18), or overlap myositis ([OM], n = 20). MHC-II immunostaining of myofibers was abnormal in 63/103 of patients (61%) but the patterns differed according to the IIM subgroup. They were diffuse in IBM (96%), negative in IMNM (83%), perifascicular in ASyS (70%), negative (61%) or perifascicular (32%) in DM, and either clustered (40%), perifascicular (30%), or diffuse heterogeneous (15%) in OM. Capillary MHC-II immunostaining also identified quantitative (capillary dropout, n = 47/88, 53%) and qualitative abnormalities, that is, architectural abnormalities, including dilated and leaky capillaries, (n = 79/98, 81%) in all IIM subgroups. Thus, MHC-II myofiber expression patterns allow distinguishing among IIM subgroups. We suggest the addition of MHC-II immunostaining to routine histological panels for IIM diagnosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Among the idiopathic inflammatory myopathies, patients harbouring an Antisynthetase syndrome exhibit a unique clinical picture, with characteristic signs such as myositis, interstitial lung disease, arthritis, rash, and/or fever. Characteristic morphological features on skeletal muscle biopsies differentiate Antisynthetase syndrome from other forms of myositis. Autoantibodies typically recognizing one of the members of the aminoacyl-tRNA synthetase family of proteins can be detected in the serum of such patients, with anti-Jo1 being most frequent. Until now, an international consensus definition of the Antisynthetase syndrome is lacking, hence this workshop has undertaken the task to inform about the clinical, morphological and autoantibody profiles of Antisynthetase syndrome. The authors also expand their aims by giving management and therapeutic strategies, and finally provide precise classification criteria for Antisynthetase syndrome., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024.)

Myotonic dystrophy type I (DM1) is a genetic disease characterized by a multisystemic RNA metabolism dysregulation and splicing toxicity. Numerous signaling pathways are deregulated, and especially AMPK, a key sensor and regulator of cellular metabolism. To restore AMPK signaling activity in DM1 muscle tissue and cells could improve mitochondrial biogenesis and dynamics, mitophagy and oxidative stress, energy production and, in fine, skeletal muscle tissue homeostasis., (© 2024 médecine/sciences – Inserm.)

Granulomatous myositis is a clinical-pathological entity, which has been rarely reported, mostly described in sarcoidosis. Currently, no clear and simple prognostic factor has been identified to predict granulomatous myositis evolution. The clinical, anatomopathological, imaging, and biological characteristics of 26 patients with granulomatous myositis were retrospectively collected to describe clinical presentation and outcomes of this condition. Twenty-six patients with granulomatous myositis were included (14 males) with a median age of symptom onset of 65 years. 54 % of patients presented a severe form of the disease defined as a Rankin score ≥2 at last follow-up visit or a progressive form of the disease (no improvement under treatment). Etiology were sarcoidosis (n = 14), inclusion body myositis (n = 4), autoimmune disease (n = 1), hematological malignancy (n = 1), and idiopathic (n = 6). Distal deficit and amyotrophy were more frequent among those with a severe disease. Corticosteroids led to improvement in 75 % of cases, but 66 % of responders relapsed. Methotrexate appeared as a promising second line therapy with clinical improvement in 50 % of patients, and no relapse in responders. Granulomatous myositis is often a severe and difficult-to-treat disease in which patients frequently progress towards severe disability. The presence of muscle atrophy and distal weakness appears to be frequently associated with a severe form of the disease., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Myositis with anti-Ku-autoantibodies is a rare inflammatory myopathy associated with various connective tissue diseases. Histopathological studies have identified inflammatory and necrotizing aspects, but a precise morphological analysis and pathomechanistic disease model are lacking. We therefore aimed to carry out an in-depth morpho-molecular analysis to uncover possible pathomechanisms. Muscle biopsy specimens from 26 patients with anti-Ku-antibodies and unequivocal myositis were analyzed by immunohistochemistry, immunofluorescence, transcriptomics, and proteomics and compared to biopsy specimens of non-disease controls, immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Clinical findings and laboratory parameters were evaluated retrospectively and correlated with morphological and molecular features. Patients were mainly female (92%) with a median age of 56.5 years. Isolated myositis and overlap with systemic sclerosis were reported in 31%, respectively. Isolated myositis presented with higher creatine kinase levels and cardiac involvement (83%), whereas systemic sclerosis-overlap patients often had interstitial lung disease (57%). Histopathology showed a wide spectrum from mild to pronounced myositis with diffuse sarcolemmal MHC-class I (100%) and -II (69%) immunoreactivity, myofiber necrosis (88%), endomysial inflammation (85%), thickened capillaries (84%), and vacuoles (60%). Conspicuous sarcoplasmic protein aggregates were p62, BAG3, myotilin, or immunoproteasomal beta5i-positive. Proteomic and transcriptomic analysis identified prominent up-regulation of autophagy, proteasome, and hnRNP-related cell stress. To conclude, Ku + myositis is morphologically characterized by myofiber necrosis, MHC-class I and II positivity, variable endomysial inflammation, and distinct protein aggregation varying from IBM and IMNM, and it can be placed in the spectrum of scleromyositis and overlap myositis. It features characteristic sarcoplasmic protein aggregation on an acquired basis being functionally associated with altered chaperone, proteasome, and autophagy function indicating that Ku + myositis exhibit aspects of an acquired inflammatory protein-aggregate myopathy., (© 2024. The Author(s).)

