Introduction
rheumatoid arthritis, RA, autoimmune diseases, cutaneous lupus erythematosus
RHEUMATOID ARTHRITIS, VIRUS, PROLIFERATION, AUTOIMMUNE DISEASES, CUTANEOUS LUPUS ERYTHEMATOSUS
Hydroxychloroquine (HCQ) is a broad immunosuppressive drug, initially developed as an antimalarial drug. However, due to its anti-inflammatory properties, HCQ is now widely used in the treatment of autoimmune diseases such as rheumatoid arthritis (RA) [The exact mechanisms behind HCQ immunosuppressive functions remain unclear. HCQ accumulates in the lysosomes and inhibits lysosomal function by autophagosome fusion with lysosomes [Besides effects on the innate immune system, HCQ affects the adaptive immune response as well. It has been shown that HCQ inhibits differentiation of class-switched memory B cells into plasmablasts and thereby decreases IgG production in response to TLR9 stimulation or inoculation with inactivated virus [However, the concentrations used in such in vitro experiments studying the immunomodulatory effects of HCQ largely exceeded obtainable clinical concentrations in patients. A study in cutaneous lupus erythematosus patients receiving HCQ in clinical doses showed that higher HCQ blood levels corresponded with lower ex vivo IFNα responses after TLR9 stimulation, but not after TLR7/8 stimulation [We aimed to assess and quantify the immunomodulatory effects of HCQ on primary human immune cells, both in vitro and ex vivo in a randomized clinical trial. We assessed the effect of HCQ on cytokine production after endosomal TLR stimulation in isolated PBMCs and on T and B cell proliferation (in vitro as well as ex vivo). In the clinical trial, healthy subjects were dosed with HCQ in the standard dosing regimen for moderate-to-severe COVID-19 that was advised in the Netherlands when the study was conceived. In the study design, we accounted for a potential age effect on the study outcomes, since general immunocompetence and drug metabolism have been reported to be age-dependent [