@article{RN351,
   author = {Lane, J. C. E. and Weaver, J. and Kostka, K. and Duarte-Salles, T. and Abrahao, M. T. F. and Alghoul, H. and Alser, O. and Alshammari, T. M. and Biedermann, P. and Banda, J. M. and Burn, E. and Casajust, P. and Conover, M. M. and Culhane, A. C. and Davydov, A. and DuVall, S. L. and Dymshyts, D. and Fernandez-Bertolin, S. and Fišter, K. and Hardin, J. and Hester, L. and Hripcsak, G. and Kaas-Hansen, B. S. and Kent, S. and Khosla, S. and Kolovos, S. and Lambert, C. G. and van der Lei, J. and Lynch, K. E. and Makadia, R. and Margulis, A. V. and Matheny, M. E. and Mehta, P. and Morales, D. R. and Morgan-Stewart, H. and Mosseveld, M. and Newby, D. and Nyberg, F. and Ostropolets, A. and Park, R. W. and Prats-Uribe, A. and Rao, G. A. and Reich, C. and Reps, J. and Rijnbeek, P. and Sathappan, S. M. K. and Schuemie, M. and Seager, S. and Sena, A. G. and Shoaibi, A. and Spotnitz, M. and Suchard, M. A. and Torre, C. O. and Vizcaya, D. and Wen, H. and de Wilde, M. and Xie, J. and You, S. C. and Zhang, L. and Zhuk, O. and Ryan, P. and Prieto-Alhambra, D.},
   title = {Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study},
   journal = {Lancet Rheumatol},
   volume = {2},
   number = {11},
   pages = {e698-e711},
   note = {2665-9913 Lane, Jennifer C E Weaver, James Kostka, Kristin Duarte-Salles, Talita Abrahao, Maria Tereza F Alghoul, Heba Alser, Osaid Alshammari, Thamir M Biedermann, Patricia Banda, Juan M Burn, Edward Casajust, Paula Conover, Mitchell M Culhane, Aedin C Davydov, Alexander DuVall, Scott L Dymshyts, Dmitry Fernandez-Bertolin, Sergio Fišter, Kristina Hardin, Jill Hester, Laura Hripcsak, George Kaas-Hansen, Benjamin Skov Kent, Seamus Khosla, Sajan Kolovos, Spyros Lambert, Christophe G van der Lei, Johan Lynch, Kristine E Makadia, Rupa Margulis, Andrea V Matheny, Michael E Mehta, Paras Morales, Daniel R Morgan-Stewart, Henry Mosseveld, Mees Newby, Danielle Nyberg, Fredrik Ostropolets, Anna Park, Rae Woong Prats-Uribe, Albert Rao, Gowtham A Reich, Christian Reps, Jenna Rijnbeek, Peter Sathappan, Selva Muthu Kumaran Schuemie, Martijn Seager, Sarah Sena, Anthony G Shoaibi, Azza Spotnitz, Matthew Suchard, Marc A Torre, Carmen O Vizcaya, David Wen, Haini de Wilde, Marcel Xie, Junqing You, Seng Chan Zhang, Lin Zhuk, Oleg Ryan, Patrick Prieto-Alhambra, Daniel OHDSI-COVID-19 consortium WT_/Wellcome Trust/United Kingdom P30 AG059307/AG/NIA NIH HHS/United States R01 LM006910/LM/NLM NIH HHS/United States RES 13-457/RD/ORD VA/United States Journal Article England 2020/08/31 Lancet Rheumatol. 2020 Nov;2(11):e698-e711. doi: 10.1016/S2665-9913(20)30276-9. Epub 2020 Aug 21.},
   abstract = {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 I (2) 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. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations. , ISSN = 2665-9913 , DOI = 10.1016/s2665-9913(20)30276-9},
   year = {2020},
   type = {Journal Article}
}