Objectives: To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM)., Methods: Patients were retrospectively recruited from 13 French centers and included if they met the ACR/EULAR criteria for SjD and for IM. They were categorized as SjD-IBM if sub-criteria for IBM were met, or as SjD-other IM if not., Results: SjD-IBM patients (n = 22) were mostly females (86%), with a median [Q1; Q3] age of 54 [38.5; 64] years at SjD diagnosis, and 62 [46.5; 70] years at first IBM symptoms. Although most patients displayed glandular and immunological abnormalities, additional extra-glandular manifestations were uncommon, resulting in moderate disease activity at SjD diagnosis (ESSDAI 5.5 [1; 7.8]). Classic IBM features were frequent, such as progressive symptom onset (59%), asymmetrical (27%) and distal (32%) involvements, dysphagia (41%), low CPK (386.5 [221.8; 670.5] UI/l) and CRP (3.0 [3; 8.5] mg/l) levels. Immunosuppressants were reported as efficient in 55% of cases.Compared with SjD-IBM patients, SjD patients with other IM (n = 50) were significantly younger, displayed more frequent additional extra-glandular disease, higher ESSDAI score (11 [3; 30]), shorter delay between SjD diagnosis and myositis onset (0 [-0.5; 26]), more frequent CPK values over 1000 UI/l (36%), and less frequent classic IBM features., Conclusion: IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values, and shorter delay after SjD diagnosis plead against IBM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Inaugural axial muscle involvement, defined as dropped head syndrome (DHS) and/or camptocormia (CC), is poorly described in inflammatory myopathies (IM). This study aimed to further characterize IM patients with inaugural DHS/CC, their outcome and care management., Methods: This retrospective study included IM patients diagnosed between 2000 and 2021. The main inclusion criterion was IM revealed by axial muscle deficit (DHS/CC)., Results: Twenty-seven patients were included; median (IQR) age at first symptoms was 66.0 years (55.5-75.0); 21 were female (77.8%). There were nine IBM, 33.3%, nine overlap myositis (OM, 33.3%), five DM, 18.5%, two immune checkpoint inhibitor-related myositis (7.4%), one focal myositis (3.7%) and one myositis with anti-Hu antibodies (3.7%). Age at first symptoms was ≤70 years in 16 patients (59.3%), including all DM patients and 8/9 OM patients (88.9%). In this group, partial remission of the disease was obtained in 9/16 (56.3%) and complete remission in 1/16 patients (6.3%); regression of DHS/CC was achieved in 3/16 patients (18.8%). Conversely, in the group of 11 patients aged >70 years at first symptoms, there were eight IBM (72.7%). Partial remission was obtained in 5/11 patients (45.5%), the disease was stable in 6/11 patients (54.5%); no complete remission was obtained nor regression of DHS/CC., Conclusion: The analysis of IM patients with inaugural DHS/CC delineates two groups of patients according to the age at first symptoms in terms of clinical and outcome specificities, and proposes an adapted diagnostic and care management approach to prevent long-term complications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: This study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies., Methods: Among a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up., Results: Among the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21-22], p<0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61-14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67-60], p<0.0001) were the three factors independently associated with poor outcomes., Discussion: This new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CB declared a shared parent affiliation with the author CC to the handling editor at the time of review., (Copyright © 2024 de Boysson, Cuchet, Cassius, Cuchet, Agard, Audemard-Verger, Marchand-Adam, Cohen-Sors, Gallay, Graveleau, Lesort, Ly, Meyer, Monseau, Néel, Bonnotte, Pérard, Schleinitz, Mariotte, Le Mauff, Bourdenet, Masmoudi, Deshayes, Dumont, Dompmartin, Kottler and Aouba.)

