Hydroxychloroquine in rheumatic autoimmune disorders and beyond

Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost-effectiveness, safety and efficacy,HCQis especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjogren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic,HCQmolecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms,CQandHCQinhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll-like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro-inflammatory cytokine production and release, one of the most marked symptoms ofRADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use ofHCQis expanding beyond the treatment of malaria andRADs.