The renaissance of hydroxychloroquine: bridging antimicrobial immunity and autoimmunity in rheumatic diseases.

Hydroxychloroquine (HCQ) has been a cornerstone of rheumatic disease therapy for more than half a century. Its best-established immunomodulatory actions arise from endosomal and lysosomal alkalinization, with inhibition of endosomal Toll-like receptor 7/9 signaling and attenuation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation. Apart from these well-established mechanisms we also discuss a proposed model in which HCQ might influence CD3ζ/CD4 endocytic turnover. A structured narrative search of PubMed/MEDLINE, Scopus, and Web of Science was performed between July and November 2025. Clinically, HCQ remains foundational in systemic lupus erythematosus (SLE), whereas evidence for antiphospholipid syndrome, primary Sjögren's syndrome, lichen planus, and chronic spontaneous urticaria is limited and does not support routine use outside selected off-label settings. Randomized trials demonstrated no clinical benefit in COVID-19. Retinopathy remains the principal dose- and duration-dependent toxicity. Limiting the daily dose to ≤5 mg/kg actual body weight and following current ophthalmic screening recommendations are the main preventive measures. HCQ blood-level monitoring may support adherence assessment and exposure-informed care, but therapeutic thresholds and laboratory interpretation are not yet universally standardized. This review integrates mechanistic, clinical, and safety evidence while explicitly distinguishing established findings from hypotheses and lower-certainty observations.