Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus

Abstract

Antimalarials are used to treat dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Although hydroxychloroquine (HCQ) is frequently used, addition of quinacrine (QC) has shown additional clinical effects when combined with HCQ. To quantify the effects of HCQ versus QC in suppressing secretion of tumor necrosis factor-α (TNF-α) and IFN-α from the peripheral blood mononuclear cells of DM and CLE patients, lipopolysaccharide-stimulated and control peripheral blood mononuclear cells from DM and CLE patients and control subjects were analyzed for the effect of HCQ and QC on TNF-α and IFN-α production using ELISA testing. Flow cytometry showed the effects of these therapies on intracellular TNF-α in myeloid dendritic cells and monocytes of DM patients and control subjects. QC significantly suppressed TNF-α relative to HCQ from unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). It suppressed IFN-α as significantly as HCQ from cytosine phosphodiester guanine—stimulated peripheral blood mononuclear cells of DM and CLE patients (P < 0.0001). Flow cytometry showed that QC significantly suppressed intracellular expression of TNF-α from the lipopolysaccharide-stimulated myeloid dendritic cells and monocytes of DM patients (P-values≤0.0008). In conclusion, QC likely has a different mechanism of action than HCQ, given the broader inhibition of proinflammatory cytokines, including both TNF-α and IFN-α.

Effect of in vivo Hydroxychloroquine and ex vivo Anti-BDCA2 mAb Treatment on pDC IFNα Production From Patients Affected With Cutaneous Lupus Erythematosus

“…In this study, both in vitro and in vivo treatment with HCQ led to a reduction in IFNα production after TLR9 stimulation and did not consistently impact IFNα production from TRL7/8 agonist (R848) or TLR7 agonist (ssRNA)- stimulated pDCs. This was similar to a previous report in which pDCs from HCQ-treated patients showed a reduction of TLR9-induced IFNα response, while TLR7-induced IFNα response using imiquimod was not significantly affected (19, 20). TLR9 and TLR7 are both thought to interact with their natural ligand in the endosomes.…”

“…The proposed mechanisms of action of HCQ include the inhibition of endosomal TLRs, antigen presentation, and autophagy all of which are involved in the function of various immune cells (18). Supporting the effect of HCQ on the activation of endosomal TLRs, pDCs from HCQ-treated SLE patients showed impaired ability to produce IFNα in response to TLR9 agonist (19, 20). Although the exact mechanism underlying the effect of HCQ is still unknown, HCQ has been proposed to increase the endosomal intracellular pH, thereby preventing TLR activation of pDCs (21).…”

Increased Myeloid Dendritic Cells and TNF-α Expression Predicts Poor Response to Hydroxychloroquine in Cutaneous Lupus Erythematosus

“…Direct binding of antimalarials to nucleic acids masks their TLR-binding epitope and may also explain the TLR inhibition by antimalarials (Kuznik et al, 2011). Antimalarials also effectively decrease the production of inflammatory cytokines, including TNF-a, IL-6, IFN-a, and IFN-g (Alves et al, 2017;van den Borne et al, 1997;Wozniacka et al, 2006). Antimalarials inhibited IFNaeenhanced TNF-a and STAT4 expression in monocytes (Lopez et al, 2014).…”

Advances in Cutaneous Lupus Erythematosus and Dermatomyositis: A Report from the 4th International Conference on Cutaneous Lupus Erythematosus—An Ongoing Need for International Consensus and Collaborations

“…Anthony P. Fernandez (Cleveland Clinic, Cleveland, OH) reviewed the pharmacodynamics of antimalarials, their mechanism of action, and clinical uses. Dr. Fernandez presented data suggesting that quinacrine is a stronger anti-inflammatory agent than hydroxychloroquine and its mechanism involves down-regulation of TLR-3, -4, and -8 responses (Alves et al, 2017). Regarding the retinal toxicity of antimalarials, Dr. Fernandez stated that ocular toxicity appears to have a cumulative dose risk that is very low during the first 5 years of use but increases sharply after about 5e7 years (Melles and Marmor, 2014).…”