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Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1‐year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo‐controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. Quantitative MRI and 31P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year‐1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross‐sectional area (cCSA), and water T2in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadricepsor triceps surae. Analyses covered patient‐control comparisons, annual change assessments via standard t‐tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. The quadricepsand gastrocnemius medialismuscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1‐year FF increase in the quadriceps was 3.2% (P< 0.001), whereas in the sirolimus group, it was 0.7% (P= 0.033). Both groups experienced a significant decrease in cCSA in the quadricepsafter 1 year (P< 0.001), with median changes of 12.6% for the placebo group and 5.5% for the sirolimus group. Differences in FF and cCSA changes between the two groups were significant (P< 0.001). SRM values for FF and cCSA were 1.3 and 1.4 in the placebo group and 0.5 and 0.8 in the sirolimus group, respectively. Water T2values were highest in the quadricepsmuscles of both groups, significantly exceeding control values in both groups (P< 0.001) and were higher in the placebo group than in the sirolimus group. After treatment, water T2increased significantly only in the sirolimus group's quadriceps(P< 0.01). Multiple 31P MRS indices were abnormal in patients compared to controls and remained unchanged after treatment. Significant correlations were identified between baseline water T2and FF at baseline and the change in FF (P< 0.001). Additionally, significant correlations were observed between FF, cCSA, water T2, and functional and strength outcome measures. This study has demonstrated that quantitative MRI/31P MRS can discern measurable differences between placebo and sirolimus‐treated IBM patients, offering promise for future therapeutic trials in idiopathic inflammatory myopathies such as IBM.

A 24-year-old Senegalese woman without remarkable history except anemia and iron deficiency related to excessive menstrual bleeding and sickle cell trait was admitted to our internal medicine department with 4-month fever, weight loss (−13 kg), dyspnea for limited efforts, intermittent productive cough, and bilateral metacarpophalangeal (MCP) and interphalangeal arthralgia. She was born and lived in France. She traveled previously to Senegal in 2015. She had no history of tobacco, alcohol, or drug use nor proximity with animals. She was taking no medication.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris–Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

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.

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.

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.

Manual muscle testing has been widely used for the evaluation of muscle strength in myositis, yet less attention has been devoted to the evaluation of muscle function and endurance. Our objective was therefore to compare the responsiveness to change of muscle strength, endurance and functional testing following induction therapy for severe myositis flare (requiring high-dose corticosteroids and combined immunotherapy) in patients with a diagnosis of dermatomyositis, immune-mediated necrotizing myopathy, or overlap myositis. Muscle status was assessed at baseline and after mean 6.4±1.9 months, using the MRC-5 scale, along with endurance (Barre and Mingazzini maneuvers) and functional evaluation (e.g. chair rise) and responsiveness to change was evaluated using the Standardized Response Mean (SRM) and Standardized Mean Difference. Among the 49 patients included, the strongest responsiveness to change was observed in the muscle testing of the psoas and deltoids (SRM: 1.23 and 1.16, respectively). Noticeably, endurance testing also demonstrated strong responsiveness (SRM: 1.05 and 0.96, respectively), compensating for the poor discriminatory ability of muscle testing and permitting to overcome its ceiling effect. Functional and endurance testing provide simple and reliable measures complementing the testing of select proximal muscle groups to evaluate responsiveness to intervention in myositis patients in daily clinical practice. Interest of functional and endurance testing should be evaluated prospectively as outcome measures in myositis clinical trials.

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.

