Circulating proteomes provide a snapshot of the physiological state of a human organism responding to pathogenic challenges and drug interventions. The outcomes of patients with COVID-19 and acute respiratory distress syndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab is an anti-interleukin-6 treatment that exerts encouraging clinical activity by controlling the cytokine storm and improving respiratory distress in patients with COVID-19. We investigate the biological determinants of therapeutic outcomes after tocilizumab treatment. Overall, 28 patients hospitalized due to severe COVID-19 who were treated with tocilizumab intravenously were included in this study. Sera were collected before and after tocilizumab, and the patient's outcome was evaluated until day 30 post-tocilizumab infusion for favorable therapeutic response to tocilizumab and mortality. Hyperreaction monitoring measurements by liquid chromatography-mass spectrometry-based proteomic analysis with data-independent acquisition quantified 510 proteins and 7019 peptides in the serum of patients. Alterations in the serum proteome reflect COVID-19 outcomes in patients treated with tocilizumab. Our results suggested that circulating proteins associated with the most significant prognostic impact belonged to the complement system, platelet degranulation, acute-phase proteins, and the Fc-epsilon receptor signaling pathway. Among these, upregulation of the complement system by activation of the classical pathway was associated with poor response to tocilizumab, and upregulation of Fc-epsilon receptor signaling was associated with lower mortality.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient’s plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.

Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.

Background and ObjectivesProgressive multifocal leukoencephalopathy (PML) is a disabling neurologic disorder resulting from the infection of the CNS by JC polyomavirus in immunocompromised individuals. For the last 2 decades, increasing use of immunotherapies leads to iatrogenic PML. Iatrogenic PML is often associated with signs of inflammation at onset (inflammatory PML) and/or after treatment withdrawal immune reconstitution inflammatory syndrome (PML-IRIS). Although immune reconstitution is a key element for viral clearance, it may also be harmful and induce clinical worsening. A C-C chemokine receptor type 5 (CCR5) antagonist (maraviroc) has been proposed to prevent and/or limit the deleterious immune responses underlying PML-IRIS. However, the data to support its use remain scarce and disputed.MethodsWe conducted a multicenter retrospective cohort study at 8 university hospitals in France and Switzerland by collecting clinical, biological, and radiologic data of patients who developed inflammatory PML (iPML) or PML-IRIS related to immunosuppressive therapies used for chronic inflammatory diseases between 2010 and 2020. We added to this cohort, a meta-analysis of individual case reports of patients with iPML/PML-IRIS treated with maraviroc published up to 2021.ResultsOverall, 27 cases were identified in the cohort and 9 from the literature. Among them, 27 met the inclusion criteria: 16 treated with maraviroc and 11 with standard of care (including corticosteroids use). Most cases were related to MS (92.6%) and natalizumab (88%). Inflammatory features (iPML) were present at onset in 12 patients (44.4%), and most patients (92.6%) received corticosteroids within the course of PML. Aggravation due to PML-IRIS was not prevented by maraviroc compared with patients who received only corticosteroids (adjusted odds ratio: 0.408, 95% CI: 0.06-2.63). Similarly, maraviroc did not influence time to clinical worsening due to PML-IRIS (adjusted hazard ratio = 0.529, 95% CI: 0.14-2.0) or disability at the last follow-up (adjusted odds ratio: 2, 95% CI: 0.23-17.3).DiscussionThe use of CCR5 blockade did not help to keep deleterious immune reconstitution in check even when associated with corticosteroids. Despite maraviroc's reassuring safety profile, this study does not support its use in iPML/PML-IRIS.Classification of EvidenceThis study provides Class IV evidence showing that adding maraviroc to the management of iatrogenic iPML/PML-IRIS does not improve the outcome.

Purpose: To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome. Methods: Retrospective case series of patients presenting with catastrophic antiphospholipid syndrome and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at catastrophic antiphospholipid syndrome diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best-corrected visual acuity. Results: This study included 23 patients (11 cases treated by the authors and 12 published case reports); 21 (91%) of them female. Their median age at diagnosis was 28 years (range, 16–79 years). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n = 11, 48%), or retinal vasculitis (n = 1, 4%). Final best-corrected visual acuity was not significantly worse than the best-corrected visual acuity at diagnosis ( P = 0.16). Retinal vascular occlusions were associated with poorer final visual acuity than choroidopathy ( P = 0.002). After a median follow-up of 14 months (range, 2–132 months), nearly half the patients (n = 11, 48%) had permanent vision loss including best-corrected visual acuity of <20/400 for 4 patients. Conclusion: Posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome were mainly bilateral retinal vascular occlusion, which had the worst visual prognosis, followed by choroidopathy and retinal vasculitis. Permanent visual loss was common.

