An umbrella review of systematic reviews with meta-analyses evaluating positive and negative outcomes of hydroxychloroquine and chloroquine therapy

Background & aims: Hydroxychloroquine (HCQ) and chloroquine (CQ) are anti-malarial drugs frequently used in the rheumatologic field. Recently they were identified as possible therapeutic options against Coronavirus Disease (COVID-19). Therefore, the present study aimed to map and grade the diverse health outcomes associated with HCQ/CQ using an umbrella review approach. Methods: Umbrella review of systematic reviews of observational and intervention studies. For observational studies, random-effects summary effect size, 95% confidence interval, and 95% prediction interval were estimated. We also assessed heterogeneity, evidence for small-study effect and evidence for excess significance bias. The quality of evidence was then graded using validated criteria from highly convincing to weak. The evidence from randomized-controlled trials (RCTs) was graded using the GRADE tool. Results: From 313 articles returned, 6 meta-analyses were included (n = 25 outcomes). Among meta-analyses of observational studies, HCQ/CQ is weakly associated with a reduced risk for cardiovascular events and diabetes when used for autoimmune diseases; it is also associated with higher risk of death when used for COVID-19 and with spontaneous abortion. Among meta-analyses of RCTs, HCQ/CQ is associated with an improvement of articular manifestations of the rheumatic diseases. Conclusions: There is high evidence of the efficacy of HCQ/CQ in the rheumatologic field. The lack of evidence for efficacy and risk of death associated with the use of HCQ/CQ for COVID-19, indicate the inappropriateness of its inclusion in recent COVID-19 therapy guidelines and urgent need for Randomised Controlled Trials to determine their eventual appropriateness as a therapy in that circumstance.