Objective: Among specific autoantibodies in DM, the anti-small ubiquitin-like modifier activating enzyme (SAE) antibody is rare. We aim to describe the clinical characteristics, cancer prevalence, and muscle pathology of anti-SAE-positive DM., Methods: Patients with a diagnosis of DM and sera positive for the anti-SAE antibody were recruited from 19 centres in this retrospective observational study. The available muscular biopsies were reviewed. We conducted a comparison with anti-SAE-negative DM and a review of the literature., Results: Of the patients in the study (n = 49), 84% were women. Skin involvement was typical in 96% of patients, with 10% having calcinosis, 18% ulceration and 12% necrosis; 35% presented with a widespread skin rash. Muscular disease affected 84% of patients, with mild weakness [Medical Research Council (MRC) scale 4 (3, 5)], although 39% of patients had dysphagia. Muscular biopsies showed typical DM lesions. Interstitial lung disease was found in 21% of patients, mainly with organizing pneumonia pattern, and 26% of patients showed dyspnoea. Cancer-associated myositis was diagnosed in 16% of patients and was responsible for the majority of deaths, its prevalence being five times that of the general population. IVIG therapy was administered to 51% of the patients during the course of the disease. Comparison with anti-SAE-negative DM (n = 85) showed less and milder muscle weakness (P = 0.02 and P = 0.006, respectively), lower creatinine kinase levels (P < 0.0001) and less dyspnoea (P = 0.003)., Conclusion: Anti-SAE positive DM is a rare subgroup associated with typical skin features but a potentially diffuse rash, a mild myopathy. Interstitial lung disease defines an organizing pneumonia pattern. Cancer associated DM prevalence is five times that of the general population., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04637672., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Polyarthritis is commonly reported in idiopathic inflammatory myositis patients, but few studies have focused on the overlap of myositis with rheumatoid arthritis which is a difficult diagnosis in the absence of well-defined diagnostic criteria. The primary objective of this scoping review was to map the field of research to explore the potential diagnoses in patients presenting with both myositis and polyarthritis., Methods: Two electronic databases (MEDLINE/PubMed® and Web of Science®) were systematically searched using the terms (myositis OR 'inflammatory idiopathic myopathies') AND (polyarthritis OR 'rheumatoid arthritis') without any publication date limit., Results: Among individual records, 280 reports met inclusion criteria after full-text review. There was heterogeneity in the definition of overlap myositis as well as the characteristics of rheumatoid arthritis. In many studies, key data were lacking; rheumatoid factor status was reported in 56.8% (n=151), anti-citrullinated proteins antibodies status in 18.8% (n=50), and presence or absence of bone erosions in 45.1% (n=120) of the studies. Thirteen different diagnoses were found to associate myositis with polyarthritis: antisynthetase syndrome (29.6%, n=83), overlap myositis with rheumatoid arthritis (16.1%, n=45), drug-induced myositis (20.0%, n=56), rheumatoid myositis (7.5%, n=21), inclusion body myositis (1.8%, n=5), overlap with connective tissue disease (20.0%, n=56), and others (5.0%, n=14)., Conclusion: The spectrum of joint and muscle inflammatory diseases encompasses many diagnoses including primitive and secondary myositis associated with RA or arthritis mimicking RA. This review highlights the need for a consensual definition of OM with RA to better individualise this entity from the numerous differential diagnoses., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge., Methods: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry., Results: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer., Discussion: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients., Competing Interests: Declaration of Competing Interest Dr. Tard reports personal fees and non-financial support from Sanofi-Genzyme. The other authors declare no conflict of interest. Dr. Salort-Campana has received from Sanofi Genzyme travel grants and honoraria for teaching courses, lectures in the last five years and has also received honoraria from Amicus for her participation to the Amicus Advisory Board meetings., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Idiopathic inflammatory myopathies are mainly defined by inflammatory infiltrates within the muscle (lymphocytes and macrophages). Eosinophil muscle infiltration has been described in idiopathic eosinophilic myositis (IEM) and rarely in EF. This study aimed to further delineate the nosological frame of idiopathic eosinophil muscle infiltration through the exhaustive analysis of IEM and EF patients., Methods: This multicentre retrospective