IMPORTANCE: Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist. OBJECTIVE: To develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria. DESIGN, SETTING, AND PARTICIPANTS: An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti–histidyl-ARN-t- synthetase (Jo1), anti–threonine-ARN-t-synthetase (PL7), anti–alanine-ARN-t-synthetase (PL12), anti–complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti–polymyositis/systemic scleroderma (PMScl), anti–topoisomerase 1 (Scl70), and anti–signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies). MAIN OUTCOMES AND MEASURES: Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups. RESULTS: Among 260 participants (163 [62.7%] women; mean age, 59.7 years; median age [range], 61.5 years [48-71 years]), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients [93.5%]; 95% CI, 85.5%-97.8%; P &lt; .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti–SRP or anti–3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 [58.2%]; 95% CI, 47.4%-68.5%; P &lt; .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti–melanoma differentiation-associated protein 5 (MDA5), or anti–transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 [82.7%]; 95% CI, 69.7%-91.8%; P &lt; .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 [90.0%]; 95% CI, 76.3%-97.2%; P &lt; .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9). CONCLUSIONS AND RELEVANCE: These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.

Several retrospective case series have suggested rituximab (RTX) might improve patients with refractory Myasthenia Gravis (MG). In this study, we aimed to evaluate prospectively the efficacy of RTX on muscle function in refractory generalized anti-acetylcholine receptor (AChR) MG patients. Enrolled patients received 1 g of RTX at day 0, day 14, and 6-month follow-up (M6). The primary endpoint was improvement of muscle function at 12-month (M12) based on myasthenic muscle score (MMS). Secondary endpoints were an improvement of the MG Foundation of America Postintervention Status (MGFA-PIS), respiratory forced vital capacity, occurrences of acute MG exacerbation and requirement of associated immunosuppressants and immunomodulatory agents. Twelve patients were enrolled, and 11 completed the study. Only a single patient presented an improvement of at least 20 points on MMS at M12, although 2 patients displayed an increase of at least 18 points at M12. MGFA-PIS had improved in 55% of patients by M12. The clinical improvement was not associated with a reduction of immunosuppressant burden. These results provide data on the effect of RTX in patients with severe, refractory anti-AChR Abs generalized MG. Even though primary outcome was only reached in a single patient at M12, a beneficial effect of RTX on muscle function was seen in half of the patients at M12 and persisted in a third of patients at M18.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti–MDA5+-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti–MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2–positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti–MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

To analyze antisynthetase syndrome–associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs).

Availability of reliable outcomes for idiopathic inflammatory myopathies (IIM) is critical to optimize treatment strategies.1The current consensus for the assessment of IIM severity and treatment efficacy relies on the evaluation of core set measures comprising manual muscle testing, muscle enzymes, extramuscular disease activity assessment, physician and patient global disease activity assessment, and patient's physical function questionnaires.2Muscle enzymes such as serum creatine kinase (CK) level are highly sensitive markers for detecting changes in disease activity though this does not correlate well with disease severity. Manual muscle testing is an operator-dependent and semiquantitative evaluation resulting in poor interrater reliability and poor sensitivity to changes. Disease burden may be imprecisely assessed when using self-reported questionnaires. Floor and ceiling effects associated with these metrics are also of major concern.1,2

A series of twelve analogs carrying fluoro, chloro, bromo and iodo halogens on the ortho, meta and para positions of a benzoyloxytropane skeleton were synthesized by a simple acylation of 8-methyl-8-aza-bicyclo[3.2.1]octan- 3-ol by halogenobenzoyl chlorides. The compounds were evaluated in vitro against Plasmodium falciparum (P. f.), Trypanosoma brucei brucei (T. b. b.), Trypanosoma cruzi (T. c.) and Leishmania infantum (L. i.). This study shows that the presence of a halogenated atom and its position on the aromatic ring are important for in vitro activity. Compounds 4 (IC50 = 3.6 µM), 8 (IC50 = 6.7 µM), 5 (IC50 = 8.1 µM) and 7 (IC50 = 9.5 µM) were found the most active against P. f., whereas compounds 12 (IC50 = 5.1 µM), 11 (IC50 = 5.6 µM) and 9 (IC50 = 5.8 µM) exhibited the most pronounced activity against T. b. b. This series of compounds can be considered as non-toxic to the human cell line MRC-5.

Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.