{"_id":"bTqqAYrN82Xz2ATKa","bibbaseid":"lane-weaver-kostka-duartesalles-abrahao-alghoul-alser-alshammari-etal-riskofhydroxychloroquinealoneandincombinationwithazithromycininthetreatmentofrheumatoidarthritisamultinationalretrospectivestudy-2020","author_short":["Lane, J. C. E.","Weaver, J.","Kostka, K.","Duarte-Salles, T.","Abrahao, M. T. F.","Alghoul, H.","Alser, O.","Alshammari, T. M.","Biedermann, P.","Banda, J. M.","Burn, E.","Casajust, P.","Conover, M. M.","Culhane, A. C.","Davydov, A.","DuVall, S. L.","Dymshyts, D.","Fernandez-Bertolin, S.","Fišter, K.","Hardin, J.","Hester, L.","Hripcsak, G.","Kaas-Hansen, B. S.","Kent, S.","Khosla, S.","Kolovos, S.","Lambert, C. G.","van der Lei, J.","Lynch, K. E.","Makadia, R.","Margulis, A. V.","Matheny, M. E.","Mehta, P.","Morales, D. R.","Morgan-Stewart, H.","Mosseveld, M.","Newby, D.","Nyberg, F.","Ostropolets, A.","Park, R. W.","Prats-Uribe, A.","Rao, G. A.","Reich, C.","Reps, J.","Rijnbeek, P.","Sathappan, S. M. K.","Schuemie, M.","Seager, S.","Sena, A. G.","Shoaibi, A.","Spotnitz, M.","Suchard, M. A.","Torre, C. O.","Vizcaya, D.","Wen, H.","de Wilde, M.","Xie, J.","You, S. C.","Zhang, L.","Zhuk, O.","Ryan, P.","Prieto-Alhambra, D."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Lane"],"firstnames":["J.","C.","E."],"suffixes":[]},{"propositions":[],"lastnames":["Weaver"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Kostka"],"firstnames":["K."],"suffixes":[]},{"propositions":[],"lastnames":["Duarte-Salles"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Abrahao"],"firstnames":["M.","T.","F."],"suffixes":[]},{"propositions":[],"lastnames":["Alghoul"],"firstnames":["H."],"suffixes":[]},{"propositions":[],"lastnames":["Alser"],"firstnames":["O."],"suffixes":[]},{"propositions":[],"lastnames":["Alshammari"],"firstnames":["T.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Biedermann"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Banda"],"firstnames":["J.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Burn"],"firstnames":["E."],"suffixes":[]},{"propositions":[],"lastnames":["Casajust"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Conover"],"firstnames":["M.","M."],"suffixes":[]},{"propositions":[],"lastnames":["Culhane"],"firstnames":["A.","C."],"suffixes":[]},{"propositions":[],"lastnames":["Davydov"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["DuVall"],"firstnames":["S.","L."],"suffixes":[]},{"propositions":[],"lastnames":["Dymshyts"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Fernandez-Bertolin"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Fišter"],"firstnames":["K."],"suffixes":[]},{"propositions":[],"lastnames":["Hardin"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Hester"],"firstnames":["L."],"suffixes":[]},{"propositions":[],"lastnames":["Hripcsak"],"firstnames":["G."],"suffixes":[]},{"propositions":[],"lastnames":["Kaas-Hansen"],"firstnames":["B.","S."],"suffixes":[]},{"propositions":[],"lastnames":["Kent"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Khosla"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Kolovos"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Lambert"],"firstnames":["C.","G."],"suffixes":[]},{"propositions":["van","der"],"lastnames":["Lei"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Lynch"],"firstnames":["K.","E."],"suffixes":[]},{"propositions":[],"lastnames":["Makadia"],"firstnames":["R."],"suffixes":[]},{"propositions":[],"lastnames":["Margulis"],"firstnames":["A.","V."],"suffixes":[]},{"propositions":[],"lastnames":["Matheny"],"firstnames":["M.","E."],"suffixes":[]},{"propositions":[],"lastnames":["Mehta"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Morales"],"firstnames":["D.","R."],"suffixes":[]},{"propositions":[],"lastnames":["Morgan-Stewart"],"firstnames":["H."],"suffixes":[]},{"propositions":[],"lastnames":["Mosseveld"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Newby"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Nyberg"],"firstnames":["F."],"suffixes":[]},{"propositions":[],"lastnames":["Ostropolets"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Park"],"firstnames":["R.","W."],"suffixes":[]},{"propositions":[],"lastnames":["Prats-Uribe"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Rao"],"firstnames":["G.","A."],"suffixes":[]},{"propositions":[],"lastnames":["Reich"],"firstnames":["C."],"suffixes":[]},{"propositions":[],"lastnames":["Reps"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["Rijnbeek"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Sathappan"],"firstnames":["S.","M.","K."],"suffixes":[]},{"propositions":[],"lastnames":["Schuemie"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Seager"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["Sena"],"firstnames":["A.","G."],"suffixes":[]},{"propositions":[],"lastnames":["Shoaibi"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Spotnitz"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Suchard"],"firstnames":["M.","A."],"suffixes":[]},{"propositions":[],"lastnames":["Torre"],"firstnames":["C.","O."],"suffixes":[]},{"propositions":[],"lastnames":["Vizcaya"],"firstnames":["D."],"suffixes":[]},{"propositions":[],"lastnames":["Wen"],"firstnames":["H."],"suffixes":[]},{"propositions":["de"],"lastnames":["Wilde"],"firstnames":["M."],"suffixes":[]},{"propositions":[],"lastnames":["Xie"],"firstnames":["J."],"suffixes":[]},{"propositions":[],"lastnames":["You"],"firstnames":["S.","C."],"suffixes":[]},{"propositions":[],"lastnames":["Zhang"],"firstnames":["L."],"suffixes":[]},{"propositions":[],"lastnames":["Zhuk"],"firstnames":["O."],"suffixes":[]},{"propositions":[],"lastnames":["Ryan"],"firstnames":["P."],"suffixes":[]},{"propositions":[],"lastnames":["Prieto-Alhambra"],"firstnames":["D."],"suffixes":[]}],"title":"Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study","journal":"Lancet Rheumatol","volume":"2","number":"11","pages":"e698-e711","note":"2665-9913 Lane, Jennifer C E Weaver, James Kostka, Kristin Duarte-Salles, Talita Abrahao, Maria Tereza F Alghoul, Heba Alser, Osaid Alshammari, Thamir M Biedermann, Patricia Banda, Juan M Burn, Edward Casajust, Paula Conover, Mitchell M Culhane, Aedin C Davydov, Alexander DuVall, Scott L Dymshyts, Dmitry Fernandez-Bertolin, Sergio Fišter, Kristina Hardin, Jill Hester, Laura Hripcsak, George Kaas-Hansen, Benjamin Skov Kent, Seamus Khosla, Sajan Kolovos, Spyros Lambert, Christophe G van der Lei, Johan Lynch, Kristine E Makadia, Rupa Margulis, Andrea V Matheny, Michael E Mehta, Paras Morales, Daniel R Morgan-Stewart, Henry Mosseveld, Mees Newby, Danielle