case series included IEM patients diagnosed between 2000 and 2022. IEM inclusion criteria were eosinophilic muscle infiltration with myositis pathological features, after the exclusion of differential diagnoses. An additional group of EF patients diagnosed between 2016 and 2022 was constituted. Inclusion criteria were an EF diagnosis and fascia thickening with inflammatory infiltrate., Results: A total of 20 IEM cases and 10 EF cases were included. The median (interquartile range) age at diagnosis was 65 (49-70) years; there were 18 males. Data analysis delineated four subgroups: focal EM (FEM, n = 3), diffuse EM (DEM, n = 6), eosinophilic myofasciitis (EMF, n = 11) and EF (n = 10). FEM represented a limited and benign form of myositis. DEM cases presented objective muscle impairment with eosinophilic muscle infiltration. EMF patients presented subjective muscle impairment (myalgia, 55%), fasciitis (on histology and/or imaging), eosinophilic muscle infiltration and frequent hypereosinophilia (55%). EF patients presented myalgia (50%), muscle lesions on histology with fascia-restricted inflammatory infiltrates with (60%) or without (40%) eosinophils., Conclusions: The analysis of IEM and EF patient characteristics delineates four subgroups (FEM, DEM, EMF and EF) in terms of clinical, laboratory, imaging, pathological and outcome specificities, and proposes an adapted diagnostic and care management approach., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aims: This study aimed to report the association of focal myositis (FM) and Behçet's disease (BD) and to analyse the main characteristics of such an association., Methods: This is a retrospective multicentre study of patients with BD and FM (BD + FM+ group) and those without FM (BD - FM+ group). Clinical, laboratory, radiological, pathological, treatment and outcome data were analysed., Results: The BD + FM+ group included 10 patients; the median [interquartile range] age at BD diagnosis was 25 [16-35] years, and at FM diagnosis, it was 30 [26-42] years. The diagnosis of BD preceded FM in the majority of cases (n = 8/10). FM occurrence was associated with BD flare-ups in three cases. The creatine kinase levels remained normal or slightly increased. Histological analyses identified relatively preserved muscle tissue, associated with vasculitis (n = 5/6). All patients required treatment; most patients relapsed (n = 9/10). The BD - FM+ group included 35 patients. A comparison of the groups identified a trend towards a younger median age at diagnosis of FM among those with BD (p = 0.063) and more frequent focal muscle swelling in the BD + FM+ group (p = 0.029). The pathological analysis identified significantly less frequent muscle alterations in the BD + FM+ group (muscle fibre size heterogeneity, p = 0.021; necrosis, p = 0.007; and fibrosis, p = 0.027). BD + FM+ patients had a higher frequency of relapse (p = 0.003) and systematic treatment (p = 0.042)., Conclusions: FM occurring during BD appears to be part of the systemic vasculitis process and presents as a vasculitis-associated focal myopathy with a specific clinico-histological pattern. Patients with this association require long-term follow-up and adapted management. This case series also highlights the need for research on BD diagnostic criteria in cases of FM., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Objective: Dermatomyositis associated with anti-MDA5 autoantibodies (DM-MDA5+) is a rare autoimmune disease usually characterized by skin involvement, often-severe lung involvement, and general features. Several reports of infections have been described, sometimes early after the introduction of immunosuppressive therapy. We studied the infection risk in a DM-MDA5+ population. Methods: A retrospective cohort study comparing the number and type of infections during the follow-up of 19 patients with DM-MDA5+ and 37 patients with another type of inflammatory myopathy was analyzed. Patients in both groups were matched on initial immunosuppressive therapy. We described and compared significant infectious complications (SIC) in each group. Results: Patients DM-MDA5+ had more SIC: 27 events in the DM-MDA5+ group versus 6 in the controls (HR 7.08, 95% CI 2.50−20.04, p < 0.0001). The number of SIC per patient was higher in DM-MDA5+ (1.4 ± 1.57 vs. 0.16 ± 0.44, p < 0.001). These were mainly lung (n = 13, 48%) and skin infections (n = 6, 22%), more often infections of an undetermined infectious agent (n = 11, 41%) or of bacterial origin (n = 9, 33%). A few cases of opportunistic infections were reported. The median duration of follow-up without SIC event in the DM-MDA5+ cohort was 3.5 months. Conclusion: Patients with DM-MDA5+ have an increased infection risk compared to others inflammatory myopathies irrespective of immunosuppressive therapy exposure. These results highlight the importance of monitoring for infection during patient follow-up.

