Abstract
Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide’s CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4CRBN) dependent pathways: IRF4/NF-ҡB and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-ҡB reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide’s side effects while maintaining its efficacy.
Highlights
Cutaneous Lupus Erythematosus (CLE) is common and encompasses a wide range of dermatologic manifestations
We found thalidomide to act by two CRL4CRBN -dependent mechanisms: (a) downregulating interferon regulatory factor 4 (IRF4) leading to an inhibition of the NF-ҡB signalling pathway; and (b) regulating
We found thalidomide to act by two CRL4CRBN-dependent mechanisms: 6 of (a) downregulating IRF4 leading to an inhibition of the NF-ҡB signalling pathway; and (b) regulating AMPK1/mechanistic target of rapamycin (mTOR) signalling pathway (Figure 2)
Summary
Cutaneous Lupus Erythematosus (CLE) is common and encompasses a wide range of dermatologic manifestations. As many as 70–80% of patients can develop skin lesions, which can be an early sign of systemic involvement [1,2]. CLE can be classified into specific and non-specific lesions, of which discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) are the most prevalent forms [3]. Effective treatment may resolve the lesions, but delayed or inadequate treatment can result in permanent scarring, especially in DLE [4]. Most patients respond to this regimen, 30 to 40% of cases will be refractory [6]. For this minority, there is no consensus treatment algorithm, and several systemic agents have shown a variable response [7]. Thalidomide, a glutamic acid derivative with immunomodulatory and anti-inflammatory effects, has been used successfully in several oncological and chronic inflammatory dermatological conditions [8,9]
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