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Objective: Idiopathic inflammatory myopathies (IIMs) cause proximal muscle weakness, which affects the ability to carry out the activities of daily living. Wearable physical activity monitors (PAMs) objectively assess continuous activity and potentially have clinical usefulness in the assessment of IIMs. We examined the psychometric characteristics for PAM outcomes in IIMs., Methods: Adult IIM patients were prospectively evaluated (at baseline, 3 months and 6 months) in an observational study. A waist-worn PAM (ActiGraph GT3X-BT) assessed average step counts/minute, peak 1-minute cadence, and vector magnitude/minute. Validated myositis core set measures (CSMs) including manual muscle testing (MMT), physician global disease activity (MD global), patient global disease activity (Pt global), extramuscular disease activity (Ex-muscular global), HAQ-DI (HAQ disability index), muscle enzymes, and patient-reported physical function were evaluated. Test-retest reliability, construct validity, and responsiveness were determined for PAM measures and CSMs, using Pearson correlations and other appropriate analyses., Results: A total of 50 adult IIM patients enrolled [mean (s.d.) age, 53.6 (14.6); 60% female, 94% Caucasian]. PAM measures showed strong test-retest reliability, moderate-to-strong correlations at baseline with MD global (r = -0.37 to -0.48), Pt global (r=-0.43 to -0.61), HAQ-DI (r = -0.47 to -0.59) and MMT (r = 0.37-0.52), and strong discriminant validity for categorical MMT and HAQ-DI. Longitudinal associations with MD global (r=-0.38 to -0.44), MMT (r = 0.50-0.57), HAQ-DI (r = -0.45 to -0.55) and functional tests (r = 0.30-0.65) were moderate to strong. PAM measures were responsive to MMT improvement ≥10% and moderate-to-major improvement on ACR/EULAR myositis response criteria. Peak 1-minute cadence had the largest effect size and standardized response means., Conclusion: PAM measures showed promising construct validity, reliability, and longitudinal responsiveness; especially peak 1-minute cadence. PAMs are able to provide valid outcome measures for future use in IIM clinical trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor-associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed., Observations: Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte-associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis., Conclusion and Relevance: This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.

Background: Rapidly progressive interstitial lung disease (RPILD) associated with the anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5ab+) dermatomyositis (DM) is a rare but life-threatening condition despite immunosuppressive treatment. We report the case of a 44-year-old woman who was diagnosed with severe RPILD associated with anti-MDA5ab+ DM 1 week before her admission in the intensive care unit. The patient underwent a successful double-lung transplant after she failed treatment with immunosuppressive therapy, including tofacitinib. At 1-year follow-up, she had experienced no relapse of the disease., Case Report: This case includes a patient recently diagnosed with RPILD for whom no treatment showed efficacy, including glucocorticoids, cyclophosphamide, plasma exchanges, tofacitinib, and tacrolimus. She was placed under mechanical ventilation and venovenous extracorporeal membrane oxygenation 2 weeks after diagnosis in a bridge-to-transplant process. She was successfully transplanted 20 days later after having been registered on the French National Lung Transplant Waiting List with high priority. One year after surgery, her pulmonary function tests were good, and she showed no sign of relapse of anti-MDA5ab+ DM., Conclusions: Lung transplantation can be a life-saving procedure in RPILD related to anti-MDA5ab+ DM. High-emergency allocation priority on the transplant list reduced the time between diagnosis and surgery. Patients without comorbidities should be promptly referred to specialized centers to rapidly assess the feasibility of transplantation in this context., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM., Methods: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with ( n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA ( n = 12)., Results: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56 dim NK cells, while CD56 bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D + on NK cells from patients with PA compared with non-PA patients, especially on the CD56 dim subset. NKG2D + and NKp46 + cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA., Conclusion: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches.