Purpose:To describe the posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome.Methods:Retrospective case series of patients presenting with catastrophic antiphospholipid syndrome and posterior segment ocular manifestations. The main outcomes were the type of posterior segment manifestations at catastrophic antiphospholipid syndrome diagnosis, specifically retinal vascular occlusion, vasculitis, or choroidopathy, and the final best-corrected visual acuity.Results:This study included 23 patients (11 cases treated by the authors and 12 published case reports); 21 (91%) of them female. Their median age at diagnosis was 28 years (range, 16-79 years). Ophthalmologic manifestations were usually bilateral (n = 19, 83%) and involved vascular occlusive retinopathy (n = 17, 74%), choroidopathy (n = 11, 48%), or retinal vasculitis (n = 1, 4%). Final best-corrected visual acuity was not significantly worse than the best-corrected visual acuity at diagnosis (P = 0.16). Retinal vascular occlusions were associated with poorer final visual acuity than choroidopathy (P = 0.002). After a median follow-up of 14 months (range, 2-132 months), nearly half the patients (n = 11, 48%) had permanent vision loss including best-corrected visual acuity of Conclusion:Posterior ophthalmic manifestations of catastrophic antiphospholipid syndrome were mainly bilateral retinal vascular occlusion, which had the worst visual prognosis, followed by choroidopathy and retinal vasculitis. Permanent visual loss was common.

Abstract Objectives Severe forms of coronavirus disease 2019 (COVID-19) are characterized by an excessive production of inflammatory cytokines. Activated monocytes secrete high levels of cytokines. Human monocytes are divided into three major populations: conventional (CD14posCD16neg), non-classical (CD14dimCD16pos), and intermediate (CD14posCD16pos) monocytes. The aim of this study was to analyze whether the distribution of conventional (CD16neg) and CD16pos monocytes is different in patients with COVID-19 and whether the variations could be predictive of the outcome of the disease. Methods We performed a prospective study on 390 consecutive patients referred to the Emergency Unit, with a proven diagnosis of SARS-CoV 2 infection by RT-PCR. Using the CytoDiff™ reagent, an automated routine leukocyte differential, we quantified CD16neg and CD16pos monocytes. Results In the entire population, median CD16neg and CD16pos monocyte levels (0.398 and 0.054×109/L, respectively) were in the normal range [(0.3–0.7×109/L) and (0.015–0.065×109/L), respectively], but the 35 patients in the intensive care unit (ICU) had a significantly (p<0.001) lower CD16pos monocyte count (0.018 × 109/L) in comparison to the 70 patients who were discharged (0.064 × 109/L) or were hospitalized in conventional units (0.058 × 109/L). By ROC curve analysis, the ratio [absolute neutrophil count/CD16pos monocyte count] was highly discriminant to identify patients requiring ICU hospitalization: with a cut-off 193.1, the sensitivity and the specificity were 74.3 and 81.8%, respectively (area under the curve=0.817). Conclusions Quantification of CD16pos monocytes and the ratio [absolute neutrophil count/CD16pos monocyte count] could constitute a marker of the severity of disease in COVID-19 patients.

Double-positive patients (DPP) exhibiting anti-glomerular basement membrane (GBM) and anti-neutrophil cytoplasmic antibodies (ANCAs) belong to an entity that is newly and poorly described, mainly in short series. We aimed to better characterize the epidemiological features, clinical presentation and therapeutic outcomes of these patients through a systematic review.We performed a systematic review of English-, German-, Spanish- and French-written publications from February 1987 to March 2020 reporting cases of DPP using the following databases: PubMed, Scielo, ScienceDirect, Google Scholar, The Cochrane Library, Open Grey, The Grey Literature Report, Clinicaltrials.gov and International Clinical Trial Registry Platform of the World Health Organization.In total, 538 DPP were identified from 90 articles. Their clinical presentations were often severe, and the majority exhibited acute kidney failure (91.8%) with a median initial serum creatinine level of 873 μmol/L; 50.7% had alveolar haemorrhage. Other manifestations were present in 30.3% of DPP, mainly ear, nose, throat and articular manifestations. ANCAs were predominantly directed against MPO (n = 377/523; 72.1%) compared to PR3 (n = 107/523; 20.5%), with rare cases of triple positivity (n = 15/538; 2.9%). Although most patients received initial immunosuppressive therapy (n = 285/317; 89.9%), the one-year overall, renal and relapse-free survival rates were 64.8%, 38.7% and 71.1%, respectively.DPP are associated with the characteristics of two eponymous vasculitis types, responsible for a poor overall and renal prognosis. Thus, simultaneous testing of both antibodies and systematic renal biopsy should be recommended in every patient with rapidly progressive glomerulonephritis to recognize this difficult-to-treat and rare disease.

