Risk of COVID-19 hospitalization/mortality in patients with rheumatic disease treated with chloroquine/hydroxychloroquine or other conventional DMARDs in Italy: A large-scale nested casecontrol study

ABSTRACT

Objective: Chloroquine (CLQ)/hydroxychloroquine (HCQ) are two of the most studied drugs for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are very limited data on the effect of treatment of patients affected by rheumatic diseases with HCQ/CLQ and other conventional disease-modifying anti-rheumatic drugs (cDMARDs) on COVID-19. The aim of this study is to investigate the hypothesis that treatment of rheumatic diseases with hydroxychloroquine (HCQ)/chloroquine (CLQ) as compared to other conventional disease-modifying anti-rheumatic drugs (cDMARDs) might decrease the COVID-19-related risk of hospitalization and mortality. Methods: This large-scale case-control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia (Emilia Romagna) Local Health Unit, covering a total of 25.1 million inhabitants. Claims databases were linked to loco-regional COVID-19 surveillance registries from the same catchment area through unique fully-anonymized patient identifiers. Risk of COVID-19-related outcomes was estimated as odds ratios (ORs) along with 95% confidence intervals (CIs), using a multivariate conditional logistic regression analysis, by comparing HCQ/CLQ vs methotrexate (primary comparator) and other cDMARDs (secondary comparator). In addition, the same risk for HCQ/CLQ, methotrexate and other cDMARDs separately vs nonuse of these drugs as well as for presence of rheumatic diseases vs. absence in a non-nested population was investigated. Results: From the cohort of cDMARD users, 1275 cases who were hospitalized due to COVID-19 were identified and matched to 12,734 controls. When compared to recent use of methotrexate, no statistically significant association between recent HCQ/CLQ monotherapy with COVID-19 hospitalization (OR 0.83 [95% CI, 0.69 to 1.00]) or mortality (OR 1.19 [95% CI, 0.85 to 1.67]) was observed. A statistically significant lower risk was found when comparing recent use of HCQ/CLQ to treatment with other cDMARDs and glucocorticoids concomitantly. In the sensitivity analysis in the non-nested population, HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use, whereas a mild statistically significant increased risk for recent use of both methotrexate as monotherapy (OR 1.19 [95% CI, 1.05 to 1.34]) or other cDMARDs (OR 1.21 [95% CI, 1.08 to 1.36]) vs non-use was found. Finally, the presence of rheumatoid arthritis or systemic lupus erythematosus was not associated with COVID-19 hospitalization (OR 0.98 [95% CI, 0.89 to 1.07]) or mortality (OR 0.88 [95% CI, 0.74 to 1.05]). Conclusion: Prior exposure to HCQ/CLQ in rheumatic patients was not associated with a protective effect against COVID-19-related hospitalization and mortality. On the contrary, an increased risk in patients receiving other cDMARDs was observed when compared to non-use, especially in those patients concomitantly treated with glucocorticoids. This is likely attributable to a synergistic immunosuppressive effect, leading to increased risk of severe SARS-CoV-2 infection.