Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

, Jennifer C. E. Lane, James Weaver, Kristin Kostka, Talita Duarte-Salles, Maria Tereza F. Abrahao, Heba Alghoul, Osaid Alser, Thamir M. Alshammari, Patricia Biedermann, Juan M. Banda, Edward Burn, Paula Casajust, Mitchell M. Conover, Aedin C. Culhane, Alexander Davydov, Scott L. DuVall, Dmitry Dymshyts, Sergio Fernandez-Bertolin, Kristina FišterJill Hardin, Laura Hester, George Hripcsak, Benjamin Skov Kaas-Hansen, Seamus Kent, Sajan Khosla, Spyros Kolovos, Christophe G. Lambert, Johan van der Lei, Kristine E. Lynch, Rupa Makadia, Andrea V. Margulis, Michael E. Matheny, Paras Mehta, Daniel R. Morales, Henry Morgan-Stewart, Mees Mosseveld, Danielle Newby, Fredrik Nyberg, Anna Ostropolets, Rae Woong Park, Albert Prats-Uribe, Gowtham A. Rao, Christian Reich, Jenna Reps, Peter Rijnbeek, Selva Muthu Kumaran Sathappan, Martijn Schuemie, Sarah Seager, Anthony G. Sena, Azza Shoaibi, Matthew Spotnitz, Marc A. Suchard, Carmine O. Torre, David Vizcaya, Haini Wen, Marcel de Wilde, Junqing Xie, Seng Chan You, Lin Zhang, Oleg Zhuk, Patrick Ryan (Lead / Corresponding author), Daniel Prieto-Alhambra

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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.

Original languageEnglish
Pages (from-to)e698-e711
Number of pages14
JournalThe Lancet Rheumatology
Issue number11
Early online date21 Aug 2020
Publication statusPublished - Nov 2020

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology


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