The current outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) represents a source of concern for the management of patients with systemic lupus erythematosus (SLE). Indeed patients with SLE have an increased risk of severe infections due to intrinsic perturbations of their immune response, the use of immunosuppressive drugs, as well as the potential presence of organ damage associated with their disease. In this context, hydroxychloroquine (HCQ), a drug that is currently part of the long-term, standard-of-care treatment for SLE, has been reported to possess antiviral activity in vitro, and recent results from a preliminary clinical trial might support its use in curative or even prophylactic treatment for COVID-19.1–3 During the first days of the COVID-19 outbreak in France, we launched an observational study with the aim to follow the clinical course of COVID-19 in patients with SLE who received long-term treatment with HCQ. To be eligible, patients with SLE had to (1) fulfil the 1997 criteria of the SLE classifications of the American College of Rheumatology or those of the 2019 European League Against Rheumatism/American College of Rheumatology4 5; (2) be on long-term treatment with HCQ; and (3) have SARS-CoV-2 carriage in their nasopharyngeal swab, as confirmed by real-time reverse transcription PCR analysis. Data …

American Journal of HematologyVolume 96, Issue 2 p. E43-E46 CORRESPONDENCEFree Access High dose romiplostim as a rescue therapy for adults with severe bleeding and refractory immune thrombocytopenia Mathilde Roumier, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Departmanet of Internal Medicine, Foch Hospital, Suresnes, FranceSearch for more papers by this authorSébastien Le Burel, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Departmanet of Internal Medicine, Bégin Hospital, Saint-Mandé, FranceSearch for more papers by this authorSylvain Audia, Department of Internal Medicine and Clinical Immunology, Bocage Central University Hospital, CR INSERM 1098, Dijon, FranceSearch for more papers by this authorAdrien Chauchet, Department of Hematology, Besancon University Hospital, Besancon, FranceSearch for more papers by this authorMarie Gousseff, Department of Internal Medicine, Centre Hospitalier Bretagne Atlantique, Vannes, FranceSearch for more papers by this authorMohammed Hamidou, Department of Internal Medicine, Hôtel Dieu University Hospital, Nantes, FranceSearch for more papers by this authorFrançois Liferman, Departmanet of Internal Medicine, Centre Hospitalier de Dax, Dax, FranceSearch for more papers by this authorGuillaume Moulis, Department of Internal Medicine, Purpan University Hospital, Toulouse, FranceSearch for more papers by this authorBertrand Lioger, Departmanet of Internal Medicine, Saint-Louis Hospital, Paris, FranceSearch for more papers by this authorLionel Galicier, Department of Clinical Immunology, Saint Louis University Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceSearch for more papers by this authorMickael Ebbo, Department of Internal Medicine, La Conception Hospital, Assistance Publique Hôpitaux de Marseille, Université Aix-Marseille, Marseille, FranceSearch for more papers by this authorJonathan London, Department of Internal Medicine, Cochin University Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceSearch for more papers by this authorSolène Poutrel, Department of Internal Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, FranceSearch for more papers by this authorLouis Terriou, Department of Internal Medecine and Clinical Hematology, Claude-Huriez University Hospital, Université Lille Nord de France, Lille, FranceSearch for more papers by this authorVirginie Zarrouk, Department of Internal Medicine, Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Clichy, FranceSearch for more papers by this authorMarc Michel, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, FranceSearch for more papers by this authorBertrand Godeau, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, FranceSearch for more papers by this authorMatthieu Mahevas, Corresponding Author matthieu.mahevas@hmn.aphp.fr orcid.org/0000-0001-9182-1434 Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Correspondence Matthieu Mahevas, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France 94000. Email: matthieu.mahevas@hmn.aphp.frSearch for more papers by this author Mathilde Roumier, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Departmanet of Internal Medicine, Foch Hospital, Suresnes, FranceSearch for more papers by this authorSébastien Le Burel, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Departmanet of Internal Medicine, Bégin Hospital, Saint-Mandé, FranceSearch