Risk of COVID-19 hospitalization and mortality in rheumatic patients treated with hydroxychloroquine or other conventional DMARDs in Italy

DOI record: { "DOI": "10.1093/rheumatology/keab348", "ISSN": [ "1462-0324", "1462-0332" ], "URL": "http://dx.doi.org/10.1093/rheumatology/keab348", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Objectives</jats:title>\n <jats:p>To ascertain if the use of hydroxychloroquine(HCQ)/cloroquine(CLQ) and other conventional DMARDs (cDMARDs) and rheumatic diseases per se may be associated with COVID-19-related risk of hospitalization and mortality.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>This case–control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia province. Claims databases were linked to COVID-19 surveillance registries. The risk of COVID-19-related outcomes was estimated using a multivariate conditional logistic regression analysis comparing HCQ/CLQ vs MTX, vs other cDMARDs and vs non-use of these drugs. The presence of rheumatic diseases vs their absence in a non-nested population was investigated.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>A total of 1275 patients hospitalized due to COVID-19 were matched to 12 734 controls. Compared with recent use of MTX, no association between HCQ/CLQ monotherapy and COVID-19 hospitalization [odds ratio (OR) 0.83 (95% CI 0.69, 1.00)] or mortality [OR 1.19 (95% CI 0.85, 1.67)] was observed. A lower risk was found when comparing HCQ/CLQ use with the concomitant use of other cDMARDs and glucocorticoids. HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use. An increased risk for recent use of either MTX monotherapy [OR 1.19 (95% CI 1.05, 1.34)] or other cDMARDs [OR 1.21 (95% CI 1.08, 1.36)] vs non-use was found. Rheumatic diseases were not associated with COVID-19-related outcomes.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>HCQ/CLQ use in rheumatic patients was not associated with a protective effect against COVID-19-related outcomes. The use of other cDMARDs was associated with an increased risk when compared with non-use and, if concomitantly used with glucocorticoids, also vs HCQ/CLQ, probably due to immunosuppressive action.</jats:p>\n </jats:sec>", "author": [ { "affiliation": [ { "name": "Pharmacoepidemiology Unit, National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy" } ], "family": "Spila Alegiani", "given": "Stefania", "sequence": "first" }, { "affiliation": [ { "name": "Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy" }, { "name": "Italian Society of Pharmacology, Milan, Italy" } ], "family": "Crisafulli", "given": "Salvatore", "sequence": "additional" }, { "affiliation": [ { "name": "Epidemiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy" } ], "family": "Giorgi Rossi", "given": "Paolo", "sequence": "additional" }, { "affiliation": [ { "name": "Epidemiology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy" } ], "family": "Mancuso", "given": "Pamela", "sequence": "additional" }, { "affiliation": [ { "name": "Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy" }, { "name": "Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Emilia-Romagna, Italy" } ], "family": "Salvarani", "given": "Carlo", "sequence": "additional" }, { "affiliation": [ { "name": "Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy" } ], "family": "Atzeni", "given": "Fabiola", "sequence": "additional" }, { "affiliation": [ { "name": "Agenzia Regionale di Sanità della Toscana, Florence, Italy" } ], "family": "Gini", "given": "Rosa", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Epidemiology ASL Roma 1, Lazio Regional Health Service, Rome, Italy" } ], "family": "Kirchmayer", "given": "Ursula", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Epidemiology ASL Roma 1, Lazio Regional Health Service, Rome, Italy" } ], "family": "Belleudi", "given": "Valeria", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, University of Cagliari, Cagliari, Italy" }, { "name": "Regional Health Trust of Sardinia Region, Cagliari, Italy" } ], "family": "Kurotschka", "given": "Peter Konstantin", "sequence": "additional" }, { "affiliation": [ { "name": "Epidemiology Observatory–Department of Health of Lombardy Region, Milan, Italy" } ], "family": "Leoni", "given": "Olivia", "sequence": "additional" }, { "affiliation": [ { "name": "Epidemiology Observatory–Department of Health of Lombardy Region, Milan, Italy" } ], "family": "Ludergnani", "given": "Monica", "sequence": "additional" }, { "affiliation": [ { "name": "Azienda Zero of the Veneto Region, Padua, Italy" } ], "family": "Ferroni", "given": "Eliana", "sequence": "additional" }, { "affiliation": [ { "name": "Azienda Zero of the Veneto Region, Padua, Italy" } ], "family": "Baracco", "given": "Susanna", "sequence": "additional" }, { "affiliation": [ { "name": "Pharmacoepidemiology Unit, National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy" } ], "family": "Massari", "given": "Marco", "sequence": "additional" }, { "affiliation": [ { "name": "Italian Society of Pharmacology, Milan, Italy" }, { "name": "Department of Diagnostics and Public Health, University of Verona, Verona, Italy" } ], "family": "Trifirò", "given": "Gianluca", "sequence": "additional" }, { "affiliation": [], "name": "the ITA-COVID-19 Network", "sequence": "additional" } ], "container-title": "Rheumatology", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2021, 4, 13 ] ], "date-time": "2021-04-13T18:52:28Z", "timestamp": 1618339948000 }, "deposited": { "date-parts": [ [ 2021, 10, 11 ] ], "date-time": "2021-10-11T02:53:00Z", "timestamp": 1633920780000 }, "funder": [ { "name": "Italian National Institute of Health" } ], "indexed": { "date-parts": [ [ 2023, 9, 1 ] ], "date-time": "2023-09-01T16:31:50Z", "timestamp": 1693585910768 }, "is-referenced-by-count": 11, "issue": "SI", "issued": { "date-parts": [ [ 2021, 4, 15 ] ] }, "journal-issue": { "issue": "SI", "published-online": { "date-parts": [ [ 2021, 4, 15 ] ] }, "published-print": { "date-parts": [ [ 2021, 10, 9 ] ] } }, "language": "en", "license": [ { "URL": "https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 4, 15 ] ], "date-time": "2021-04-15T00:00:00Z", "timestamp": 1618444800000 } } ], "link": [ { "URL": "http://academic.oup.com/rheumatology/advance-article-pdf/doi/10.1093/rheumatology/keab348/38657160/keab348.pdf", "content-type": "application/pdf", "content-version": "am", "intended-application": "syndication" }, { "URL": "http://academic.oup.com/rheumatology/article-pdf/60/SI/SI25/40544655/keab348.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "syndication" }, { "URL": "http://academic.oup.com/rheumatology/article-pdf/60/SI/SI25/40544655/keab348.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "page": "SI25-SI36", "prefix": "10.1093", "published": { "date-parts": [ [ 2021, 4, 15 ] ] }, "published-online": { "date-parts": [ [ 2021, 4, 15 ] ] }, "published-other": { "date-parts": [ [ 2021, 10, 1 ] ] }, "published-print": { "date-parts": [ [ 2021, 10, 9 ] ] }, "publisher": "Oxford University Press (OUP)", "reference": [ { "key": "2021101018332747100_keab348-B1" }, { "DOI": "10.1002/jmv.25440", "article-title": "Antimalarial drugs and their metabolites are potent Zika virus inhibitors", "author": "Han", "doi-asserted-by": "crossref", "first-page": "1182", "journal-title": "J Med Virol", "key": "2021101018332747100_keab348-B2", "volume": "91", "year": "2019" }, { "DOI": "10.1371/journal.pone.0060579", "article-title": "A systematic screen of FDA-approved drugs for inhibitors of biological threat agents", "author": "Madrid", "doi-asserted-by": "crossref", "first-page": "e60579", "journal-title": "PLoS One", "key": "2021101018332747100_keab348-B3", "volume": "8", "year": "2013" }, { "DOI": "10.1038/s41421-020-0156-0", "article-title": "Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro", "author": "Liu", "doi-asserted-by": "crossref", "first-page": "16", "journal-title": "Cell Discov", "key": "2021101018332747100_keab348-B4", "volume": "6", "year": "2020" }, { "DOI": "10.1093/cid/ciaa237", "article-title": "In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)", "author": "Yao", "doi-asserted-by": "crossref", "first-page": "732", "journal-title": "Clin Infect Dis", "key": "2021101018332747100_keab348-B5", "volume": "71", "year": "2020" }, { "DOI": "10.1073/pnas.2014441117", "article-title": "Favipiravir at high doses has potent antiviral activity in SARS-CoV-2–infected hamsters, whereas hydroxychloroquine lacks activity", "author": "Kaptein", "doi-asserted-by": "crossref", "first-page": "26955", "journal-title": "Proc Natl Acad Sci USA", "key": "2021101018332747100_keab348-B6", "volume": "117", "year": "2020" }, { "DOI": "10.1038/s41584-020-0372-x", "article-title": "Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology", "author": "Schrezenmeier", "doi-asserted-by": "crossref", "first-page": "155", "journal-title": "Nat Rev Rheumatol", "key": "2021101018332747100_keab348-B7", "volume": "16", "year": "2020" }, { "DOI": "10.1007/s12016-010-8243-x", "article-title": "Hydroxychloroquine: from malaria to autoimmunity", "author": "Ben-Zvi", "doi-asserted-by": "crossref", "first-page": "145", "journal-title": "Clin Rev Allergy