Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

Hamidou, M.; Néel, A.; Poupon, Joël; Amoura, Zahir; Ebbo, Mikaël; Sibilia, Jean; Viallard, Jean‐François; Gaborit, Benjamin; Volteau, Christelle; Hardouin, Jean Benoit; Hachulla, É.; Rieger, François

doi:10.1186/s13075-021-02454-6

Cited by 15 publications

(10 citation statements)

References 42 publications

(11 reference statements)

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“…Arsenic trioxide (ATO) is a well-known traditional Chinese drug used to treat acute promyelocytic leukemia (APL) [29,30]. In recent years, several reports have shown that ATO is a promising treatment for dysregulated immune disease [31][32][33][34]. Moreover, ATO could improve the clinical symptoms in mice with sclerodermatous GVHD [35].…”

Section: Introductionmentioning

confidence: 99%

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Sun

Liu

et al. 2022

J Hematol Oncol

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Background Both extracellular vesicles from mesenchymal stromal cell-derived human umbilical cords (hUC-EVs) and arsenic trioxides (ATOs) have been demonstrated to treat acute graft-versus-host disease (aGVHD) via immunomodulation. Apart from immunomodulation, hUC-EVs have a unique function of drug delivery, which has been proposed to enhance their efficacy. In this study, we first prepared ATO-loaded hUC-EVs (hUC-EVs-ATO) to investigate the therapeutic effect and potential mechanisms of hUC-EVs-ATO in a mouse model of aGVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Methods An aGVHD model was established to observe the therapeutic effects of hUC-EVs-ATO on aGVHD. Target organs were harvested for histopathological analysis on day 14 after transplantation. The effects of hUC-EVs-ATO on alloreactive CD4+ were evaluated by flow cytometry in vivo and in vitro. Flow cytometry, RT-PCR, immunofluorescence colocalization analysis and Western blot (Wb) analysis were performed to examine macrophage polarization after hUC-EV-ATO treatment. The cytokines in serum were measured by a cytometric bead array (CBA). TEM, confocal microscopy and Wb were performed to observe the level of autophagy in macrophages. A graft-versus-lymphoma (GVL) mouse model was established to observe the role of hUC-EVs-ATO in the GVL effect. Results The clinical manifestations and histological scores of aGVHD in the hUC-EVs-ATO group were significantly reduced compared with those in the ATO and hUC-EVs groups. The mice receiving hUC-EVs-ATO lived longer than the control mice. Notably, hUC-EVs-ATO interfering with alloreactive CD4+ T cells differentiation were observed in aGVHD mice but not in an in vitro culture system. Additional studies showed that depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. Mechanistically, hUC-EVs-ATO induced autophagic flux by inhibiting mammalian target of rapamycin (mTOR) activity to repolarize M1 to M2 macrophages. Additionally, using a murine model of GVL effects, hUC-EVs-ATO were found not only to reduce the severity of aGVHD but also to preserve the GVL effects. Taken together, hUC-EVs-ATO may be promising candidates for aGVHD treatment. Conclusions hUC-EVs-ATO enhanced the alleviation of aGVHD severity in mice compared with ATO and hUC-EVs without weakening GVL activity. hUC-EVs-ATO promoted M1 to M2 polarization via the mTOR-autophagy pathway. hUC-EVs-ATO could be a potential therapeutic approach in aGVHD after allo-HSCT.

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Section: Introductionmentioning

confidence: 99%

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Sun

Liu

et al. 2022

J Hematol Oncol

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Section: Results and Context Of Included Studiesmentioning

confidence: 99%

“…Arsenic trioxide (ATO), used for treating acute promyelocytic leukemia, has shown the potential to treat lupus-like disease processes in animal models ( Hamidou et al, 2021 ). In a phase IIa clinical study, researchers evaluated the efficacy and safety of intravenous ATO treatment for patients with active SLE ( Hamidou et al, 2021 ). The outcome of this study shows that ATO as a complementary treatment resulted in a decrease in corticosteroid dosage from 11.25 mg/day at baseline to 6 mg/day at week 24 ( Hamidou et al, 2021 ).…”

Section: Results and Context Of Included Studiesmentioning

confidence: 99%

“…In a phase IIa clinical study, researchers evaluated the efficacy and safety of intravenous ATO treatment for patients with active SLE ( Hamidou et al, 2021 ). The outcome of this study shows that ATO as a complementary treatment resulted in a decrease in corticosteroid dosage from 11.25 mg/day at baseline to 6 mg/day at week 24 ( Hamidou et al, 2021 ). The researchers concluded that ATO offers a good safety profile and is efficacious in treating patients with SLE ( Hamidou et al, 2021 ).…”

Section: Results and Context Of Included Studiesmentioning

confidence: 99%

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Medicinal Plant Extracts and Natural Compounds for the Treatment of Cutaneous Lupus Erythematosus: A Systematic Review

et al. 2022

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Cutaneous lupus erythematosus (CLE) is a group of autoimmune connective tissue disorders that significantly impact quality of life. Current treatment approaches typically use antimalarial medications, though patients may become recalcitrant. Other treatment options include general immunosuppressants, highlighting the need for more and more targeted treatment options. The purpose of this systematic review was to identify potential compounds that could be repurposed for CLE from natural products since many rheumatologic drugs are derived from natural products, including antimalarials. This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number CRD42021251048). We comprehensively searched Ovid Medline, Cochrane Library, and Scopus databases from inception to April 27th, 2021. These terms included cutaneous lupus erythematosus; general plant, fungus, bacteria terminology; selected plants and plant-derived products; selected antimalarials; and JAK inhibitors. Our search yielded 13,970 studies, of which 1,362 were duplicates. We screened 12,608 abstracts, found 12,043 to be irrelevant, and assessed 565 full-text studies for eligibility. Of these, 506 were excluded, and 59 studies were included in the data extraction. The ROBINS-I risk of bias assessment tool was used to assess studies that met our inclusion criteria. According to our findings, several natural compounds do reduce inflammation in lupus and other autoimmune skin diseases in studies using in vitro methods, mouse models, and clinical observational studies, along with a few randomized clinical trials. Our study has cataloged evidence in support of potential natural compounds and plant extracts that could serve as novel sources of active ingredients for the treatment of CLE. It is imperative that further studies in mice and humans are conducted to validate these findings.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=251048.

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“…Experimental models have greatly improved our understanding of the pathogenesis of GvHD and have led to newer approaches targeting different components of immune dysregulation. ATO is a drug recognized in the treatment of acute promyelocytic leukemia ( 12 , 13 ) and is also a therapeutic alternative tested in clinical studies in acute ( 14 , 15 ) and chronic GvHD ( 16 , 17 ) but also lupus progression ( 18 ). In a mouse model of cGvHD, the administration of ATO increased the production of reactive oxygen species (ROS), especially H 2 O 2 and hydroxyl radicals ( 16 ), which induced apoptosis of activated alloreactive lymphocytes and plasmacytoid dendritic cells ( 19 ), leading to a reduction of systemic inflammation and fibrosis of the skin and lung ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice

Chêne

Jeljeli²,

Rongvaux-Gaïda³

et al. 2022

Front. Immunol.

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Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro, among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo, in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl2 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress.

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Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

Cited by 15 publications

References 42 publications

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

Medicinal Plant Extracts and Natural Compounds for the Treatment of Cutaneous Lupus Erythematosus: A Systematic Review

A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice

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