for more papers by this authorSylvain Audia, Department of Internal Medicine and Clinical Immunology, Bocage Central University Hospital, CR INSERM 1098, Dijon, FranceSearch for more papers by this authorAdrien Chauchet, Department of Hematology, Besancon University Hospital, Besancon, FranceSearch for more papers by this authorMarie Gousseff, Department of Internal Medicine, Centre Hospitalier Bretagne Atlantique, Vannes, FranceSearch for more papers by this authorMohammed Hamidou, Department of Internal Medicine, Hôtel Dieu University Hospital, Nantes, FranceSearch for more papers by this authorFrançois Liferman, Departmanet of Internal Medicine, Centre Hospitalier de Dax, Dax, FranceSearch for more papers by this authorGuillaume Moulis, Department of Internal Medicine, Purpan University Hospital, Toulouse, FranceSearch for more papers by this authorBertrand Lioger, Departmanet of Internal Medicine, Saint-Louis Hospital, Paris, FranceSearch for more papers by this authorLionel Galicier, Department of Clinical Immunology, Saint Louis University Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceSearch for more papers by this authorMickael Ebbo, Department of Internal Medicine, La Conception Hospital, Assistance Publique Hôpitaux de Marseille, Université Aix-Marseille, Marseille, FranceSearch for more papers by this authorJonathan London, Department of Internal Medicine, Cochin University Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceSearch for more papers by this authorSolène Poutrel, Department of Internal Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, FranceSearch for more papers by this authorLouis Terriou, Department of Internal Medecine and Clinical Hematology, Claude-Huriez University Hospital, Université Lille Nord de France, Lille, FranceSearch for more papers by this authorVirginie Zarrouk, Department of Internal Medicine, Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Clichy, FranceSearch for more papers by this authorMarc Michel, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, FranceSearch for more papers by this authorBertrand Godeau, Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, FranceSearch for more papers by this authorMatthieu Mahevas, Corresponding Author matthieu.mahevas@hmn.aphp.fr orcid.org/0000-0001-9182-1434 Department of Internal Medicine, National Referral Center for Adult'Immune Cytopenias Henri Mondor University Hospital, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France Correspondence Matthieu Mahevas, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France 94000. Email: matthieu.mahevas@hmn.aphp.frSearch for more papers by this author First published: 30 October 2020 https://doi.org/10.1002/ajh.26040Citations: 4AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat To the Editor: Life-threatening bleeding is a rare event in immune thrombocytopenia (ITP) and intracranial hemorrhage (ICH) occurs in less than 1% but is associated with a mortality rate of 44% in adults.1 Even if no controlled study has been conducted in patients with life-threatening bleeding, high-dose corticosteroids, IVIg and platelet transfusions are widely used. In an emergency with uncontrolled bleeding, starting high dose of TPO-RAs can be considered to rapidly increase the platelet count to a level where the risk of severe bleeding is minimized.2 Such off-label strategy has not been systematically evaluated. To evaluate the safety of this "rescue therapy" we carried out a multicenter retrospective cohort study of ITP patients treated with maximal dose of romiplostim for bleeding emergency from 2017 to 2019 in centers belonging to French national network for adult ITP. We included patients who fulfilled the following criteria:(a) Platelet count <30 × 109/L; (b) Severe bleeding manifestations defined as a score ˃ 8 according to the bleeding score previously reported by our group which takes into account cutaneous, mucosal and visceral bleeding3; (c) No response to corticosteroids and IVIg; (d) Rescue therapy with maximal dose of romiplostim (ie, 10 μg/kg body weight). Response (R) and Complete response (CR) were defined according to standardized international criteria.2 We included 30 patients (15 men) with ITP and severe bleeding manifestations (Table S1, Figure S1). The median age was 65 years [range 18-77]. Twenty-seven patients had newly diagnosed ITP and three chronic ITP. All patients had severe bleeding symptoms, characterized by skin and mucosal bleedings. The median bleeding score was 20 [range 8-33], including intracranial hemorrhage (n = 9), visceral hemorrhage — metrorrhagia, macroscopic hematuria, gastrointestinal or peritoneal bleeding (n = 16) (some patients had