Background: COVID-19 diabetic adults are at increased risk of severe forms irrespective of obesity. In patients with type-II diabetes, fat distribution is characterized by visceral and ectopic adipose tissues expansion, resulting in systemic inflammation, which may play a role in driving the COVID-19 cytokine storm. Our aim was to determine if cardiac adipose tissue, combined to interleukin-6 levels, could predict adverse short-term outcomes, death and ICU requirement, in COVID-19 diabetic patients during the 21 days after admission., Methods: Eighty one consecutive patients with type-II diabetes admitted for COVID-19 were included. Interleukin-6 measurement and chest computed tomography with total cardiac adipose tissue index (CATi) measurement were performed at admission. The primary outcome was death during the 21 days following admission while intensive care requirement with or without early death (ICU-R) defined the secondary endpoint. Associations of CATi and IL-6 and threshold values to predict the primary and secondary endpoints were determined., Results: Of the enrolled patients (median age 66 years [IQR: 59-74]), 73% male, median body mass index (BMI) 27 kg/m 2 [IQR: 24-31]) 20 patients had died from COVID-19, 20 required intensive care and 41 were in conventional care at day 21 after admission. Increased CATi and IL-6 levels were both significantly related to increased early mortality (respectively OR = 6.15, p = 0.002; OR = 18.2, p < 0.0001) and ICU-R (respectively OR = 3.27, p = 0.01; OR = 4.86, p = 0.002). These associations remained significant independently of age, sex, BMI as well as troponin-T level and pulmonary lesion extension in CT. We combined CATi and IL-6 levels as a multiplicative interaction score (CATi*IL-6). The cut-point for this score was ≥ 6386 with a sensitivity of 0.90 and a specificity of 0.87 (AUC = 0.88) and an OR of 59.6 for early mortality (p < 0.0001)., Conclusions: Cardiac adipose tissue index and IL-6 determination at admission could help physicians to better identify diabetic patients with a potentially severe and lethal short term course irrespective of obesity. Diabetic patients with high CATi at admission, a fortiori associated with high IL-6 levels could be a relevant target population to promptly initiate anti-inflammatory therapies., (© 2021. The Author(s).)

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients., Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2., Results: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs)., Conclusion: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Patients with solid cancer or haematologic malignancies have been considered to be more susceptible to SARS-CoV-2 infection and to more often develop severe complications. We aimed to compare the differences in clinical features and outcomes of COVID-19 patients with and without cancer., Methods: This was a prospective observational cohort study of consecutive adult patients hospitalised in a COVID-19 unit at Pitié-Salpêtrière Hospital, Paris, France (NCT04320017)., Results: Among the 262 patients hospitalised in a medical ward during the pandemics with a confirmed COVID-19 diagnosis, 62 patients had cancer. Clinical presentation, comorbidities, and outcomes were similar between cancer and non-cancer patients. However, cancer patients were more likely to have been contaminated while being hospitalised., Conclusions: Oncologic and non-oncologic patients hospitalised for COVID-19 shared similar outcomes in terms of death, admission in intensive care, or thrombosis/bleeding. They should benefit from the same therapeutic strategy as the general population during the COVID-19 pandemic., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression., Methods: In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment., Results: Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM., Conclusions: Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement., Key Points: • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

Dermatomyositis (DM) is a systemic idiopathic inflammatory disease affecting skeletal muscle and skin, clinically characterized by symmetrical proximal muscle weakness and typical skin lesions. Recently, myositis-specific autoantibodies (MSA) became of utmost importance because they strongly correlate with distinct clinical manifestations and prognosis. Antibodies against transcription intermediary factor 1γ (TIF-1γ) are frequently associated with increased risk of malignancy, a specific cutaneous phenotype and limited response to therapy in adult DM patients. Anti-Mi-2 autoantibodies, in contrast, are typically associated with classic DM rashes, prominent skeletal muscle weakness, better therapeutic response and prognosis, and less frequently with cancer. Nevertheless, the sensitivity of autoantibody testing is only moderate, and alternative reliable methods for DM patient stratification and prediction of cancer risk are needed. To further investigate these clinically distinct DM subgroups, we herein analyzed 30 DM patients (n = 15 Mi-2 + and n = 15 TIF-1 γ + ) and n = 8 non-disease controls (NDC). We demonstrate that the NanoString technology can be used as a very sensitive method to clearly differentiate these two clinically distinct DM subgroups. Using the nCounter PanCancer Immune Profiling Panel™, we identified a set of significantly dysregulated genes in anti-TIF-1γ + patient muscle biopsies including VEGFA, DDX58, IFNB1, CCL5, IL12RB2, and CD84. Investigation of type I IFN-regulated transcripts revealed a striking type I interferon signature in anti-Mi-2 + patient biopsies. Our results help to stratify both subgroups and predict, which DM patients require an intensified diagnostic procedure and might have a poorer outcome. Potentially, this could also have implications for the therapeutic approach., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Although idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases nearly all patients display muscle inflammation. Originally, muscle biopsy was considered as the gold standard for IIM diagnosis. The development of muscle imaging led to revisiting not only the IIM diagnosis strategy but also the patients' follow-up. Different techniques have been tested or are in development for IIM including positron emission tomography, ultrasound imaging, ultrasound shear wave elastography, though magnetic resonance imaging (MRI) remains the most widely used technique in routine. Whereas guidelines on muscle imaging in myositis are lacking here we reviewed the relevance of muscle imaging for both diagnosis and myositis patients' follow-up. We propose recommendations about when and how to perform MRI on myositis patients, and we describe new techniques that are under development., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

