Lenalidomide treatment of cutaneous lupus erythematosus: the Mayo Clinic experience

Kindle, Scott A.; Wetter, David A.; Davis, Mark D.P.; Pittelkow, Mark R.; Sciallis, Gabriel F.

doi:10.1111/ijd.13226

Cited by 33 publications

(25 citation statements)

References 27 publications

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“…For example, in addition to the in vitro inhibitory effect of these compounds on TLR-induced cytokine and type 1 IFN production (5, 7), clinical studies have shown IMiDs to be effective in the treatment of immunological disorders, including cutaneous lupus erythematous and multiple sclerosis (18,19). However, although the therapeutic potential of IMiDs is widely recognized, concerns over teratogenicity have restricted their wider use in the treatment of sublethal diseases, including inflammatory and autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

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Section: Discussionmentioning

confidence: 99%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…For this reason, analogues of thalidomide have been developed in order to avoid the undesired side effects. Of these, lenalidomide displayed similar efficacy and relapse rates as thalidomide [67][68][69][70][71][72], and iberdomide (CC-220) improved significantly moderate-to-severe lupus skin manifestations [73]. Lenalidomide has greater immunomodulatory properties than thalidomide, being more potent in the stimulation of T-cell proliferation and IFN-γ/IL-1 production [74].…”

Section: Limited Clinical Use Of Thalidomide In Dle: Need Of Novel Samentioning

confidence: 99%

Efficacy of Thalidomide in Discoid Lupus Erythematosus: Insights into the Molecular Mechanisms

Domingo¹,

Solé²,

Moliné³

et al. 2020

Dermatology

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Background: Thalidomide has been used successfully in a variety of chronic refractory inflammatory dermatological conditions with underlying autoimmune or infectious pathogenesis. It was first used for refractory discoid lupus erythematosus (DLE) in 1983 and has steadily grown since then. Method: In this review, we describe the therapeutic benefits of thalidomide for DLE treatment and its biological properties. We explain how new discoveries in DLE pathogenesis are relevant to understand thalidomide's mechanism of action and the need to find an alternative safe drug with similar therapeutic effects. Summary: Thalidomide's efficacy in DLE patients is significant, with 80-90% reaching clinical remission according to different studies. However, thalidomide's use is still limited by serious adverse effects such as teratogenicity, neurotoxicity, and thrombosis. In addition, there is a frequent rate of relapse and many patients require a longterm low dose of thalidomide as maintenance. The achievement of clinical response within weeks is key to avoid irreversible DLE fibrotic sequelae, making it critical to introduce thalidomide earlier in the DLE treatment algorithm. Recently, microarray and miRNA screenings demonstrated a significant CD4 + T enrichment and T-helper 1 response predominance with a dysregulation of regulatory T cell (Treg) expression in DLE lesions that induced high levels of proinflammatory, chemotaxis, and apoptotic proteins that induce the chronic inflammation response. Thalidomide's anti-inflammatory, antiangiogenic, and T-cell co-stimulatory effects may be beneficial for DLE since it promotes cytokine inhibition, inhibits macrophage activation, regulates Treg responses, inhibits angiogenesis, modulates T cells, and promotes NK cell-mediated cytotoxicity.

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“…with sunscreens, topical corticosteroids, and antimalarial agents is often effective. However, immunosuppressive and/or immunomodulatory agents may be required for recalcitrant disease (Kindle et al, 2016).…”

Section: Therapymentioning

confidence: 99%

“…Cutaneous Lupus Erythematosus (CLE) can be divided into three main subtypes: acute, subacute, and chronic, all of them demonstrate photosensitivity. Acute Cutaneous Lupus Erythematosus (ACLE) most commonly presents as symmetric erythema overlying the malar cheeks and nasal bridge with sparing of the nasolabial folds (butterfly rash) (Kindle et al, 2016).…”

mentioning

confidence: 99%

Measurement of level of vitamin D and Antioxidants in Discoid Lupus Erythematosus patients

Elessawi¹,

Radwan

Bassyouni

2018

Egypt. J. Rad.Sci.

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D ISCOID Lupus Erythematosus (DLE) is a chronic dermatological disease that can lead to scarring, hair loss, and hyperpigmentation changes in skin if it is not treated early and promptly. Diagnosis of discoid lupus is generally made based on clinical features. Sometimes, tests are required, including blood and urine samples. Similar to other many autoimmune conditions, DLE is generally a lifelong condition. However, there are treatments available that are usually effective and can help keep symptoms under control. IL-17 isoforms (IL-17A and IL-17F) are implicated in DLE. Active Vitamin D3 (1, 25(OH) 2D3) is a fat-soluble vitamin that its principle action is to increase the absorption of calcium and phosphate ions from the intestine and directly affect the calcification process. Beside its crucial role in calcium metabolism and bone remodeling, active vitamin D3 is considered an immunomodulator. Increased reactive oxygen species (ROS), lipid peroxides, and low antioxidant status occur in autoimmune disorder. This study aims to assess the level of vitamin D3 [25(OH) D3] in Discoid Lupus Erythematosus (DLE) patients compared to normal controls, its correlation with disease activity parameters, laboratory parameters and antioxidants levels. Twenty patients with (DLE) and 20 healthy controls matched for age and gender were included into this prospective study. Serum vitamin D3 [25(OH) D3] is measured as it is the precursor of active vitaminD3 [1, 25(OH) 2D3 ] which has a very short half-life. Oxidative stress was assessed by measuring serum malondialdehyde (MDA) and enzymatic antioxidant status by estimating superoxide dismutase (SOD) and glutathione peroxidase (GPX). The results of the present work are highly suggestive of the importance of vitamin D3 supplementation in (DLE) and the importance of topical antioxidants to control flare in DLE patients. The serum levels of vitamin D3, SOD, and GPX were significantly lower in DLE patients when compared to their levels in the control group (p< 0.000) .On the other hand, MDA was significantly higher in the DLE patients than that in the healthy control subjects (p<0.001). A highly statistical negative correlation between vitamin D3 with MDA level (P <0.004and r =-0.615) was observed. On the other hand, SOD and GPX positively correlated with vitamin D3 level (P < 0.001 and P<0.000 respectively and r = 0.680 and 0.734 respectively). It could be suggested that low vitamin D3 and disturbed antioxidant levels are prevalent in the Egyptian DLE patients. There is a clear association between vitamin D3 and antioxidants with different signs of disease activity. A routine vitamin D3 and antioxidant supplementations are recommended to DLE patients for better prognosis.

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Lenalidomide treatment of cutaneous lupus erythematosus: the Mayo Clinic experience

Abstract: Lenalidomide was effective for the treatment of CLE (particularly DLE) but not for the treatment of lupus panniculitis in this series.

Cited by 33 publications

References 27 publications

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Efficacy of Thalidomide in Discoid Lupus Erythematosus: Insights into the Molecular Mechanisms

Measurement of level of vitamin D and Antioxidants in Discoid Lupus Erythematosus patients

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