Nyberg, Fredrik Ostropolets, Anna Park, Rae Woong Prats-Uribe, Albert Rao, Gowtham A Reich, Christian Reps, Jenna Rijnbeek, Peter Sathappan, Selva Muthu Kumaran Schuemie, Martijn Seager, Sarah Sena, Anthony G Shoaibi, Azza Spotnitz, Matthew Suchard, Marc A Torre, Carmen O Vizcaya, David Wen, Haini de Wilde, Marcel Xie, Junqing You, Seng Chan Zhang, Lin Zhuk, Oleg Ryan, Patrick Prieto-Alhambra, Daniel OHDSI-COVID-19 consortium WT_/Wellcome Trust/United Kingdom P30 AG059307/AG/NIA NIH HHS/United States R01 LM006910/LM/NLM NIH HHS/United States RES 13-457/RD/ORD VA/United States Journal Article England 2020/08/31 Lancet Rheumatol. 2020 Nov;2(11):e698-e711. doi: 10.1016/S2665-9913(20)30276-9. Epub 2020 Aug 21.","abstract":"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 I (2) 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. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations. , ISSN = 2665-9913 , DOI = 10.1016/s2665-9913(20)30276-9","year":"2020","bibtex":"@article{RN351,\r\n author = {Lane, J. C. E. and Weaver, J. and Kostka, K. and Duarte-Salles, T. and Abrahao, M. T. F. and Alghoul, H. and Alser, O. and Alshammari, T. M. and Biedermann, P. and Banda, J. M. and Burn, E. and Casajust, P. and Conover, M. M. and Culhane, A. C. and Davydov, A. and DuVall, S. L. and Dymshyts, D. and Fernandez-Bertolin, S. and Fišter, K. and Hardin, J. and Hester, L. and Hripcsak, G. and Kaas-Hansen, B. S. and Kent, S. and Khosla, S. and Kolovos, S. and Lambert, C. G. and van der Lei, J. and Lynch, K. E. and Makadia, R. and Margulis, A. V. and Matheny, M. E. and Mehta, P. and Morales, D. R. and Morgan-Stewart, H. and Mosseveld, M. and Newby, D. and Nyberg, F. and Ostropolets, A. and Park, R. W. and Prats-Uribe, A. and Rao, G. A. and Reich, C. and Reps, J. and Rijnbeek, P. and Sathappan, S. M. K. and Schuemie, M. and Seager, S. and Sena, A. G. and Shoaibi, A. and Spotnitz, M. and Suchard, M. A. and Torre, C. O. and Vizcaya, D. and Wen, H. and de Wilde, M. and Xie, J. and You, S. C. and Zhang, L. and Zhuk, O. and Ryan, P. and Prieto-Alhambra, D.},\r\n title = {Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study},\r\n journal = {Lancet Rheumatol},\r\n volume = {2},\r\n number = {11},\r\n pages = {e698-e711},\r\n note = {2665-9913 Lane, Jennifer C E Weaver, James Kostka, Kristin Duarte-Salles, Talita Abrahao, Maria Tereza F Alghoul, Heba Alser, Osaid Alshammari, Thamir M Biedermann, Patricia Banda, Juan M Burn, Edward Casajust, Paula Conover, Mitchell M Culhane, Aedin C Davydov, Alexander DuVall, Scott L Dymshyts, Dmitry Fernandez-Bertolin, Sergio Fišter, Kristina Hardin, Jill Hester, Laura Hripcsak, George Kaas-Hansen, Benjamin Skov Kent, Seamus Khosla, Sajan Kolovos, Spyros Lambert, Christophe G van der Lei, Johan Lynch, Kristine E Makadia, Rupa Margulis, Andrea V Matheny, Michael E Mehta, Paras Morales, Daniel R Morgan-Stewart, Henry Mosseveld, Mees Newby, Danielle Nyberg, Fredrik Ostropolets, Anna Park, Rae Woong Prats-Uribe, Albert Rao, Gowtham A Reich, Christian Reps, Jenna Rijnbeek, Peter Sathappan, Selva Muthu Kumaran Schuemie, Martijn Seager, Sarah Sena, Anthony G Shoaibi, Azza Spotnitz, Matthew Suchard, Marc A Torre, Carmen O Vizcaya, David Wen, Haini de Wilde, Marcel Xie, Junqing You, Seng Chan Zhang, Lin Zhuk, Oleg Ryan, Patrick Prieto-Alhambra, Daniel OHDSI-COVID-19 consortium WT_/Wellcome Trust/United Kingdom P30 AG059307/AG/NIA NIH HHS/United States R01 LM006910/LM/NLM NIH HHS/United States RES 13-457/RD/ORD VA/United States Journal Article England 2020/08/31 Lancet Rheumatol. 