The classification of idiopathic inflammatory myopathies (IIM) is based on clinical, serological and histological criteria. The identification of myositis-specific antibodies has helped to define more homogeneous groups of myositis into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), sporadic inclusion body myositis (sIBM) and immune-mediated necrotising myopathy (IMNM). sIBM and IMNM patients present predominantly with muscle involvement, whereas DM and ASyS patients present additionally with other extramuscular features, such as skin, lung and joints manifestations. Moreover, the pathophysiological mechanisms are distinct between each myositis subsets. Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In DM, the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in muscle, blood and skin of DM patients. In addition, DM-specific antibodies are targeting antigens involved in the IFN signalling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signalling pathways induces systemic manifestations such as interstitial lung disease, myositis and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signalling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in ASyS, available data suggest a role of type II IFN in blood, muscle and lung. Indeed, transcriptomic analyses highlighted a type II IFN gene expression in ASyS muscle tissue. In sIBM, type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to myodegenerative features. For IMNM, currently published data are scarce, suggesting a minor implication of type II IFN. This review highlights the involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system.CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases.

Background: Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis., Methods: This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45-80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days -15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02481453., Findings: Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI -10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients., Interpretation: We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus., Funding: Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management., Methods: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed., Results: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies., Conclusion: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations., Competing Interests: Competing interests: MK: honoraria from Abbvie, BMS, Lilly, Novartis, Pfizer; TRDJR: grants from AbbVie, Takeda, UCB, Janssen, GSK and honoraria from Abbvie, Pfizer, Takeda, Lilly, Medimmune, Novartis, GSK, BMS, AstraZeneca, Janssen; XM: honoraria from BMS; COB: grants and honoraria from BMS and honoraria from Genetech/Roche, Sanofi/Regeneron; OL: grant from Gilead and honoraria from BMS, MSD, AstraZeneca, Janssen; JLe: grants from Novartis, Pfizer and honoraria from Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; AM: grants from BMS, Merus and honoraria from Merck Serono, Lytix, BMS, Symphogen, Amgen, AZ/Medimmune, Servier, Gritstone, Pierre Fabre, EISAI, Sanofi; TS: honoraria from Pfizer, Lilly, Novartis, BMS, Abbvie, Sanofi; EHC: grants from Biogen, grants and honoraria from Amgen, Bio-Cancer, Roche, UCB, Pfizer, honoraria from Chugai Pharma, Abbvie, BMS, Celgene, Eli Lilly, Janssen, ObsEva, Regeneron, Sanofi, SynAct Pharma, Tonix, Gilead; LT: honoraria from Novartis; KB: grants from Abbvie, Novartis, Rheumaliga Baden-Württemberg and honoraria from MSD, Abbvie, BMS, Janssen, Lilly, Mundipharma, Novartis, Pfizer, Roche, UCB; KV: speaker fees from BMS; JLa: grants from Aveo and Pharmacyclics, grants and honoraria from Achilles Therapeutics, MSD, Nektar, Novartis, Pierre Fabre, Pfizer, Roche/Genetech and Immunocore, honoraria from AstraZeneca, Boston Biomedical, BMS, Eisai, EUSA Pharma, GSK, Ipsen, Imugen, Incyte, iOnctura, Kymab, Merck Serono, Secarna, Vitaccess and Covance; JBAGH: grants from BMS, Novartis and advisory boards and/or lectures for MSD, BMS, Roche, Novartis; J-EG: grants from BMS, UCB, Pfizer, Sanofi and honoraria from BMS, Lilly, Pfizer, Sanofi-Genzyme, UCB., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.

