Upcoming therapeutic targets in cutaneous lupus erythematous

Abstract

Novel insights into molecular mechanisms have altered our understanding of the pathogenesis of autoimmune skin disorders. Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by auto-aggressive skin inflammation which histologically presents with interface dermatitis. This inflammation is driven by interferon (IFN)-regulated proinflammatory cytokines that orchestrate the B- and T-cell mediated lesional inflammation. During the last years, therapeutic strategies have focused on these players: biologicals targeting type I IFNs and their receptors as well as anti-B-cell drugs have been investigated in clinical trials with variable success. Very recently, CLE gene expression analyses revealed lesional activation of several pathways of the immune system, thus providing potential new therapeutic targets. In this article, we review the current knowledge concerning pathways and key mediators involved in the pathogenesis of cutaneous lupus erythematosus (including TLR-dependent and TLR-independent immune activation, NfkB, TBK1, PI3K, MAPK, JAK/STAT-pathway) and their inhibitors (e.g. chloroquine, bufalin, duvelisib, rapamycin, R788, KN-93, amlexanox, tofacitinib, ruxolitinib, baricitinib), and discuss emerging strategies for the treatment of CLE and related diseases.

Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus

“…In active CLE skin lesions, cytotoxic T cells invade the epidermis and induce cell death of keratinocytes. The release of nuclear debris, including fragments of different nucleic acids, is one mechanism that has been suggested to amplify the lesional inflammation in CLE (Klaeschen and Wenzel, 2016). To test this hypothesis, we isolated eNAs from HaCaT cells, an immortalized keratinocyte cell line, and stimulated other HaCaT cells with these eNAs.…”

JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus

“…[8] In humans, ruxolitinib has been shown to be effective in the treatment of patients suffering from psoriasis, alopecia areata and vitiligo. [5,6] Inhibition of the activation of proinflammatory cytokines may explain the anti-inflammatory potential of ruxolitinib in our ChLE patient. This view is supported by our in vitro data demonstrating a significant ruxolitinib-mediated reduction of CXCL10, a key regulator of the CLE-typical interface dermatitis.…”

“…Ruxolitinib blocks IFN‐induced STAT‐1 phosphorylation in vitro, thereby inhibiting the pathway utilized by type I IFNs, a hallmark of CLE . Ruxolitinib was shown to be a potent inhibitor of various immune cells in vivo, and studies on MRL/lpr mice indicate that ruxolitinib can significantly attenuate CLE‐like lesions in vivo . In humans, ruxolitinib has been shown to be effective in the treatment of patients suffering from psoriasis, alopecia areata and vitiligo .…”

“…Ruxolitinib was shown to be a potent inhibitor of various immune cells in vivo, and studies on MRL/lpr mice indicate that ruxolitinib can significantly attenuate CLE‐like lesions in vivo . In humans, ruxolitinib has been shown to be effective in the treatment of patients suffering from psoriasis, alopecia areata and vitiligo . Inhibition of the activation of proinflammatory cytokines may explain the anti‐inflammatory potential of ruxolitinib in our ChLE patient.…”

A double‐blind, randomized, placebo‐controlled, phase II trial of baricitinib for systemic lupus erythematosus: how to optimize lupus trials to examine effects on cutaneous lupus erythematosus

“…Baricitinib met its primary end point and several secondary end points, demonstrating promise for this mechanism as a treatment for lupus. Since this mechanism may have key relevance for cutaneous lupus erythematosus (CLE), it is also important that the trial specifically examined skin at three end points. However, no evidence for specific efficacy in skin was observed.…”