Background: Rapidly progressive interstitial lung disease (RP-ILD) is a frequent and severe manifestation of anti-MDA5 dermatomyositis (MDA5-DM) associated with poor outcome. The optimal treatment regimen for MDA5-DM RP-ILD is yet to be determined. Specifically, the value of adding plasma exchange (PLEX) to corticosteroids and immunosuppressants remains unclear. We aimed to evaluate the effect of PLEX on the outcome of patients with MDA5-DM RP-ILD., Methods: This French nationwide multicentre retrospective study included all MDA5-DM RP-ILD patients from 2012 to 2021 admitted to 18 centres. The primary endpoint was one-year transplant-free survival., Results: 51 patients with MDA5-DM RP-ILD (female 67%; mean age at disease onset: 51 ± 11.6 years) were included. Thirty-two (63%) patients required mechanical ventilation and twenty-five (49%) received PLEX. One-year mortality or lung transplant occurred in 63% cases after a median follow-up of 77 [38-264] days. The Cox proportional hazards multivariable model only retained mechanical ventilation but not PLEX (p = 0.7) as independent predictor of the primary endpoint. One-year transplant-free survival rates in PLEX + vs. PLEX-were 20% vs. 54% (p = 0.01), respectively. The Kaplan-Meier estimated probabilities of one-year transplant-free survival was statistically higher in PLEX-compared to PLEX + patients (p = 0.05). PLEX + compared to PLEX-patients more frequently received mechanical ventilation and immunosuppressants suggesting PLEX + patients had a more severe disease., Conclusion: MDA5-DM RP-ILD is associated with poor rate of one-year transplant-free survival. The use of PLEX was not associated with a better outcome albeit they were mainly given to more severe patients. While our study reports the largest series of MDA5-DM RP-ILD given PLEX, these results needs to be interpreted with caution owing the numerous selection, indication and interpretation bias. Further studies are needed to evaluate their efficacy in this setting., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Anti-synthetase syndrome (ASyS)-associated myositis is a major subgroup of the idiopathic inflammatory myopathies (IIM) and is characterized by disease chronicity with musculoskeletal, dermatological and pulmonary manifestations. One of eight autoantibodies against the aminoacyl-transferase RNA synthetases (ARS) is detectable in the serum of affected patients. However, disease-specific therapeutic approaches have not yet been established.To obtain a deeper understanding of the underlying pathogenesis and to identify putative therapeutic targets, we comparatively investigated the most common forms of ASyS associated with anti-PL-7, anti-PL-12 and anti-Jo-1. Our cohort consisted of 80 ASyS patients as well as healthy controls (n = 40), diseased controls (n = 40) and non-diseased controls (n = 20). We detected a reduced extent of necrosis and regeneration in muscle biopsies from PL-12 + patients compared to Jo-1 + patients, while PL-7 + patients had higher capillary dropout in biopsies of skeletal muscle. Aside from these subtle alterations, no significant differences between ASyS subgroups were observed. Interestingly, a tissue-specific subpopulation of CD138 + plasma cells and CXCL12 + /CXCL13 + CD20 + B cells common to ASyS myositis were identified. These cells were localized in the endomysium associated with alkaline phosphatase + activated mesenchymal fibroblasts and CD68 + MHC-II + CD169 + macrophages. An MHC-I + and MHC-II + MxA negative type II interferon-driven milieu of myofiber activation, topographically restricted to the perifascicular area and the adjacent perimysium, as well as perimysial clusters of T follicular helper cells defined an extra-medullary immunological niche for plasma cells and activated B cells. Consistent with this, proteomic analyses of muscle tissues from ASyS patients demonstrated alterations in antigen processing and presentation. In-depth immunological analyses of peripheral blood supported a B-cell/plasma-cell-driven pathology with a shift towards immature B cells, an increase of B-cell-related cytokines and chemokines, and activation of the complement system. We hypothesize that a B-cell-driven pathology with the presence and persistence of a specific subtype of plasma cells in the skeletal muscle is crucially involved in the self-perpetuating chronicity of ASyS myositis. This work provides the conceptual framework for the application of plasma-cell-targeting therapies in ASyS myositis., (© 2022. The Author(s).)