Background: Our objective was to define the pattern and severity of muscle damage in immune-mediated necrotizing myopathy (IMNM) and its relationship with clinical and serological features., Methods: IMNM patients with a whole-body MRI (n=42) were included and compared to sporadic inclusion-body myositis (s-IBM) patients (n=60). Fat replacement was estimated using the Mercuri score in 55 muscles. Overall lesion load was defined as the sum of all abnormal Mercuri scores (reported in % maximal score) and lesion load quotient was defined as the overall lesion load divided by disease duration. Linear relationships between variables were assessed and multidimensional analysis was performed to define homogenous groups of patients., Results: IMNM patients were aged 48.1±15.8 years and had a disease duration of 9.8±8.1 years. Most severely affected muscle groups were located in the pelvifemoral and lumbar region. Unsupervised analysis showed two subgroups of patients: one with mild lesion load (15±10%, n=32/42) and another with severe lesion load (60±10%, n=10/42: p<0.001) associated with a mean disease duration of 6.8±6.0 years and 19.5±5.7 years, respectively (p<0.0001). Correlational studies confirmed that disease duration was the most important predictor of muscle damage. Multivariate analyses demonstrated a more severe involvement in select muscle groups in females and seropositive patients. No difference was found in overall lesion load quotient of IMNM compared to IBM (p=0.07) but with a distinct muscle pattern., Conclusion: IMNM is associated with severe axial and pelvifemoral muscle damage. Disease duration is an important predictor of muscle damage. IMNM and s-IBM patients have a comparable damage burden., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19., Methods: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population., Results: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04)., Conclusion: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14., Competing Interests: TP has several USPTO patents related to the performance of Apoa1 in patients with liver disease, including #10,198,552 Method of diagnosis of fibrotic diseases, #7,860,656 Diagnosis method of hepatic steatosis using biochemical markers, 7,856,319, Diagnosis method of alcoholic steato-hepatitis using biochemical markers, #7,225,080 Diagnosis method of inflammatory, fibrotic or cancerous disease using biochemical markers, and # 6,631,330 Diagnosis method of inflammatory, fibrotic or cancerous disease using biochemical markers, and applications pending: #20200011879 Method of diagnosis of drug induced liver injury, 20190265241 Method of diagnosis of non-alcoholic fatty liver diseases, #3 20140329260 Method of diagnosis of fibrotic diseases, and #20090111132 Diagnosis method of hepatic steatosis using biochemical markers. The data underlying the findings described in the manuscript are fully detailed including the confounding factors, without restriction, in the numerous supplementary files. The commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Prognostic factors of coronavirus disease 2019 (COVID-19) patients among European population are lacking. Our objective was to identify early prognostic factors upon admission to optimize the management of COVID-19 patients hospitalized in a medical ward. This French single-center prospective cohort study evaluated 152 patients with positive severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase-polymerase chain reaction assay, hospitalized in the Internal Medicine and Clinical Immunology Department, at Pitié-Salpêtrière's Hospital, in Paris, France, a tertiary care university hospital. Predictive factors of intensive care unit (ICU) transfer or death at day 14 (D14), of being discharge alive and severe status at D14 (remaining with ventilation, or death) were evaluated in multivariable logistic regression models; models' performances, including discrimination and calibration, were assessed (C-index, calibration curve, R2, Brier score). A validation was performed on an external sample of 132 patients hospitalized in a French hospital close to Paris, in Aulnay-sous-Bois, Île-de-France. The probability of ICU transfer or death was 32% (47/147) (95% CI 25-40). Older age (OR 2.61, 95% CI 0.96-7.10), poorer respiratory presentation (OR 4.04 per 1-point increment on World Health Organization (WHO) clinical scale, 95% CI 1.76-9.25), higher CRP-level (OR 1.63 per 100mg/L increment, 95% CI 0.98-2.71) and lower lymphocytes count (OR 0.36 per 1000/mm3 increment, 95% CI 0.13-0.99) were associated with an increased risk of ICU requirement or death. A 9-point ordinal scale scoring system defined low (score 0-2), moderate (score 3-5), and high (score 6-8) risk patients, with predicted respectively 2%, 25% and 81% risk of ICU transfer or death at D14. Therefore, in this prospective cohort study of laboratory-confirmed COVID-19 patients hospitalized in a medical ward in France, a simplified scoring system at admission predicted the outcome at D14., Competing Interests: The authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO 2 ≤ 96% despite O 2 -support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3-0.81), p -value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135-0.51, p = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis ( p < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19.

