Exploring the long-term hydroxychloroquine's effects on COVID-19 outcomes in patients with autoimmune diseases: a systematic review and meta-analysis.

backgroundHydroxychloroquine (HCQ) usage in COVID patients was a popular topic of study, especially during the first wave of the pandemic. However, the long-term impact of HCQ therapy on infected COVID-19 patients remains unclear.

objectivesHolding a PROSPERO registration (CRD42025113906), this study aimed to investigate the impact of long-term treatment with HCQ in patients with autoimmune diseases on mortality, as well as on the development of disease-related complications.

methodsA comprehensive search was conducted across multiple databases. Full-text reports were included for clinical trials and observational studies on adult patients with autoimmune disease and confirmed COVID-19 infection subjected to HCQ therapy.

resultsThe search process has identified 1,126 studies, of which 17 observational studies were included.No randomized controlled trials meeting the inclusion criteria were found. Eligible studies involved 229,142 autoimmune patients treated with HCQ, of which 197,118 patients were diagnosed with COVID-19. In 14 observational studies (196,965 patients), HCQ use was associated with a lower overall mortality rate by 21% in patients with autoimmune diseases and COVID-19 (RR 0.79; 95% CI: 0.64-0.97, p = 0.02). This association may reflect a potential survival benefit; however, given the observational nature of the studies included, causal inference cannot be established, and the findings should be interpreted cautiously. There was no significant difference between HCQ-treated patients and untreated patients regarding hospitalization (12 studies with 2,238 patients included), ICU admission (8 studies with 527 patients included), mechanical ventilation (8 studies with 546 patients included), sepsis (2 studies with 132 patients included), or thrombo-embolic events rates (2 studies with 195 patients included) (RR 0.92, 95% CI 0.75- 1.14; p = 0.46), (RR 1.45; 95% CI; 0.82- 2.56, p = 0.2) and (RR 1.28; 95% CI; 0.68- 2.4, p = 0.44), (RR 1.44; 95% CI; 0.57 - 3.65, p = 0.44), (RR 0.89; 95% CI; 0.16-4.97, p = 0.89), respectively. Nonetheless, the incidence of Acute Kidney Injury (AKI) in 2 studies (136 patients) was higher in HCQ-treated groups compared to the untreated groups (RR 2.31; 95% CI; 1.29-4.12, p = 0.0047).

conclusionHCQ was associated with a significantly lower overall mortality rate in patients with autoimmune diseases and COVID-19; this association is consistent with its known immunomodulatory properties. On the other hand, it does not prevent COVID-19-related complications and could be associated with an increased risk for developing AKI. However, given the observational nature of all included studies, causal inference cannot be established. Future research is needed to confirm these observed survival benefits and to establish clear safety parameters regarding renal toxicity.