TY - JOUR
T1 - Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis
T2 - a multinational, retrospective study
AU - Lane, Jennifer C. E.
AU - Weaver, James
AU - Kostka, Kristin
AU - Duarte-Salles, Talita
AU - Abrahao, Maria Tereza F.
AU - Alghoul, Heba
AU - Alser, Osaid
AU - Alshammari, Thamir M.
AU - Biedermann, Patricia
AU - Banda, Juan M.
AU - Burn, Edward
AU - Casajust, Paula
AU - Conover, Mitchell M.
AU - Culhane, Aedin C.
AU - Davydov, Alexander
AU - DuVall, Scott L.
AU - Dymshyts, Dmitry
AU - Fernandez-Bertolin, Sergio
AU - Fišter, Kristina
AU - Hardin, Jill
AU - Hester, Laura
AU - Hripcsak, George
AU - Kaas-Hansen, Benjamin Skov
AU - Kent, Seamus
AU - Khosla, Sajan
AU - Kolovos, Spyros
AU - Lambert, Christophe G.
AU - van der Lei, Johan
AU - Lynch, Kristine E.
AU - Makadia, Rupa
AU - Margulis, Andrea V.
AU - Matheny, Michael E.
AU - Mehta, Paras
AU - Morales, Daniel R.
AU - Morgan-Stewart, Henry
AU - Mosseveld, Mees
AU - Newby, Danielle
AU - Nyberg, Fredrik
AU - Ostropolets, Anna
AU - Park, Rae Woong
AU - Prats-Uribe, Albert
AU - Rao, Gowtham A.
AU - Reich, Christian
AU - Reps, Jenna
AU - Rijnbeek, Peter
AU - Sathappan, Selva Muthu Kumaran
AU - Schuemie, Martijn
AU - Seager, Sarah
AU - Sena, Anthony G.
AU - Shoaibi, Azza
AU - Spotnitz, Matthew
AU - Suchard, Marc A.
AU - Torre, Carmine O.
AU - Vizcaya, David
AU - Wen, Haini
AU - de Wilde, Marcel
AU - Xie, Junqing
AU - You, Seng Chan
AU - Zhang, Lin
AU - Zhuk, Oleg
AU - Ryan, Patrick
AU - Prieto-Alhambra, Daniel
N1 - Funding Information:
JW is an employee and shareholder at Janssen Research and Development. SLDV reports grants from Anolinx, Astellas Pharma, AstraZeneca Pharmaceuticals, Boehringer Ingelheim International, Celgene, Eli Lilly, Genentech, Genomic Health, Gilead Sciences, GlaxoSmithKline, Innocrin Pharmaceuticals, Janssen Pharmaceuticals, Kantar Health, Myriad Genetic Laboratories, Novartis International, Parexel International through the Western Institute for Biomedical Research, the non-profit corporation associated with the Department of Veterans Affairs (Salt Lake City, UT, USA; outside the submitted work). GH reports grants from the US National Library of Medicine and Janssen Research (outside the submitted work). BSK-H reports grants from the Innovation Fund Denmark (5153-00002B) and Novo Nordisk Foundation (NNF14CC0001; outside the submitted work). SKh is an employee of and stockholder in AstraZeneca. JvdL reports grants from the Innovative Medicines Initiative (during the conduct of the study). AVM is an employee of RTI Health Solutions, a unit of the independent, non-profit research organisation RTI international. DRM reports funding support from the Wellcome Trust, the UK National Institute for Health Research (NIHR), Scottish Chief Scientist Office, and Tenovus Scotland (outside the submitted work). MM and MdW report grants from the Innovative Medicines Initiative (during the conduct of the study). FN was an employee of AstraZeneca until September, 2019. GAR is an employee of Janssen Research and Development. PRi reports grants from the Innovative Medicines Initiative and Janssen Research and Development (during the conduct of the study). MSc is an employee of and shareholder in Janssen Research and Development. JH, JR, RM, PRy, MSc, and AGS are employees of Janssen Research and Development and shareholders in Johnson & Johnson. AS, LH, and MMC are employees of Janssen Research and Development. HM-S, KK, CR, COT, and SS are employees of IQVIA. MAS reports grants from the US National Science Foundation and US National Institutes of Health, and personal fees from Janssen Research and Development (during the conduct of the study). DV reports personal fees from Bayer (outside the submitted work) and is a full-time employee of Bayer. SCY reports grants from the Korean Ministry of Health and Welfare and the Korean Ministry of Trade, Industry and Energy (during the conduct of the study). DP-A reports grants from Amgen, UCB Biopharma, and Les Laboratoires Servier; personal fees (paid to his department) from Amgen and UCB Biopharma; and support for training programmes organised by his department from Innovative Medicines Initiative-funded European Health Data and Evidence Network and European Medical Information Framework consortiums, and Synapse Management Partners. All other authors declare no competing interests.
Funding Information:
This research received partial support from the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Korean Ministry of Health and Welfare (grant number HI16C0992 to SCY). Personal funding was provided by Versus Arthritis (21605; to JCEL), UK Medical Research Council (MRC) Doctoral Training Partnership (MR/K501256/1; to JCEL); MRC (MR/K501256/1 and MR/N013468/1; to AP-U) and Fundacion Alfonso Martin Escudero (to AP-U); Innovation Fund Denmark (5153-00002B) and the Novo Nordisk Foundation (NNF14CC0001; to BSK-H); Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant (NMRC/OFLCG/001/2017; to SMKS); VINCI (VA HSR RES 13-457; to SLD, MEM, and KEL); and NIHR Senior Research Fellowship (SRF-2018-11-ST2-004 to DP-A). The European Health Data and Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 806968. The Innovative Medicines Initiative 2 Joint Undertaking receives support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations. The views and opinions expressed are those of the authors and do not necessarily reflect those of the NIHR senior Research Fellowship programme, NIHR, US Department of Veterans Affairs, or the US Government, UK National Health Service, or the UK Department of Health. We thank Catherine Hartley and Eli Harriss (Bodleian Health Care Libraries, University of Oxford, Oxford, UK), Runsheng Wang (Division of Rheumatology, Columbia University Irving Medical Center, New York, NY, USA), Joel Swerdel (Janssen Research and Development, Titusville, NJ, USA), Zeshan Ghory (IQVIA, Cambridge, MA, USA), Michael Kallfelz (Odysseus Data Services, Berlin, Germany), and Nigel Hughes (Janssen Research and Development, Beerse, Belgium). Finally, we acknowledge the tremendous work and dedication of the 350 participants from 30 nations in the March, 2020, Observational Health Data Sciences and Informatics COVID-19 Virtual Study-a-thon , without whom this study could not have been realised.
Publisher Copyright:
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4.Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.
AB - Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4.Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.
UR - http://www.scopus.com/inward/record.url?scp=85090162682&partnerID=8YFLogxK
U2 - 10.1016/S2665-9913(20)30276-9
DO - 10.1016/S2665-9913(20)30276-9
M3 - Article
C2 - 32864627
SN - 2665-9913
VL - 2
SP - e698-e711
JO - The Lancet Rheumatology
JF - The Lancet Rheumatology
IS - 11
ER -