Objective: This study aimed to investigate the relationship between changes in clinical status on daily life physical activity (PA) in patients with idiopathic inflammatory myopathy (IIM)., Methods: Patients with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) or overlap myositis (OM) who presented either a new-onset or relapsing IIM, stable disease on maintenance therapy or were undergoing immunosuppressant tapering were included. Patients were evaluated at inclusion (V0), and at two follow-up visits (V1, 94±12 days from V0; V2, 96±17 days from V1). The American College of Rheumatology/European League against Rheumatism (ACR/EULAR) response criteria was recorded. PA assessed using 14-days raw accelerometry data gathered using a wrist-worn accelerometer after each visit (mean daily Euclidean norm minus 1 g (ENMO) was computed)., Results: Fifty-five patients (16 OM, 27 IMNM and 12 DM) were included. At baseline, 67% of patients had an ENMO Z-score less than 1. At inclusion, ENMO mainly correlated with health assessment questionnaire score (HAQ, ρ=-0.51, p<0.01), manual muscle testing 8 (MMT8, ρ=0.42, p<0.01), creatinine level (ρ=0.41, p<0.01), and SF-36 physical functioning score (ρ=0.38, p<0.002). At follow-up, ENMO changes mainly correlated with changes in MMT8, HAQ, SF-36 fatigue, and depression score (all ρ>0.43, all p<0.001). Level of agreement between ACR/EULAR response criteria and changes in PA was 15, 45, and 90% for minimal (n = 13), moderate (n = 20), and major (n = 10) improvements, respectively., Conclusion: Baseline PA levels and change in PA correlated with muscle strength and function, yet changes in PA were also influenced by psychological status. Only patients with major improvements on the ACR/EULAR criteria had significant increase in PA. Accelerometer may serve as an objective tool to define a clinically relevant real-life outcome., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Aims: Edema of the limbs is uncommon in idiopathic inflammatory myopathies (IIM). The few reported cases have been associated with severe and refractory dermatomyositis (DM), sometimes in association with cancers. We aimed to determine if edematous myositis is a homogeneous subtype based on clinical, serological and pathological features., Methods: This is a retrospective observational study performed between 2008 and 2015 in the French national referral center for myositis. All adult patients with an inflammatory muscle biopsy and upper limbs edema were included as well as IIM cases without limb edema as controls. Clinical, biological and pathological features were collected., Results: Seventeen edematous myositis were included and compared to 174 IIM without edema, including 50 DM controls. Edema was the first manifestation in 23% of patients. Muscle weakness was severe and symmetric, 71% of patients presented dysphagia and a restrictive ventilatory pattern was found in 40%. Fifty-two percent of patients had a typical DM skin rash and 23% had cancer within 3 years of diagnosing myositis. Fifty-three percent of patients presented a myositis specific antibody and only DM-specific antibodies were detected. Classic pathological DM features (perifascicular atrophy, perifascicular/perimysial perivascular inflammation) were uncommon but capillary C5b-9 deposition and MxA expression were seen in 79% and 73% of cases, respectively. A perimysial edema was found in 82% of cases. Seventeen percent of patients died (median follow up of 18 months). Edematous myositis demonstrated more marked capillary C5b-9 deposition compared to IIM controls. There was no clinical, biological or pathological difference with DM controls except for limb edema., Conclusion: Our study underlines that limb edema could be a symptom of IIM and that edematous myositis are mostly DM. The vasculopathy seems to play a key role in its pathophysiology. Limb edema associated with muscle impairment should suggest the diagnosis of DM in clinical settings., (© 2020 International Society of Neuropathology.)

Objectives: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2)., Methods: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes., Results: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported., Conclusion: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI., Patients Methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC 025 (lower end of the IC 95% credibility interval) >0 is deemed significant., Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC 025  = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC 025  = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC 025  = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC 025  = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC 025  = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC 025  = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001)., Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis., (Copyright © 2020 Elsevier B.V. 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: Drug-induced uveitis is a rare but sight-threatening condition. We seek to determine the spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors (ICI)., Methods: Retrospective pharmacovigilance study based on adverse drug reactions reported within VigiBase, the WHO international pharmacovigilance database. We included deduplicated individual case safety reports (ICSRs) reported as 'uveitis' at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities between 1967 and 04/28/2019. We performed a case/non-case analysis to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. We excluded drugs with potential indication bias., Results: 1404 ICSRs corresponding to 37 drugs had a significant over-reporting signal with a median age of 57 [42-68] years and 45.7% of males. We identified five major groups of treatments: bisphosphonates (26.9%), non-antiviral anti-infectious drugs (25.4%), protein kinase inhibitors (15.5%), ICI (15.0%), and antiviral drugs (11.1%). Severe visual loss was reported in 12.1% of cases. ICI and protein kinase inhibitors were the most recently emerging signals. The time to onset between first infusion and uveitis was significantly different between groups ranging from 5 days [2-19] in the bisphosphonate group to 138.5 [47.25-263.75] in protein kinase inhibitors group (p < 0.0001). Anti-Programmed Cell death 1 represented more than 70% of ICI-induced uveitis. We identified Vogt-Koyanagi-Harada (VKH)-like syndrome as being associated with ICI use., Conclusions: The spectrum of drug-induced uveitis has changed with the evolution of pharmacopeia and the recent emergence of ICIs. VKH-like syndrome has been reported with ICI and protein kinase inhibitors therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To refine the predictive significance of muscle granuloma in patients with myositis., Methods: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM)., Results: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis., Conclusion: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care., (© 2019 American Academy of Neurology.)

Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune-mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone-assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB-crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2-associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM-specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process., (© 2019 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Dermatomyositis are rare chronic auto-immune diseases characterized by cutaneous involvement. Diagnosis could be made in childhood or in aldult. There are some different clinical and histological presentation associated with different myositis specific antibody. There are five dermatomyositis specific autoantibodies, anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5, and anti-SAE. Anti-Mi2 are associated with "classical form" of DM with cutaneous and muscular involvement. Anti-Tif1γ and anti-NXP2 are found in juvenile and adult dermatomyositis, and are associated with recurrent diseases with cutaneous involvement at the forefront. In adults, they are associated with cancer. Anti-MDA5 antibodies are associated with a systemic involvement and an interstitial lung disease. Finally, anti-SAE have been found only in adults, with a classic form., (© 2019 médecine/sciences – Inserm.)

Objectives: To compare the performance of magnetic resonance (MR) relaxometry parameters to discriminate myocardial and skeletal muscle inflammation in idiopathic inflammatory myopathy (IIM) patients from healthy controls., Materials and Methods: For this retrospective case-control study, 20 consecutive IIM patients (54 ± 18 years, 11 females) with cardiac involvement (troponin level > 50 ng/l) and 20 healthy controls (47 ± 12 years, 9 females) were included. All patients without cardiac MR imaging < 2 weeks prior to the laboratory testings were excluded. T1/T2 relaxation times, as well as T1-derived extracellular volume (ECV), relative tissue T1 shortening ΔT1 = (native T1 tissue -post contrast T1 tissue )/native T1 tissue ), and enhancement fraction EHF = (native T1 tissue -post contrast T1 tissue )/(native T1 blood -post contrast T1 blood ), were compared using Mann-Whitney U test and ROC analysis., Results: All measured MR relaxometry parameters significantly discriminated IIM patients and healthy controls, except T2 in skeletal muscles and ECV in the myocardium. In skeletal muscles, post contrast T1 and T1-derived parameters showed the best performance to discriminate IIM patients from healthy controls (AUC = 0.98 for post contrast T1 and AUC 0.94-0.97 for T1-derived parameters). Inversely, in the myocardium, native T1 and T2 showed better diagnostic performance (AUC = 0.89) than post contrast T1 (AUC = 0.76), ECV (AUC = 0.58), ΔT1 (AUC = 0.80) and EHF (0.82)., Conclusions: MR relaxometry parameters applied to the myocardium and skeletal muscles might be useful to separate IIM patients from healthy controls. However, different tissue composition and vascularization should be taken into account for their interpretation. ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium., Key Points: • MR relaxometry parameters applied to the myocardium and skeletal muscles are highly useful to separate IIM patients from healthy controls. • Different tissue composition and vascularization should be taken into account for T1 and T2 mapping parameter interpretation. • ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium.