several manifestations). Twelve patients had received red blood cell transfusions because of severe anemia related to bleeding. The median platelet count was 2 × 109/L [range 0-10] at the time of severe bleeding. All 30 patients had received corticosteroids and IVIg treatment [median dose 2 g/kg.bw, range 1-4] as first-line therapy, and had failed to achieve any response. Twenty patients (67%) received platelet transfusions. Twenty-six patients had received intravenous vinca alkaloid (VA), in median 8 days (range 3-36) after initial bleeding symptoms: either concomitantly (ie,:1-3 days to romiplostim administration) in 20 cases; or 4-14 days before in six cases (8 mg vinblastine, n = 24 and 1 mg/m2 vincristine n = 2). Four patients did not receive VA including two patients who had a contra-indication to VA. Eight patients had received one or two other concomitant therapies. Romiplostim was started at a median of 9 days [range 3-40] after the first bleeding episode. At that time, bleeding symptoms were severe (bleeding score > 83), and for all but two patients, the platelet count was ≤20 × 109/L. These two patients received repeated platelet transfusions because of cerebral bleeding, with platelet counts 63 and 47 × 109/L, respectively. All patients received a starting dose of romiplostim at 10 μg/kg.bw/week from the first injection (n = 26), or from the second administration after a first attenuated dose of 5-8 μg/kg.bw (n = 4). During the first month of follow-up, the median peak platelet count among responders was 531 × 109/L [range 70-3840]; for 16 patients, the platelet count was >500 × 109/L and for nine it was >1000 × 109/L. Patients with a platelet count >1000 × 109/L received empirically low-dose aspirin. Three serious adverse events were noted. One 52-year-old woman who was bed-ridden because of a muscular hematoma, experienced deep-vein thrombosis with an asymptomatic pulmonary embolism 13 days after IVIg treatment and 5 days after the first romiplostim injection; the platelet count was 629 × 109/L at the time of thrombosis. One 70-year-old woman was diagnosed with ischemic stroke in the left parietal and right temporal lobes 13 days after IVIg administration and 10 days after the first romiplostim injection; at that time. Her platelet count was then in normal range (239 × 109/L). No predisposing condition for arterial thrombo-embolic events was found. Lastly, one 67-year-old patient who presented with cerebellar hemorrhage when diagnosed with ITP, died of cerebellar oedema 1 month after initial surgical treatment with external ventricular drains which had to be replaced several times because of infection or occlusion. At that time, cerebellar hemorrhage was stable and complete response was achieved 3 weeks before. We then evaluated response in the 20 patients who received romiplostim and concomitant VA treatment (VA + ROMI group) and compared to an historical cohort of 22 subjects with severe bleeding with absence of response to steroids and IVIg and who received VA without romiplostim (VA group) from 2008 to 2014. The two groups were not closely similar since patients in the VA + ROMI group had more severe bleeding manifestations, with a higher bleeding score (18 [range 8-33] vs 10 [range 8-28]), more ICH (30% vs 5%) and visceral hemorrhage (58% vs 36%) (Table 1). The day of VA administration was considered the starting point for evaluation. During the 14 days period of analysis, steroids were maintained at stable dose in all patients. Additional treatments administered are detailed in Table S1. At day 7 after VA +/− ROMI initiation, there was no significant difference in terms of response between the two groups (VA + ROMI: 70% vs VA: 48%, P = .15), but complete response was significantly higher in the group of patients who received VA + ROMI compared to those who received VA alone [60% vs 29%, P < .05]. Between day 7 and day 14, 13 patients (65%) received a second administration of ROMI in the VA + ROMI group; and 6 (30%) and 9 (41%) patients received a second administration of VA, respectively in the VA + ROMI and in the VA group. At day 14, both response and complete response were significantly higher in the VA + ROMI group compared to VA group [R: 80% vs 43%, P < .05; and CR: 70 vs 17%, P < .0001] (Figure 1). In the group receiving VA alone, one patient died at day 5 from uncontrolled bleeding and hemorrhagic shock, four experienced severe adverse events (agranulocytosis, n = 2, and urinary tract infection, n = 2). No thrombotic event was observed. TABLE 1. Characteristics of patients receiving VA plus ROMI and VA alone VA + ROMI (n = 20) VA (n = 22) Median age (range) 56 (18-93) 53 (22; 93) Gender: women / men 9 (45%) / 11 (55%) 14 (64%) / 8 (36%) Newly diagnosed 18 (90%) 18 (82%) Secondary ITP 4 (20%)aa Systemic lupus erythematosus (n = 2), EBV Infection (n = 1), Evan's syndrome (n = 1). 