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We appreciate the interest in our paper1 and the opportunity to provide additional clarification and context. It is now generally accepted that there are different phases of COVID-19 illness.2 Our study investigated baseline use, presumably at the earliest phase of infection where viral replication is most pronounced. Clinical trials have typically tested the efficacy of medication use among hospitalised patients where pathologic hyperinflammation may mediate poor clinical outcomes. Therefore, the timing of immunomodulator use related to the COVID-19 disease course may have different effects on clinical outcomes, and trial results may not be able to be extrapolated to observational studies of baseline medication use.
Observational results may lend insight into key immune mechanisms that could alter the trajectory of COVID-19, but the results could be confounded. To limit possible confounding by indication, our study used an active comparator study design that included patients with a single disease, rheumatoid arthritis (RA), who were taking biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD).1 In doing so, we included patients with similar disease severity who had the opportunity to receive advanced therapy. We compared each class of b/tsDMARD to tumour necrosis factor inhibitors (TNFi) since this was the most commonly used b/tsDMARD. Of note, medications were collected by mechanism of action, rather than individual drugs. While this observational study design minimised possible confounding, all patients were on some immunomodulator regimen, so it is possible that some of these medications might have had favourable effects on the COVID-19 disease trajectory.
We agree that our finding associating rituximab for use in RA with worsened COVID-19 severity compared with TNFi use1 has biologic plausibility due to the importance of the adaptive immune response to infections and to SARS-CoV-2 in particular. A previous GRA study also associated rituximab use with increased COVID-19-related …
Handling editor Josef S Smolen
Twitter @zach_wallace_md, @jeffsparks, @philipcrobinson, @pedrommcmachado
ZSW and JAS contributed equally.
Contributors ZSW and JAS conceptualised and drafted the paper. All authors 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 the participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology (ACR), the European Alliance of Associations for Rheumatology (EULAR), the (UK) National Health Service (NHS), the National Institute for Health Research (NIHR) or the (UK) Department of Health, or any other organisation.
Competing interests JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253 and P30 AR072577), the Rheumatology Research Foundation (K Supplement Award and R Bridge Award), the Brigham Research Institute, and the R Bruce and Joan M Mickey Research Scholar Fund. JAS has received research support from Amgen and Bristol-Myers Squibb and performedconsultancy for Bristol-Myers Squibb, Gilead, Inova, Janssen and Optum, unrelated to this work. ZSW reports grant support from Bristol-Myers Squibb and Principia/Sanofi and performed consultancy for Viela Bio and MedPace, outside the submitted work. His work is supported by grants from the National Institutes of Health. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this study (all <$10 000). PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). PCR reports no competing interests related to this work. Outside of this work, he reports personal consulting and/or speaking fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and UCB, and travel assistance from Roche (all <$10 000). JY reports no competing interests related to this work. Her work is supported by grants from the National Institutes of Health, Centers for Disease Control and the Agency for Healthcare Research and Quality. She has performed consulting for Eli Lilly and AstraZeneca, unrelated to this project.
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.