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.)

Recent data suggest the implication of T, B and NK cells in the anti-synthetase syndrome (ASyS); nevertheless their role and activation states are poorly described. We performed deep immune-profiling using 37 markers on peripheral blood cells from 10 ASyS patients versus 17 healthy donors (HD) and 26 myositis control patients. We show decreased percentages of memory B cells in ASyS patients (mean ± SEM: ASyS = 13 ± 3%, HD = 37 ± 4% and 'myositis controls' = 32 ± 3), counterbalanced by increased percentages of naïve B cells. Interestingly, perifascicular infiltrations of memory B cells within muscle biopsies of ASyS patients suggest that they niche within the muscle., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome., Competing Interests: Dr Bonaca reports consulting for Amgen, AstraZeneca, Bayer, Janssen, Pfizer, Sanofi-Aventis, Merck as well as research funding from AstraZeneca, MedImmune, Merck, and Pfizer. Dr Salem was supported by Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): “Plan Cancer 2014 to 2019”. Dr Wiviott reports ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer-Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, Xoma, and research grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck and Sanofi-Aventis. Dr Wiviott’s spouse is an employee of Merck Research Laboratories. Dr Ederhy has received consultant and lecture fees from Eli Lilly, Daiichy-Sankyo, Celgene, Pfizer, EspeRare, Bristol-Myers Squibb, Janssen, Philips Healthcare, Bayer, Novartis, Amgen, and Ipsen. Dr Cohen has received consultant and lecture fees from, Amgen, AstraZeneca, Bayer Pharma, BMS-Pfizer alliance, Boehringer-Ingelheim and Novartis, and has received research grants from ARS, RESICARD, Bayer, and Boehringer-Ingelheim. Dr Di Carli has received consulting honoraria from Sanofi and General Electric and research grants from SpectrumDynamics. Dr Choueiri has been a consultant for AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Ipsen and has received research funding from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, and Ipsen. Dr Kumbhani has received an honoraria from American College of Cardiology. Dr Heinzrling has been a principal investigator in clinical studies for Bristol-Myers Squibb, Merck, Roche, Amgen, GlaxoSmithKline, Curevac, and Novartis; had received consultancy and speaker fees from from Bristol-Myers Squibb, Merck, Roche, Amgen, Novartis, Curevac, and Pierre Fabre. Dr Lyon has received speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Clinigen Group, Takeda, Roche, Eli Lily, Eisai, Bristol Myers Squibb, Ferring Pharmaceuticals, and Boehringer Ingelheim. Dr Johnson has served on an advisory board for Array, Bristol-Myers Squibb, Genoptix, Incyte, Merck, and Novartis, and has received research funding from Bristol-Myers Squibb and Incyte. Dr Moslehi has served on an advisory board for Pfizer, Novartis, Bristol-Myers Squibb, Takeda, Regeneron, and Myokardia and received research funding from Pfizer and Novartis. The other authors report no conflicts., (© 2019 American Heart Association, Inc.)

Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to mechanisms hypothesized to cause adverse events and their management strategies.

Objective: A pathogenic role of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies has been proposed. Our objective was to assess efficacy of rituximab (RTX) in anti-HMGCR immune-mediated necrotizing myopathy., Methods: All patients who had been treated with RTX were retrospectively reviewed to assess features and outcome., Results: Three of 9 patients demonstrated stable or improved muscle strength ± decline in creatine kinase levels, or T2/short-tau inversion recovery hypersignal decrease on magnetic resonance imaging following RTX treatment. RTX permitted intravenous immunoglobulin discontinuation and corticosteroid reduction to low dose in 2 patients., Conclusion: One-third of patients with refractory anti-HMGCR had improved strength or other evidence of improved disease activity following RTX treatment.