3 (14%)bb Systemic lupus (n = 1), hepatitis C (n = 1), chronic lymphoid leukemia (n = 1). Median platelet count, 109/L (range) 1 (0–5) 3 (1-10) Bleeding manifestations Median bleeding score 18 (9-33) 10 (8–28) Skin and mucosal bleeding 20 (100%) 22 (100%) Visceral hemorrhage 11 (58%) 8 (36%) Intracranial hemorrhage 6 (30%) 1 (4,5%) Red blood cell transfusions 8 (40%) 7 (32%) Treatment received prior to alkaloid/romiplostim initiation Steroids 20 (100%) 22 (100%) IVIg 20 (100%)cc Median dosage 2 g/kg.bw (range 2–4). 22 (100%)dd Median dosage 2 g/kg.bw (range 2-9). Other specific treatments 5 (25%)ee rituximab (n = 3), hydroxychloroquin (n = 1), eltrombopag (n = 3). 8 (36%)ff rituximab (n = 2), splenectomy (n = 1), danatrol (n = 2), disulone (n = 2), hydroxychloroquin (n = 1), anti-D gammaglobulins (n = 1); IVIg: Intraveinous immunoglobulin. Platelet transfusions 14 (70%) 10 (46%) a Systemic lupus erythematosus (n = 2), EBV Infection (n = 1), Evan's syndrome (n = 1). b Systemic lupus (n = 1), hepatitis C (n = 1), chronic lymphoid leukemia (n = 1). c Median dosage 2 g/kg.bw (range 2–4). d Median dosage 2 g/kg.bw (range 2-9). e rituximab (n = 3), hydroxychloroquin (n = 1), eltrombopag (n = 3). f rituximab (n = 2), splenectomy (n = 1), danatrol (n = 2), disulone (n = 2), hydroxychloroquin (n = 1), anti-D gammaglobulins (n = 1); IVIg: Intraveinous immunoglobulin. FIGURE 1Open in figure viewerPowerPoint Initial response to VA plus ROMI or VA in ITP patients refractory to IVIg and steroids. We compared the response at day 7 and 14 in the 20 patients who received romiplostim (ROMI) and concomitant vinca-alkaloid treatment (VA + ROMI) and compared to a historical cohort of 22 subjects receiving vinca-alkaloids without romiplostim (VA). (* P < .05, ***P < .001) Our work raises safety concerns, as major thrombotic events (TEs) occurred in two patients out of 30. It is noteworthy that in the present series, the platelet count was >500 × 109/L at time of thrombosis in one patient but <250 × 109/L in the other. This is in line with previous observations showing that thrombosis with TPO-RAs occurred independently from the platelet count4, 5 and may result from platelet activation. We cannot rule out a deleterious pro-thrombotic synergistic effect with other treatments, especially with IVIg which can itself promote TEs when other risk factors are present.6 Thrombocytosis with a platelet count over 1000 × 109/L was observed in a third of the patients, none of whom experienced a symptomatic thrombotic event. However, all were empirically treated with low dose aspirin. Our study strongly suggests that romiplostim given at a maximal dose is effective for treating patients with refractory ITP in emergency bleeding situations. Patients included in this study had life-threatening hemorrhage despite first-line therapy with corticosteroids + IVIg and with platelet transfusion in about two thirds of patients. Failure to respond to this first-line rescue therapy has been found to be associated with the risk of intracranial hemorrhage which occurred in 32% of our patients. Regarding the initial response, most patients received concomitant therapies that may have interfered with the interpretation of platelet response. In particular, vinca alkaloids were used in most patients, with an expected time to initial response that is similar to that of romiplostim.4 To minimize the risk of an interpretation bias, we focused our efficacy analysis on those patients who received romiplostim and VA concomitantly and compared their outcome to an historical group of patients who were treated only with VA in the same situation. We found a significantly higher overall response rate at day 14 in the ROMI + VA group and a significantly higher CR rate at days 7 and 14. The use of romiplostim rather than eltrombopag was preferred firstly because the subcutaneous route of administration was more suitable for critically ill patients with life-threatening bleeding, especially in the intensive care unit, and secondly because the range of dose of romiplostim [1-10 μg/kg/week] is higher than that of eltrombopag [25-75 mg daily]. However, there is no reason to speculate that eltrombopag at 75 mg/day would not also have been effective. The use of a lower dose of romiplostim (ie, 5 μg/kg) could potentially decrease the risk of thrombocytosis but also the efficacy rate. The main limitation of this study is the retrospective design and potential bias of analysis. In conclusion, this study shows that the use of