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      Rheumatic disease and COVID-19: initial data from the COVID-19 Global Rheumatology Alliance provider registries

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          Abstract

          Individuals with inflammatory rheumatic disease require special consideration with regard to coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many of these individuals are considered at-risk for serious infections due to their immunocompromised state resulting from their underlying immune conditions and use of targeted immune-modulating therapies such as biologics.1, 2, 3, 4 However, some disease-modifying drugs commonly used to treat rheumatic diseases, such as hydroxychloroquine, are being investigated as potential therapies for COVID-19. 5 Other commonly used therapies, such as biologics targeting interleukin (IL)-6 (eg, tocilizumab, sarilumab) and IL-1 (eg, anakinra), are being assessed in patients with COVID-19 and who have subsequently developed pathological immune responses, including cytokine storm (eg, reactive haemophagocytic lymphohistiocytosis). 6 Whether background immunosuppressive medications put individuals with rheumatic disease at an increased or decreased risk for severe SARS-CoV-2 infection is unknown, 7 and evidence is lacking to guide treatment decisions. A general understanding of COVID-19 characteristics in this population is urgently needed to inform management guidelines and identify high-risk individuals during the pandemic. The need for data to answer these key clinical questions was quickly realised and coordinated on a global scale by rheumatologists, researchers, and patients with rheumatic diseases. Despite the recognised track-record of high-quality observational drug safety research in rheumatology within multiple national biological registries, 8 immediate data on COVID-19-specific outcomes would need to be collected to address this demand. Therefore, the international rheumatology community mobilised at an unprecedented pace to create the COVID-19 Global Rheumatology Alliance. In less than 1 week, the COVID-19 Global Rheumatology Alliance successfully developed online portals and case report forms to enable health-care providers around the world to enter information on individuals with rheumatic disease who have been diagnosed with COVID-19. Registry data elements include provider name, city, country, and clinic, and individual patient-level sociodemographic information, including age, sex, race, and ethnicity. Data regarding rheumatic disease are captured, including medications before COVID-19 diagnosis, disease activity, and comorbidities. Information on COVID-19-related illness includes diagnosis date, symptoms, treatment, and outcomes, such as admission to hospital and maximum level of care (eg, need for supplemental oxygen, invasive ventilation). Laboratory results for other co-infections, IL-6 concentrations, leucopenia, and more are also collected, if available. Due to international data legislation, in particular, the European General Data Protection Regulations, parallel data entry points (one limited to European League Against Rheumatism [EULAR]-participating countries, the other limited to sites globally have been launched. Both data entry points link to secure RedCap survey platforms hosted by The University of Manchester (Manchester, UK), and the University of California, San Francisco (UCSF; San Francisco, CA, USA), where providers submit data on individuals with rheumatic disease who have been diagnosed with COVID-19. Individual patient consent is not required for this registry, which was determined “not human subjects research” by the UK Health Research Authority, The University of Manchester, the US Federal Guidelines by UCSF, and several other institutions. As of April 1, 2020, 110 individuals with rheumatic disease who have been diagnosed with COVID-19 are included from six continents: Europe, North America, South America, Asia, Africa, and Oceania; a summary of data associated with these individuals is shown in the table . Table Demographic and disease characteristics of individuals with rheumatic disease diagnosed with COVID-19 in the COVID 19 Global Rheumatology Alliance registry as of April 1, 2020 Cohort (n=110) Sex Female 79 (72%) Male 31 (28%) Aged >65 years 20 (18%) Primary rheumatic disease* Rheumatoid arthritis 40 (36%) Psoriatic arthritis 19 (17%) Systemic lupus erythematosus 19 (17%) Axial spondyloarthritis 7 (6%) Vasculitis 7 (6%) Sjogren's syndrome 5 (5%) Other 17 (15%) Medications before diagnosis of COVID-19 Conventional synthetic DMARDs† 69 (63%) Biological DMARDs‡ 49 (45%) JAK inhibitor 5 (5%) NSAIDs† 28 (25%) Glucocorticoids 27 (25%) Other§ 5 (5%) Five most common COVID-19 symptoms at onset Fever 87 (79%) Cough 85 (77%) Shortness of breath 55 (50%) Myalgia 49 (45%) Sore throat 41 (37%) Admitted to hospital 39 (35%) Died 6 (5%) Five most common comorbid conditions Hypertension 31 (28%) Lung disease¶ 22 (20%) Cardiovascular disease 12 (11%) Morbid obesity (BMI ≥40 kg/m2) 9 (8%) Diabetes 9 (8%) Data are n (%). COVID-19=coronavirus disease 2019. DMARD=disease-modifying antirheumatic drug. NSAID=nonsteroidal anti-inflammatory drugs. JAK=Janus kinase. BMI=body-mass index. * Individuals could have more than one rheumatic disease diagnosis; other included (all with n <5): inflammatory myopathy, ocular inflammation, other inflammatory arthritis, polymyalgia rheumatica, sarcoidosis, systemic sclerosis, osteoporosis, psoriasis, isolated pulmonary capillaritis, gout, and autoinflammatory disease. † Conventional synthetic DMARD medications included antimalarials, azathioprine, cyclophosphamide, ciclosporine, leflunomide, methotrexate, mycophenolate mofetil, mycophenolic acid, sulfasalazine, and tacrolimus. ‡ Biological DMARDs included abatacept, belimumab, CD20 inhibitors, IL-1 inhibitors, IL-6 inhibitors, IL-12 and IL-23 inhibitors, IL-17 inhibitors, and tumor necrosis factor inhibitors. § Other included antifibrotics, apremilast, intravenous immunoglobulin, thalidomide or lenalidomide, and other not specified. ¶ Chronic obstructive pulmonary disease, asthma, interstitial lung disease, or other not specified. We present proof-of-principle that, with global cooperation, the rapid collection of data during an international crisis is possible. Within 1 week of launching the registry, rheumatology providers from around the world have submitted data on more than 100 cases, allowing very preliminary characterisation and rapid dissemination of information regarding COVID-19 in individuals with rheumatic disease. Over time, the registry aims to examine differences in severity of outcomes by sociodemographic and rheumatic disease characteristics, medications taken before diagnosis of COVID-19, and medications administered on diagnosis. These data will serve to inform treatment strategies and better characterise individuals at increased risk of infection. The strengths of the COVID-19 Global Rheumatology Alliance registry include global representation of individuals with rheumatic disease with COVID-19, which increases the power of the evidence base to examine important risk factors and outcomes. We expect that a major contribution of the COVID-19 Global Rheumatology Alliance will be rapid dissemination of information, since existing national patient registries might be less equipped to capture data on a global scale, given fixed timepoints and restrictions on consent of new individuals. The registry is not without limitations, including a potential selection bias towards more severe cases, because in many countries only individuals with severe symptoms are being tested for COVID-19. Rheumatologists reporting cases are also under extreme pressure to work outside of rheumatology and provide front-line medical care to all patients with COVID-19 and might be unable to report cases, or reporting might be delayed. Duplicate entries might occur across different providers, although our data analytics teams carefully examine and address data quality on a regular basis. Also, despite including individuals from across the world, specific adjusted analyses might not be possible due to sample size. Finally, as the whole denominator of individuals with rheumatic diseases who acquire COVID-19 is unknown, the database will be unable to provide accurate estimates of the risk of specific outcomes across the entire rheumatic disease population or in association with specific treatments. With time, existing patient registries and administrative databases will provide these data, but likely not until the current pandemic has ended, thus strengthening the current and critical role of this database. In summary, the COVID-19 Global Rheumatology Alliance represents the commitment of rheumatologists to generate rapid data to help inform the care of individuals with rheumatic disease and those using immunomodulating therapies. Information from this database will provide timely and responsive real-world data where large literature gaps exist, informing providers of treatment patterns for individuals diagnosed with COVID-19, and offering a better understanding of possible risk factors associated with severe outcomes in the rheumatic disease population.

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            COVID-19 infection and rheumatoid arthritis: Faraway, so close!

            The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.
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              A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

              Hydroxychloroquine, an essential treatment for many patients with rheumatologic conditions, has recently garnered widespread attention as a potential treatment for COVID-19 infection. The authors appraise the study generating this interest and highlight the potential consequences of rapid dissemination of overinterpreted data, particularly for people with conditions for which hydroxychloroquine has demonstrated benefits in preventing organ damage and life-threatening disease flares.
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                Author and article information

                Contributors
                Journal
                Lancet Rheumatol
                Lancet Rheumatol
                The Lancet Rheumatology
                Elsevier Ltd.
                2665-9913
                16 April 2020
                16 April 2020
                Affiliations
                [a ]Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, 94143 CA, USA
                [b ]Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
                [c ]National Institute of Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
                [d ]Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris France
                [e ]Rheumatology Department, Pitié-Salpêtrière hospital, AP-HP, Paris, France
                [f ]Epidemiology Unit, German Rheumatism Research Center (DRFZ Berlin), Berlin, Germany
                [g ]Instituto de Salud Musculoesquelética, Madrid, Madrid, Spain
                [h ]Portuguese League Against Rheumatic Diseases (LPCDR), Lisbon, Portugal
                [i ]EULAR Standing Committee of PARE (People with Arthritis Rheumatism in Europe), Zurich, Switzerland
                [j ]Healthpartners, St. Paul, MN, USA
                [k ]Department of Medicine, University of Otago, Dunedin, Otago, New Zealand
                [l ]Massachusetts General Hospital and Program in Rheumatology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
                [m ]Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
                [n ]Crystal Run Health, Middletown, NY, USA
                [o ]Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
                [p ]Canadian Arthritis Patient Alliance, Toronto, ON, Canada
                [q ]Division of Rheumatology, University of Washington, Seattle, WA, USA
                [r ]Irish Children's Arthritis Network (iCAN), Tipperary, Ireland
                [s ]University of Queensland Faculty of Medicine, Brisbane, QLD, Australia
                [t ]Centre for Rheumatology and Department of Neuromuscular Diseases, University College London, London, UK
                [u ]Department of Rheumatology and Queen Square Centre for Neuromuscular Diseases, University College London Hospitals NHS Foundation Trust, London, UK
                [v ]Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS trust, London, UK
                Author notes
                [†]

                Members of the COVID-19 Global Rheumatology Alliance Steering Committee are listed in the appendix (p 1).

                Article
                S2665-9913(20)30095-3
                10.1016/S2665-9913(20)30095-3
                7162647
                32309814
                7ae191ec-a997-499c-9275-f72865834dc7
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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