Background and Objectives: The idiopathic inflammatory myopathy dermatomyositis is an acquired disease that involves muscle, lung, and skin impairments. Patients with dermatomyositis show a wide range of severity of proximal skeletal muscle weakness, associated with inflammatory infiltrates, vasculitis, capillary dropout, and perifascicular myofiber atrophy. Muscles of patients with dermatomyositis show signs of muscle regeneration. Because muscle stem cells (MuSCs) are responsible for myofiber repair, we wondered whether the proliferative properties of MuSCs are altered in dermatomyositis muscle. We investigated the role of type I interferon (IFN-I) in this process because dermatomyositis is associated with sustained inflammation with high IFN-I levels., Methods: MuSCs isolated from normal muscles and those from adult and juvenile patients with dermatomyositis were grown in culture and analyzed in vitro for their proliferating properties, myogenic capacities, and senescence. Gain- and loss-of-function experiments were performed to assess the role of IFN-I signaling in the proliferative capacities of MuSCs., Results: MuSCs derived from 8 adult patients with dermatomyositis (DM-MuSCs) (5 severe form and 3 mild form, established from histologic evaluation), from 3 patients with juvenile dermatomyositis, and from normal muscle were used to analyze their myogenesis in vitro. DM-MuSCs exhibited strongly reduced proliferating capacities as compared with healthy MuSCs (-31% to -43% for mild and severe dermatomyositis, respectively), leading to poor myotube formation (-36% to -71%). DM-MuSCs were enriched in senescent, β-galactosidase-positive cells, partly explaining the proliferation defect. Gain- and loss-of-function experiments were performed to assess the role of IFN-I on the proliferative capacity of MuSCs. High concentrations of IFN-I decreased the proliferation of healthy MuSCs. Similarly, conditioned medium from DM-MuSCs decreased the proliferation of healthy MuSCs (-15% to -22%), suggesting the delivery of an autocrine effector. Pharmacologic blockade of IFN signaling (using ruxolitinib or anti-IFN receptor antibodies) in DM-MuSCs rescued their proliferation up to the control values., Discussion: These results show that autocrine IFN-I signaling prevents MuSC expansion, leading to muscle repair deficit. This process may explain the persistent muscle weakness observed in patients with severe dermatomyositis., (© 2022 American Academy of Neurology.)