romiplostim at maximal dosage as rescue therapy for ITP patients with severe bleeding not responding to standard rescue therapy is feasible and effective. The risk of thrombo-embolic events and the risk over benefit ratio should however be carefully assessed. Therefore, we suggest that this strategy should be restricted to life-threatening situations while awaiting more robust safety data. CONFLICT OF INTEREST MMa received research grants from GSK, and meeting attendance grants from GSK and Amgen. GM received research grants form CSL Behring, Novartis, Grifols, and meeting attendance grants from Amgen and Novartis. LG participated to educational boards for GSK. BG received research grant from Amgen, and B.G. served as an expert for Amgen, Novartis, LFB and Roche. ME has participated in advisory boards for Amgen, Grifols, GSK and Novartis. AUTHOR CONTRIBUTIONS M.Ma designed the study and initiated this work; B.G., M.M., M.R and S.LB wrote the report; all authors made substantial contributions to acquisition of data, revised the article critically and gave final approval of the manuscript to be submitted. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Supporting Information Filename Description ajh26040-sup-0001-FigureS1.tifTIFF image, 2.7 MB Figure S1 Patient flow chart. ajh26040-sup-0002-TableS1.docxWord 2007 document , 27.6 KB Table S1 Initial characteristics of ITP patients receiving romiplostim as rescue therapy at the maximal dosage (ie, 10 μg/kg.bw/week). Bleeding score was graded by an ITP specific bleeding scale by Khellaf et al. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Melboucy-Belkhir S, Khellaf M, Augier A, et al. Risk factors associated with intracranial hemorrhage in adults with immune thrombocytopenia: a study of 27 cases. Am J Hematol. 2016; 91(12): E499- E501. https://doi.org/10.1002/ajh.24529. Wiley Online LibraryPubMedWeb of Science®Google Scholar 2Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019; 3(22): 3780- 3817. https://doi.org/10.1182/bloodadvances.2019000812. CrossrefPubMedWeb of Science®Google Scholar 3Khellaf M, Michel M, Schaeffer A, Bierling P, Godeau B. Assessment of a therapeutic strategy for adults with severe autoimmune thrombocytopenic purpura based on a bleeding score rather than platelet count. Haematologica. 2005; 90(6): 829- 832. PubMedWeb of Science®Google Scholar 4Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019; 104(6): 1112- 1123. https://doi.org/10.3324/haematol.2018.212845. CrossrefCASPubMedWeb of Science®Google Scholar 5Rodeghiero F, Stasi R, Giagounidis A, et al. Long-term safety and tolerability of romiplostim in patients with primary immune thrombocytopenia: a pooled analysis of 13 clinical trials. Eur J Haematol. 2013; 91(5): 423- 436. https://doi.org/10.1111/ejh.12181. Wiley Online LibraryCASPubMedGoogle Scholar 6Moulis G, Audemard-Verger A, Arnaud L, et al. Risk of thrombosis in patients with primary immune thrombocytopenia and antiphospholipid antibodies: a systematic review and meta-analysis. Autoimmun Rev. 2016; 15(3): 203- 209. https://doi.org/10.1016/j.autrev.2015.11.001. CrossrefPubMedWeb of Science®Google Scholar Citing Literature Volume96, Issue2February 1, 2021Pages E43-E46 FiguresReferencesRelatedInformation

Background: High levels of serum Interleukin-6 correlate with disease severity in COVID-19 pneumonia. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. Methods: The TOCICOVID study included a prospective cohort of patients aged 16-80 years with severe (requiring >6L/min of oxygen therapy to obtain Sp02 >94%) rapidly deteriorating (increase by ≥3L/min of oxygen flow within the previous 12 hours) COVID-19 pneumonia with ≥5 days of symptoms and high C-reactive protein levels who entered a compassionate use program of treatment with intravenous tocilizumab (8mg/kg with a maximum of 800mg per infusion; and if needed a second infusion 24 to 72 hours later) and a control group (retrospectively selected with the same inclusion criteria). Outcomes were assessed at D15 using inverse probability of treatment weighted (IPTW) methodology. Findings: Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, disease severity and concomitant medications were well balanced between groups (tocilizumab, n=49; control, n=47). In the IPTW analysis, t reatment with tocilizumab prevented the need for ventilatory support (49 vs. 87%, wHR: 0.42 [0.29–0.60]; p<0.001) and invasive mechanical ventilation (29% vs. 46%; wHR: 0.56 [0.34–0,90]; p=0.017) within D15 after baseline, with an acceptable safety profile . However, tocilizumab did not improve overall survival at D15 (wHR=0.69 [0.26 – 1.77], p=0.438). Among the patients still alive at D15 (n=87/96, 91%) , those