Immunol", "key": "2021101018332747100_keab348-B8", "volume": "42", "year": "2012" }, { "DOI": "10.1080/15548627.2020.1779467", "article-title": "Autophagy as an emerging target for COVID-19: lessons from an old friend, chloroquine", "author": "Bonam", "doi-asserted-by": "crossref", "first-page": "2260", "journal-title": "Autophagy", "key": "2021101018332747100_keab348-B9", "volume": "16", "year": "2020" }, { "DOI": "10.1007/s00210-020-01964-5", "article-title": "Hydroxychloroquine use and progression or prognosis of COVID-19: a systematic review and meta-analysis", "author": "Zang", "doi-asserted-by": "crossref", "first-page": "775", "journal-title": "Naunyn Schmiedebergs Arch Pharmacol", "key": "2021101018332747100_keab348-B10", "volume": "394", "year": "2021" }, { "DOI": "10.1093/jac/dkaa403", "article-title": "Efficacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis", "author": "Kashour", "doi-asserted-by": "crossref", "first-page": "30", "journal-title": "J Antimicrob Chemother", "key": "2021101018332747100_keab348-B11", "volume": "76", "year": "2021" }, { "DOI": "10.1056/NEJMcp2009249", "article-title": "Mild or moderate Covid-19", "author": "Gandhi", "doi-asserted-by": "crossref", "first-page": "1757", "journal-title": "N Engl J Med", "key": "2021101018332747100_keab348-B12", "volume": "383", "year": "2020" }, { "author": "Engl", "first-page": "2030", "journal-title": "Med", "key": "2021101018332747100_keab348-B13", "volume": "383", "year": "2020" }, { "DOI": "10.1056/NEJMoa2019014", "article-title": "Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19", "author": "Cavalcanti", "doi-asserted-by": "crossref", "first-page": "2041", "journal-title": "N Engl J Med", "key": "2021101018332747100_keab348-B14", "volume": "383", "year": "2020" }, { "DOI": "10.7326/M20-4207", "article-title": "Hydroxychloroquine in nonhospitalized adults with early COVID-19", "author": "Skipper", "doi-asserted-by": "crossref", "first-page": "623", "journal-title": "Ann Intern Med", "key": "2021101018332747100_keab348-B15", "volume": "173", "year": "2020" }, { "article-title": "Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial", "author": "Mitjà", "journal-title": "Clin Infect Dis", "key": "2021101018332747100_keab348-B16", "year": "2020" }, { "DOI": "10.1056/NEJMoa2016638", "article-title": "A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19", "author": "Boulware", "doi-asserted-by": "crossref", "first-page": "517", "journal-title": "N Engl J Med", "key": "2021101018332747100_keab348-B17", "volume": "383", "year": "2020" }, { "DOI": "10.1001/jamainternmed.2020.6319", "article-title": "Efficacy and safety of hydroxychloroquine vs placebo for pre-exposure SARS-CoV-2 prophylaxis among health care workers", "author": "Abella", "doi-asserted-by": "crossref", "first-page": "195", "journal-title": "JAMA Intern Med", "key": "2021101018332747100_keab348-B18", "volume": "181", "year": "2021" }, { "DOI": "10.1056/NEJMoa2021801", "article-title": "A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19", "author": "Mitjà", "doi-asserted-by": "crossref", "first-page": "417", "journal-title": "N Engl J Med", "key": "2021101018332747100_keab348-B19", "volume": "384", "year": "2021" }, { "article-title": "Hydroxychloroquine as pre-exposure prophylaxis for coronavirus disease 2019 (COVID-19) in healthcare workers: a randomized trial", "author": "Rajasingham", "journal-title": "Clin Infect Dis", "key": "2021101018332747100_keab348-B20", "year": "2020" }, { "DOI": "10.1016/S2665-9913(20)30305-2", "article-title": "Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study", "author": "Gentry", "doi-asserted-by": "crossref", "first-page": "e689", "journal-title": "Lancet Rheumatol", "key": "2021101018332747100_keab348-B21", "volume": "2", "year": "2020" }, { "DOI": "10.1016/j.cmi.2020.12.003", "article-title": "Effect of hydroxychloroquine preexposure on infection with SARS-CoV-2 in rheumatic disease patients: a population-based cohort study", "author": "Jung", "doi-asserted-by": "crossref", "first-page": "611", "journal-title": "Clin Microbiol Infect", "key": "2021101018332747100_keab348-B22", "volume": "27", "year": "2021" }, { "DOI": "10.1016/S2665-9913(20)30378-7", "article-title": "Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform", "author": "Rentsch", "doi-asserted-by": "crossref", "first-page": "e19", "journal-title": "Lancet Rheumatol", "key": "2021101018332747100_keab348-B23", "volume": "3", "year": "2020" }, { "DOI": "10.1016/j.jaad.2020.04.111", "article-title": "Risks of hydroxychloroquine use for COVID-19 prophylaxis", "author": "Sachdeva", "doi-asserted-by": "crossref", "first-page": "e73", "journal-title": "J