2020 Nov;2(11):e698-e711. doi: 10.1016/S2665-9913(20)30276-9. Epub 2020 Aug 21.},\r\n abstract = {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 I (2) 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. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations. , ISSN = 2665-9913 , DOI = 10.1016/s2665-9913(20)30276-9},\r\n year = {2020},\r\n type = {Journal Article}\r\n}\r\n\r\n","author_short":["Lane, J. C. E.","Weaver, J.","Kostka, K.","Duarte-Salles, T.","Abrahao, M. T. F.","Alghoul, H.","Alser, O.","Alshammari, T. M.","Biedermann, P.","Banda, J. M.","Burn, E.","Casajust, P.","Conover, M. M.","Culhane, A. C.","Davydov, A.","DuVall, S. L.","Dymshyts, D.","Fernandez-Bertolin, S.","Fišter, K.","Hardin, J.","Hester, L.","Hripcsak, G.","Kaas-Hansen, B. S.","Kent, S.","Khosla, S.","Kolovos, S.","Lambert, C. G.","van der Lei, J.","Lynch, K. E.","Makadia, R.","Margulis, A. V.","Matheny, M. E.","Mehta, P.","Morales, D. R.","Morgan-Stewart, H.","Mosseveld, M.","Newby, D.","Nyberg, F.","Ostropolets, A.","Park, R. W.","Prats-Uribe, A.","Rao, G. A.","Reich, C.","Reps, J.","Rijnbeek, P.","Sathappan, S. M. K.","Schuemie, M.","Seager, S.","Sena, A. G.","Shoaibi, A.","Spotnitz, M.","Suchard, M. A.","Torre, C. O.","Vizcaya, D.","Wen, H.","de Wilde, M.","Xie, J.","You, S. C.","Zhang, L.","Zhuk, O.","Ryan, P.","Prieto-Alhambra, D."],"key":"RN351","id":"RN351","bibbaseid":"lane-weaver-kostka-duartesalles-abrahao-alghoul-alser-alshammari-etal-riskofhydroxychloroquinealoneandincombinationwithazithromycininthetreatmentofrheumatoidarthritisamultinationalretrospectivestudy-2020","role":"author","urls":{},"metadata":{"authorlinks":{}},"html":""},"bibtype":"article","biburl":"https://bibbase.org/network/files/qwipow2DJsAxqNp83","dataSources":["gYHzosaj6P7Z4gkGW","PJSqX8FMpCPRdw3CQ","qLDnCcKM9omXNrRY8","TB9sD3avjy7bNxfgS","vDmJPYmHEKAT3tMNL","PcZMFHooKwpboi2he","jZMXEeHTfokmisJDv","LKj7QkGgRgaPTmbcp"],"keywords":[],"search_terms":["risk","hydroxychloroquine","alone","combination","azithromycin","treatment","rheumatoid","arthritis","multinational","retrospective","study","lane","weaver","kostka","duarte-salles","abrahao","alghoul","alser","alshammari","biedermann","banda","burn","casajust","conover","culhane","davydov","duvall","dymshyts","fernandez-bertolin","fišter","hardin","hester","hripcsak","kaas-hansen","kent","khosla","kolovos","lambert","van der lei","lynch","makadia","margulis","matheny","mehta","morales","morgan-stewart","mosseveld","newby","nyberg","ostropolets","park","prats-uribe","rao","reich","reps","rijnbeek","sathappan","schuemie","seager","sena","shoaibi","spotnitz","suchard","torre","vizcaya","wen","de wilde","xie","you","zhang","zhuk","ryan","prieto-alhambra"],"title":"Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study","year":2020}