Eosinophilic myositis belong to the idiopathic inflammatory myopathies and are defined by an inflammatory infiltrate composed of eosinophils within the muscle. To date, no consensus exists for diagnosis and care of such patients. The aim of this review was to describe clinical and histological presentation, treatment, and outcome of eosinophilic myositis based on a systematic review of all published histologically proven cases of eosinophilic myositis. A total of 453 records were identified in MEDLINE until November 2020. A total of 69 published cases were identified. The analysis of these allowed the distinction of the 3 previously described pathological subtypes: focal eosinophilic myositis (n = 17); diffuse eosinophilic myositis (n = 36); and eosinophilic perimyositis (n = 16). We propose a simple algorithm for diagnosis and treatment strategy for the care of patient with muscular symptoms and blood eosinophilia. This work also highlights eosinophilic myositis pathogenesis and the need for careful investigations in order to rule out differential diagnoses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Abstract: Patients with systemic rheumatic disease (SRD) share the risks of multi-organ flare-up, cardiovascular diseases, and immunosuppression. Such situations can lead to an acute critical illness. The present study describes the clinical features of SRD patients admitted to the intensive care unit (ICU) and their short- and long- term mortality.We performed a multicentre retrospective study in 10 French ICU in Lyon, France. Inclusion criteria were SRD diagnosis and admission for an acute organ failure. The primary endpoint was ICU mortality.A total of 271 patients were included. SRD included systemic lupus erythematosus (23.2% of included patients), vasculitis (10.7%), systemic sclerosis (10.7%), idiopathic inflammatory myopathy (6.3%), and other connective tissue disorders (rheumatoid arthritis, Sjögren and Sharp syndromes; 50.9%). Initial organ failure(s) were shock (43.5% of included patients), acute kidney injury (30.5%), and acute respiratory failure (23.2%). The cause(s) of ICU admission included sepsis (61.6%), cardiovascular events (33.9%), SRD-flare up (32.8%), and decompensations related to comorbidities (28%). The ICU mortality reached 14.3%. The factors associated with ICU mortality were chronic cardiac failure, invasive ventilation and admission in ICU for another reason than sepsis or SRD flare-up. The median follow-up after ICU discharge was 33.6 months. During follow-up, 109 patients died. The factors associated with long-term mortality included age, Charlson comorbidity index, and ICU admission for sepsis or SRD flare-up.The ICU mortality of patients with SRD was low. Sepsis was the first cause of admission. Cardiovascular events and comorbidities negatively impacted ICU mortality. Admission for sepsis or SRD flare-up exerted a negative effect on the long-term outcome., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To assess the effectiveness of corticosteroids among older adults with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen., Methods: We used routine care data from 36 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids with at least 0.4 mg/kg/day equivalent prednisone (treatment group) versus standard of care (control group). Participants were adults aged 80 years or older with PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or CT scan images typical of COVID-19 pneumonia, requiring oxygen ≥3 L/min, and with an inflammatory syndrome (C-reactive protein ≥40 mg/L). The primary outcome was overall survival at day 14. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting., Results: Among the 267 patients included in the analysis, 98 were assigned to the treatment group. Their median age was 86 years (interquartile range 83-90 years) and 95% had a SARS-CoV-2 PCR-confirmed diagnosis. In total, 43/98 (43.9%) patients in the treatment group and 84/166 (50.6%) in the control group died before day 14 (weighted hazard ratio 0.67, 95% CI 0.46-0.99). The treatment and control groups did not differ significantly for the proportion of patients discharged to home/rehabilitation at day 14 (weighted relative risk 1.12, 95% CI 0.68-1.82). Twenty-two (16.7%) patients receiving corticosteroids developed adverse events, but only 11 (6.4%) from the control group., Conclusions: Corticosteroids were associated with a significant increase in the overall survival at day 14 of patients aged 80 years and older hospitalized for severe COVID-19., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To assess the effectiveness of corticosteroids on outcomes of patients with coronavirus disease 2019 (COVID-19) pneumonia requiring oxygen without mechanical ventilation., Methods: We used routine care data from 51 hospitals in France and Luxembourg to assess the effectiveness of corticosteroids at 0.8 mg/kg/day eq. prednisone (CTC group) versus standard of care (no-CTC group) among adults 18-80 years old with confirmed COVID-19 pneumonia requiring oxygen without mechanical ventilation. The primary outcome was intubation or death by day 28. In our main analysis, characteristics of patients at baseline (i.e. time when patients met all inclusion criteria) were balanced by using propensity-score inverse probability of treatment weighting., Results: Among the 891 patients included in the analysis, 203 were assigned to the CTC group. Use of corticosteroids was not significantly associated with risk of intubation or death by day 28 (weighted hazard ratio (wHR) 0.92, 95%CI 0.61-1.39) nor cumulative death rate (wHR 1.03, 95%CI 0.54-1.98). However, use of corticosteroids was associated with reduced risk of intubation or death by day 28 in the prespecified subgroups of patients requiring oxygen ≥3 L/min (wHR 0.50, 95%CI 0.30-0.85) or C-reactive protein level ≥100 mg/L (wHR 0.44, 95%CI 0.23-0.85). The number of hyperglycaemia events was higher for patients with corticosteroids than for those without, but the number of infections was similar., Conclusions: We found no association between the use of corticosteroids and intubation or death in the broad population of patients 18-80 years old, with COVID-19, hospitalized in settings non intensive care units. However, the treatment was associated with a reduced risk of intubation or death for patients with ≥3 L/min oxygen or C-reactive protein level ≥100 mg/L at baseline. Further research is needed to confirm the right timing for corticosteroids in patients with COVID-19 requiring oxygen only., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease., Methods: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data., Results: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis., Conclusion: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist., (© 2020 American Academy of Neurology.)