treated with tocilizumab had a higher rate of oxygen withdrawal: 58% vs 41%, wHR=1.75 [1.13 – 2.74], p=0.012), with a shorter delay (10 vs 11 days; p=0.021). The levels of CRP, fibrinogen (p<0.001 for both variables) and neutrophil-to-lymphocyte ratios (p=0.03) were significantly lower in the tocilizumab group (interaction test, mixed model). Interpretation: These findings support the fostering of research efforts in the fight against COVID-19-induced inflammation. Funding Statement: All costs (including funding for tocilizumab) were beared by Foch hospital. Declaration of Interests: MR: investigator of NCT04315298 trial which investigates the efficacy and safety of Sarilumab (licensed by Sanofi) in hospitalized patients with COVID-19; non-financial support from Novartis Pharma SAS, Bristol Myers Squibb, Swedish Orphan Biovitrum (outside the submitted work); HS: non-financial support from Oxyvie; grants for Foch Fundation, Fonds de dotation pour la recherche en sante respiratoire, Philips Fundation (outside the submitted work); GG: non-financial support from Bard (outside the submitted work); YS: non-financial support from Astra Zeneca, Novartis Pharma, Bristol Myers Squibb, Sanofi Aventis France, Shire France, Chugai Pharma France, Pfizer SAS (outside the submitted work); JLC: personal fees and non-financial support from Novartis, Boehringer Ingelheim and Astra Zeneca; grants and other from LVL Air Liquide, outside the submitted work; JEK: none; MG: consulting fees from GlaxoSmithKline and Astra Zeneca (outside the submitted work); FA: investigator of NCT04315298 trial which investigates the efficacy and safety of Sarilumab (licensed by Sanofi) in hospitalized patients with COVID-19; all other authors declare no competing interest. Ethics Approval Statement: The TOCICOVID study was approved by the Foch IRB (approval number IRB00012437) and was registered on the National Institute of Health data platform INDS (n°4710280420).

Abstract Objective To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. Design Comparative observational study using data collected from routine care. Setting Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. Participants 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. Interventions Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). Main outcome measures The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. Conclusions Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.

Objectives There is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD. Methods Individuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderatesevere) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities. Results Of 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05-1.10), female gender (OR=0.45, 95% CI: 0.25-0.80), body mass index (OR=1.07, 95% CI: 1.02-1.12), hypertension (OR=1.86, 95% CI: 1.01-3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09-3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47-29.62) and rituximab (OR=4.21, 95% CI: 1.61-10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87-2.42) (n=175 each group). Conclusions In the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD.

AbstractIn the context of COVID-19 pandemic and growing tensions worldwide regarding healthcare facilities, there is an urgent need for effective treatments likely to reduce the crunch of ICU beds. Following the assumption by Mehta and colleagues who exhorted physicians to screen patients with severe COVID-19 for hyperinflammation and investigate immunomodulatory drugs in this setting, we relate our short-term - yet promising - experience regarding IL6 blockade with tocilizumab in 30 selected patients of less than 80 years of age, >5 days of prior disease duration, severe (i.e. requiring strictly over 6L/min of oxygen therapy) rapidly deteriorating (i.e. increase by more than 3L/min of oxygen flow within the previous 12 hours) COVID-19-related pneumonia. By comparison with a control group of patients (matched for age, gender and disease severity using the inverse probability of treatment weighted methodology) that did not receive tocilizumab. We demonstrate that, in highly selected patients, IL6 blockade could curb the “cytokine storm”, prevent ICU admission and the requirement for mechanical ventilation. Notwithstanding the shortcomings of this retrospective small sample-size study, we believe that these preliminary findings support the fostering of research efforts in the fight against COVID-19-induced inflammation, especially before patients require admission to the ICU.

Treatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies. We used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting.