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Response to: ‘Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician reported registry’’ by Mulhearn et al
  1. Martin Schäfer1,
  2. Anja Strangfeld1,
  3. Kimme L Hyrich2,3,
  4. Loreto Carmona4,
  5. Milena Gianfrancesco5,
  6. Saskia Lawson-Tovey2,3,
  7. Elsa F Mateus6,7,
  8. Laure Gossec8,9,
  9. Philip C Robinson10,11,
  10. Jinoos Yazdany5,
  11. Pedro M Machado12,13,14
  1. 1 German Rheumatism Research Center (DRFZ Berlin), Epidemiology and Health Care Research, Berlin, Germany
  2. 2 Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  3. 3 National Institute of Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
  4. 4 Instituto de Salud Musculoesquelética, Madrid, Spain
  5. 5 Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA
  6. 6 Portuguese League Against Rheumatic Diseases (LPCDR), Lisbon, Portugal
  7. 7 Standing Committee of People with Arthritis/Rheumatism in Europe (PARE), European Alliance of Associations for Rheumatology (EULAR), Kilchberg, Switzerland
  8. 8 Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, Sorbonne Universite, Paris, France
  9. 9 Rheumatology Department, Pitié-Salpêtrière hospital, AP-HP.Sorbonne Université, Paris, France
  10. 10 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  11. 11 Royal Brisbane & Women’s Hospital, Metro North Hospital & Health Service, Herston, Queensland, Australia
  12. 12 Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK
  13. 13 National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, London, UK
  14. 14 Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, UK
  1. Correspondence to Dr Pedro M Machado, Centre for Rheumatology, University College London, London, UK; p.machado{at}

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We thank Ben Mulhearn1 for his correspondence on our article.2 The correspondence raises the important question of whether moderate-dose to high-dose glucocorticoid (GC) therapy is an independent risk factor for COVID-19-related death or whether this association is rather due to confounding by indication.

First of all, we would like to re-emphasise that causal interpretation of results based on data from a cross-sectional observational study like the one we report is not possible. The only study design that rises to the level of demonstrating cause and effect is the randomised controlled trial. Confounding by indication is a particularly important and very common type of bias in observational studies, and it occurs when an exposure appears to be associated with an outcome (distorted association), but the outcome (eg, ‘death’) is, in fact, caused by the indication for which the exposure was used, that is, the indication (eg, ‘disease activity’) prompted the exposure (eg, ‘GC therapy’).3

For these reasons, in our manuscript we explicitly caution against interpreting our estimates causally. Specifically, we use non-directional and non-causal language, reporting an ‘association’ of GC prednisolone-equivalent dosage >10 mg/day with COVID-19-related death and avoiding language that could imply a causal relationship.

Due to space constraints, in our discussion we focused on other aspects of the results. However, this correspondence provides an opportunity for us to extend the discussion about the interplay between disease activity and GC therapy, bearing in mind that this aspect is particularly important for the treating clinician. Indeed, the benefit to risk ratio of GC in the context of rheumatic diseases has been a matter of significant debate for many years.4

In our data set, the vast majority of patients who did not receive GCs or received them in prednisolone-equivalent dosages equal to or less than 10 mg/day were …

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  • Handling editor Josef S Smolen

  • Twitter @carmona_loreto, @philipcrobinson, @pedrommcmachado

  • Contributors MS, AS and PMM drafted the first version of the manuscript. All authors revised the manuscript and approved the final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Disclaimer The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the UK National Health Service, the National Institute for Health Research or the UK Department of Health, or any other organisation.

  • Competing interests MS has nothing to disclose. AS reports personal fees from lectures for AbbVie, MSD, Roche, BMS and Pfizer, all outside the submitted work. KLH reports she has received non-personal speaker’s fees from AbbVie and grant income from BMS, UCB and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as AbbVie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal and UCB Pharma. MG reports grants from the National Institutes of Health, NIAMS, outside the submitted work. SL-T has nothing to disclose. EFM reports that LPCDR received support for specific activities: grants from AbbVie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal, MSD, Celgene, Medac, Pharma Kern and GAfPA; grants and non-financial support from Pfizer; and non-financial support from Grünenthal, outside the submitted work. LG reports personal consultant fees from AbbVie, Amgen, BMS, Biogen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis and UCB; and grants from Amgen, Lilly, Janssen, Pfizer, Sandoz, Sanofi and Galapagos, all unrelated to this manuscript. PCR reports personal fees from AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Roche and UCB; non-financial support from BMS; and research funding from Janssen, Novartis, Pfizer and UCB, all outside the submitted work. JY reports consulting fees from AstraZeneca and Eli Lilly; and grants from Pfizer, outside the submitted work. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC).

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; internally peer reviewed.

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