Purpose of Review: The present review describes the interferon (IFN)-signature currently emerging as a tool for the diagnosis of idiopathic inflammatory myopathies (IIMs), and aims at presenting the interests and limitations of this recent tool for the clinics and the research., Recent Findings: Recent in-vivo and in-vitro transcriptomic studies have evidenced the involvement of IFNs in the pathogenesis of IIMs. A correlation between the IFN-signature and the clinical severity of IIMs has been established. Moreover, studies pointed out differences in the IFN-signature regarding the IIM subgroup (dermatomyositis, polymyositis, inclusion body myositis, anti-synthetase syndrome, immuno-mediated necrotizing myopathies), raising the hypothesis of several pathogenic processes in IIMs., Summary: IIM pathogenesis remains partially understood. IFN-signature represents one of the main recent advances in the field. IFN-signature was identified thanks to transcriptomic analyses of tissues or cells from IIM patients (muscle, skin, blood cells, muscle cells) and should allow to establish new diagnosis and better monitoring of IIM patients. It also provides a tool for investigation of IIM pathogenesis. Nevertheless, IFN-signature still requires accurate definition in order to standardize its use, notably in the clinical practice.

Objective: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM., Methods: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model., Results: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality., Conclusion: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients., (© 2019, American College of Rheumatology.)

Purpose of Review: Antisynthetase syndrome (ASyS) is an acquired myopathy characterized by the presence of myositis-specific autoantibodies directed against tRNA-synthetases. ASyS is potentially life threatening due to lung involvement and treatment remains a challenge to date. With symptoms not limited to muscles but also involving lung, skin and joints, ASyS appears specific and has a particular pathogenesis, different from the other inflammatory myopathies. This review is intended to discuss the current understanding of ASyS pathogenesis, pointing its current knowledge and also the crucial prospects that may lead to critical improvement of ASyS care., Recent Findings: Regarding ASyS pathogenesis, initiation of the disease seems to arise in a multifactorial context, with first lesions occurring within the lungs. This may lead to aberrant self-antigen exposure and tolerance breakdown. The consequences are abnormal activation of both innate and adaptive immunity, resulting in the patients with favourable genetic background to autoimmune-mediated organ lesions. Immune and nonimmune roles of the antigen, as well as antigen presentation leading to specific T-cell and B-cell activation and to the production of specific autoantibodies belong to the disease process., Summary: This work aims to detail ASyS pathogenesis understanding, from initiation to the disease propagation and target tissue lesions, in order to considering future treatment directions.

Objective: To better define in a cohort study the clinical and pathologic features of focal myositis (FM)., Methods: With the use of the usual clinicopathologic definition, each confirmed case of FM in the Lyon University Hospital's myopathologic database between 2000 and 2016 was retrieved. Clinical, pathologic, imaging, serologic, and therapeutic data were collected. When data were missing but feasible, appropriate pathologic analyses were performed., Results: Of the 924 patients included in the database, 37 (4%) had confirmed FM (14 female, 23 male patients). The main symptoms were pain (n = 30, 81%), muscular mass (n = 16, 43%), erythema at the site of FM (n = 12, 32%), and fever (n = 9, 24%). Serum creatine kinase was normal in most patients (81%); serum immune abnormalities were frequent (inflammatory syndrome in sera [39%], dysglobulinemia [52%], and anti-nuclear antibody positivity [29%]). In addition to confirming previously reported findings, pathologic analyses found significant rates of vasculitis (68%) and fasciitis (73%). Here, FM appeared frequently to be associated with other diseases such as immune-mediated inflammatory disease (IMID; 32%), neoplasia (24%), and radiculopathy (11%). Regarding outcomes, 64% of the cases had received immunosuppressive drugs, and the relapse rate was 41%., Conclusion: The present study suggests that FM is not as innocuous as previously believed, particularly considering the associated disorders. Notably, patients with FM should receive careful IMID and neoplasia screening., (© 2018 American Academy of Neurology.)