Necrotizing myopathy exhibits a specific histological pattern, characterized by significant necrosis, with simultaneous muscle fiber regeneration, but without or with little inflammation. This histological pattern may be observed in acquired myopathies but also in muscular dystrophy. Acquired necrotizing myopathy can be secondary to drugs or toxics agents, and if not, autoimmune mechanisms have to be suspected. Necrotizing autoimmune myopathy (NAM) is now recognized as a subgroup of idiopathic inflammatory myopathies. This review aims to further describe the different acquired myopathies, with special focus on NAM since specific autoantibodies have been discovered.

Objective.To analyze the characteristics, outcomes, and predictive factors of disease-modifying antirheumatic drug (DMARD) use in 48 patients with antisynthetase syndrome [characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud’s phenomenon (RP), and/or mechanic’s hands] and the presence of anti-histidyl-transfer RNA synthetase (anti-Jo1) autoantibodies.Methods.Forty-eight patients (33 women, 15 men) who were anti-Jo1-positive referred to one center between 1998 and 2008 were analyzed retrospectively.Results.The median age of disease onset was 43 years [interquartile range (IQR) 33–53 yrs]. The median followup was 5 years (IQR 2–8 yrs). At diagnosis, 81% of patients presented with myositis, 80% ILD, 77% arthralgia, 48% RP, and 21% mechanic’s hands. During the followup, 14 patients (29%) had no need for DMARD, while 34 (71%) required DMARD. Patients with mechanic’s hands (p = 0.02) and higher creatine phosphokinase at diagnosis (median 6070 IU/l vs 1121 IU/l; p = 0.002) were more likely to need DMARD. ILD, noted on computed tomography scan by a nonspecific interstitial pneumonia score, was lower in the group of patients with no DMARD need (4 vs 7; p = 0.04). Twenty patients (44%) presented with a pulmonary aggravation (worsening of radiologic score of ILD and/or pulmonary function test results) leading to DMARD use. Nonspecific interstitial pneumonia score (7 vs 5; p = 0.05) and total lung volume (57.5% vs 70%; p = 0.02) values predicted pulmonary aggravation.Conclusion.Our study outlines the burden of chest involvement for the prognosis of antisynthetase syndrome in terms of patients’ requirement for DMARD therapy.

Schizanthus grahamiiis an endemic Chilean plant that is known to contain tropane alkaloids. Five new alkaloids, grahamines A–E (1–5), were isolated and characterized by extensive spectroscopic analysis. Their structures were determined to be 2-{[(3α-hydroxytropo-6β-yl)oxy]carbonyl}-2-methyl-3-{[((6β-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylic acid (1), 2-{[(3α-hydroxytropo-6β-yl)oxy]carbonyl}-2-methyl-3-{[((6β-tigloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylic acid (2), 1-methyl-2-{[(3α-hydroxytropo-6β-yl)oxy]carbonyl}-4-{[((6β-angeloyloxy)-3α-yl)oxy]carbonyl}-3-phenylcyclobutanecarboxylic acid (3), 1,2-bis{[(3α-hydroxytropo-6β-yl)oxy]carbonyl}-2-methyl-3-{[((6β-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylate (4), and 1-{[(3α-mesaconyloxytropo-6β-yl)oxy]carbonyl}-2-{[(3α-hydroxytropo-6β-yl)oxy]carbonyl}-2-methyl-3-{[((6β-angeloyloxy)-3α-yl)oxy]carbonyl}-4-phenylcyclobutanecarboxylate (5).

Polymyositis is a rare and severe inflammatory muscle disorder. Treatments are partially efficacious but have many side effects. New therapeutic approaches must be first tested in a relevant animal model. Regulatory CD4+CD25+ T cells (Tregs) have been rediscovered as a pivotal cell population in the control of autoimmunity, but the connection between polymyositis and Tregs is currently unknown. To develop a reproducible experimental autoimmune myositis model of polymyositis, mice were immunized once a week for 3 weeks with 1 mg of partially purified myosin emulsified in complete Freund's adjuvant. All mice injected with myosin and complete Freund's adjuvant developed myositis. The infiltrates were composed of CD4+and CD8+cells, as well as macrophages, but did not contain B lymphocytes. In mice that were depleted of Tregs, the myositis was more severe, as determined by quantitative scoring of muscle inflammation (2.36 ± 0.9 vs.1.64 ± 0.8, P= 0.019). In contrast, injection of in vitroexpanded polyclonal Tregs at the time of immunization significantly improved the disease (quantitative score of inflammation 0.87 ± 1.06 vs.2.4 ± 0.67, P= 0.047). Transfer of sensitized or CD4+-sorted cells from the lymph nodes of experimental autoimmune myositis mice induced myositis in naïve, irradiated, recipient mice. Thus, experimental autoimmune myositis is a reproducible, transferable disease in mice, both aggravated by Treg depletion and improved by polyclonal Treg injection.

An efficient approach to alk-4-yne-1,2,3,6-tetraols is described by stereoselective addition of terminal 2-alkyn-1-yl esters to Ley's butane-2,3-diacetal-protected glyceraldehyde. The application of this methodology to a convenient synthesis of a (-)-polyoxamic acid derivative is disclosed herein.

The formal 1,3-cycloaddition of 2-diazocyclohexane-1,3-diones 1a–1d to acyclic and cyclic enol ethers in the presence of Rh^II-catalysts to afford dihydrofurans has been investigated. Reaction with a cis/trans mixture of 1-ethoxyprop-1-ene (13a) yielded the dihydrofuran 14a with a cis/trans ratio of 85 : 15, while that with (Z)-1-ethoxy-3,3,3-trifluoroprop-1-ene (13b) gave the cis-product 14b exclusively. The stereochemical outcome of the reaction is consistent with a concerted rather than stepwise mechanism for cycloaddition. The asymmetric cycloaddition of 2-diazocyclohexane-1,3-dione (1a) or 2-diazodimedone (=2-diazo-5,5-dimethylcyclohexane-1,3-dione; 1b) to furan and dihydrofuran was investigated with a representative selection of chiral, nonracemic Rh^II catalysts, but no significant enantioselectivity was observed, and the reported enantioselective cycloadditions of these diazo compounds could not be reproduced. The absence of enantioselectivity in the cycloadditions of 2-diazocyclohexane-1,3-diones is tentatively explained in terms of the Hammond postulate. The transition state for the cycloaddition occurs early on the reaction coordinate owing to the high reactivity of the intermediate metallocarbene. An early transition state is associated with low selectivity. In contrast, the transition state for transfer of stabilized metallocarbenes occurs later, and the reactions exhibit higher selectivity.

Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.

Les patients ayant un cancer solide ou hématologique ont été considérés comme étant plus susceptibles de contracter une infection à SARS-COV-2, et de développer plus fréquemment des complications graves. Nous avons voulu comparer les caractéristiques cliniques et le pronostic des patients atteints de COVID-19 avec ou sans cancer.

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 800 mg/day administered for 1 to 11 days and median HCQ plasma concentration was 151 ng/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 102 h. 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 68 L/h, 2440 L and 19.5 h, 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 (240 ng/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 inter-individual 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 1600 mg HCQ followed by 600 mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72 hours in ≥60% (95% confidence-interval: 49.5-69.0%) of COVID-19 patients.

Necrotizing autoimmune myopathies (NAM) have recently been defined as a distinct group of severe acquired myopathies, characterized by prominent myofiber necrosis without significant muscle inflammation. Because of the lack of appropriate biomarkers, these diseases have been long misdiagnosed as atypical forms of myositis. NAM may be associated to autoantibodies directed against signal recognition particle (SRP) or 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). The objective of this work was to quantify anti-HMGCR autoantibodies in patients with suspicion of NAM through the development of a new addressable laser bead immunoassay (ALBIA).

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