Am Acad Dermatol", "key": "2021101018332747100_keab348-B24", "volume": "83", "year": "2020" }, { "article-title": "Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis", "author": "Akiyama", "journal-title": "Ann Rheum Dis", "key": "2021101018332747100_keab348-B25", "year": "2020" }, { "article-title": "“TheShinISS”: an open-source tool for conducting distributed analyses within pharmacoepidemiological multi-database studies", "author": "Massari", "first-page": "39", "journal-title": "Boll Epidemiol Naz", "key": "2021101018332747100_keab348-B26", "volume": "1", "year": "2020" }, { "DOI": "10.1007/s40264-020-00994-5", "article-title": "Renin–angiotensin–aldosterone system inhibitors and risk of death in patients hospitalised with COVID-19: a retrospective Italian cohort study of 43,000 patients", "author": "Trifirò", "doi-asserted-by": "crossref", "first-page": "1297", "journal-title": "Drug Saf", "key": "2021101018332747100_keab348-B27", "volume": "43", "year": "2020" }, { "DOI": "10.2147/CLEP.S271763", "article-title": "Survival of hospitalized COVID-19 patients in northern Italy: a population-based cohort study by the ITA-COVID19 Network", "author": "Ferroni", "doi-asserted-by": "crossref", "first-page": "1337", "journal-title": "Clin Epidemiol", "key": "2021101018332747100_keab348-B28", "volume": "12", "year": "2020" }, { "article-title": "The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: a systematic review and meta-analysis of randomized trials", "author": "Lewis", "first-page": "e0244778", "key": "2021101018332747100_keab348-B29", "volume-title": "PLoS One", "year": "2021" }, { "DOI": "10.1111/bcp.14622", "article-title": "Hospitalization for COVID-19 in patients treated with selected immunosuppressant and immunomodulating agents, compared to the general population: a Danish cohort study", "author": "Nørgård", "doi-asserted-by": "crossref", "first-page": "2111", "journal-title": "Br J Clin Pharmacol", "key": "2021101018332747100_keab348-B30", "volume": "87", "year": "2021" }, { "DOI": "10.1136/annrheumdis-2015-207841", "article-title": "Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance", "author": "Winthrop", "doi-asserted-by": "crossref", "first-page": "2107", "journal-title": "Ann Rheum Dis", "key": "2021101018332747100_keab348-B31", "volume": "74", "year": "2015" }, { "DOI": "10.1136/annrheumdis-2020-217871", "article-title": "Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry", "author": "Gianfrancesco", "doi-asserted-by": "crossref", "first-page": "859", "journal-title": "Ann Rheum Dis", "key": "2021101018332747100_keab348-B32", "volume": "79", "year": "2020" }, { "DOI": "10.1053/j.gastro.2020.05.032", "article-title": "Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry", "author": "Brenner", "doi-asserted-by": "crossref", "first-page": "481", "journal-title": "Gastroenterology", "key": "2021101018332747100_keab348-B33", "volume": "159", "year": "2020" }, { "DOI": "10.1002/art.41456", "article-title": "COVID-19 in patients with inflammatory arthritis: a prospective study on the effects of comorbidities and disease-modifying antirheumatic drugs on clinical outcomes", "author": "Haberman", "doi-asserted-by": "crossref", "first-page": "1981", "journal-title": "Arthritis Rheumatol", "key": "2021101018332747100_keab348-B34", "volume": "72", "year": "2020" }, { "DOI": "10.1177/0961203318792352", "article-title": "Corticosteroid dose and the risk of opportunistic infection in a national systemic lupus erythematosus cohort", "author": "Yang", "doi-asserted-by": "crossref", "first-page": "1819", "journal-title": "Lupus", "key": "2021101018332747100_keab348-B35", "volume": "27", "year": "2018" }, { "DOI": "10.1002/art.41596", "article-title": "American College of Rheumatology guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic: version 1", "author": "Mikuls", "doi-asserted-by": "crossref", "first-page": "e1", "journal-title": "Arthritis Rheumatol", "key": "2021101018332747100_keab348-B36", "volume": "73", "year": "2021" }, { "key": "2021101018332747100_keab348-B37" } ], "reference-count": 37, "references-count": 37, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/rheumatology/article/60/SI/SI25/6226505" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Pharmacology (medical)", "Rheumatology" ], "subtitle": [], "title": "Risk of coronavirus disease 2019 hospitalization and mortality in rheumatic patients treated with hydroxychloroquine or other conventional disease-modifying anti-rheumatic drugs in Italy", "type": "journal-article", "volume": "60" }