A Randomized, Double-Blind, Placebo-Controlled Trial of Quinacrine in Patients with Cutaneous Lupus

Cutaneous lupus erythematosus (CLE) is a chronic autoimmune skin condition that causes scarring and pigment changes – significantly affecting quality of life. Despite its impact, no CLE-specific treatments have been approved by the FDA in over 60 years. For patients who don’t respond to the first-line drug, hydroxychloroquine, quinacrine has served as a second-line therapy. However, it is only effective in a subset of patients, and its mechanism of action remains poorly understood, limiting our ability to predict who will benefit and, ultimately, slowing the development of better therapies.

Dr. Werth’s research aims to uncover how quinacrine helps hydroxychloroquine-nonresponsive CLE patients by studying its unique immunologic effects. Early findings suggest quinacrine may be effective in responsive patients by blocking the immune receptor TLR8 in myeloid dendritic cells, suppressing four key inflammatory mediators not affected by hydroxychloroquine. To test this, Dr. Werth and her team will conduct lab studies and a prospective randomized clinical trial to analyze skin and blood samples from CLE patients. The goal is to identify biomarkers that can guide personalized treatment and improve outcomes.

What this means for people with lupus: This work could lead to faster, more effective care by identifying patients likely to benefit from quinacrine earlier, reducing delays in treatment. It may also uncover new therapeutic targets for CLE.

Cutaneous lupus erythematosus (CLE) profoundly worsens quality of life. For years, quinacrine (QC) has been a key second-line therapy in CLE, used for the subset of ~50% of CLE patients whose disease is refractory to the first-line medication hydroxychloroquine (HCQ). The mechanism of action of QC remains poorly understood. This gap in knowledge limits our ability to identify QC-responsive versus QC-nonresponsive patients ahead of time, which would substantially improve management, given that QC typically takes at least two months to act. Moreover, the lack of mechanistic understanding has hindered further development of QC, as well as the development of new therapies. To explore how the addition of QC to HCQ improves lupus management, we focused on actions of QC that are not shared with HCQ. Our published work identified four key inflammatory mediators that QC inhibits but HCQ does not: phosphorylated (p) STING, pNFκB, TNFa, and IFNγ. We and others demonstrated roles for toll-like receptor (TLR)8 on myeloid dendritic cells (mDCs). Thus, our central hypothesis is that QC acts in HCQ nonresponding patients as an antagonist of TLR8 in mDCs, to specifically inhibit pSTING, pNFΚB, TNFa, and IFNγ. To test our hypothesis, we propose two Aims to examine these four mediators, their upstream activators, and their downstream effectors in vitro and in vivo. The mechanism of action of QC will be examined after activation of TLR and STING pathways, followed by careful identification of cell types affected by QC. Aim 1. To identify key pathways and inflammatory cell types inhibited by quinacrine in vitro and in vivo. We will use multicolor flow cytometry to examine the effects of antimalarials on stimulated peripheral blood mononuclear cells (PBMCs) from HCQ responsive and HCQ-nonresponsive CLE patients (the latter group from Aim 2). The effect of QC added in vitro to stimulate PBMCs from CLE patients will also be studied by multicolor flow of specific signaling pathways and cell types. Aim 2. Clinical trial to distinguish HCQ+QC-responsive versus HCQ+QC-nonresponsive CLE patients. We propose a prospective randomized placebo controlled trial to investigate the mechanism of action of QC in a clinical setting and thereby test potential biomarkers to predict which HCQ-nonresponders will, or will not, respond to the addition of QC. HCQ-nonresponsive CLE patients will be randomized to HCQ+QC versus HCQ+placebo (weeks 1-12), followed by open-label treatment of both arms with HCQ+QC (weeks 13-24). This design provides a robust opportunity to serially study PBMCs by multicolor flow cytometry, skin biopsies for immunohistochemistry and imaging mass cytometry, and scRNAseq using dermal patches. Biomarkers for patients who then respond, or not, to QC will facilitate earlier selection of appropriate treatment. The proposed studies will provide important insights into the heterogeneity of response to treatment in CLE and crucially improve management.