Efficacy of mTOR Inhibitors in Antiphospholipid Syndrome

Efficacy of Mammalian Target of Rapamycin Inhibitors in Antiphospholipid Syndrome and Antiphospholipid Syndrome Nephropathy

Dr. Ege Sinan Torun1

  1. Prof. Dr. Cemil Taşcıoğlu City Hospital, Department of Internal Medicine, Division of Rheumatology, İstanbul, Turkey

OPEN ACCESS

PUBLISHED: 31 December 2024

CITATION: Torun, ES., 2024. Efficacy of Mammalian Target of Rapamycin Inhibitors in Antiphospholipid Syndrome and Antiphospholipid Syndrome Nephropathy. Medical Research Archives, [online] 12(12). https://doi.org/10.18103/mra.v12i12.6128

COPYRIGHT: © 2024 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI https://doi.org/10.18103/mra.v12i12.6128

ISSN 2375-1924

ABSTRACT

Antiphospholipid syndrome (APS) is a potentially devastating clinical condition that is usually associated with recurrent arterial or venous thrombotic events and/or pregnancy morbidity. This condition can also affect the kidneys. APS nephropathy (APSN) is an increasingly recognized and studied renal small vessel vasculopathy that is characterized by non-inflammatory occlusion of renal blood vessels. Renin angiotensin aldosterone blockers and anticoagulants are frequently used to treat APS nephropathy. In 2014, the study by Canaud et al, demonstrated the interaction of antiphospholipid antibodies with endothelial cells through mammalian target of rapamycin (mTOR) pathway and the relationship between activation of mTOR complex and proliferation of endothelial cells, suggesting a possible mechanism for the efficacy of mTOR inhibitors in APSN. This study provided a new possible pathogenetic mechanism and a new possible therapeutic avenue for APSN. This review aims to cover the increasing number of animal studies, in vitro studies and clinical studies on the role of mTOR pathway in APS and the available clinical data on the efficacy of mTOR inhibitors in APSN.

Keywords

Antiphospholipid syndrome, APS nephropathy, mTOR inhibitors, thrombotic events, renal vasculopathy

Introduction

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by recurrent thrombotic events and/or pregnancy morbidity associated with the presence of antiphospholipid antibodies (aPL). Until the introduction of 2023 EULAR/ACR classification criteria, numerous cardiac, pulmonary, hematological, renal manifestations of APS have been defined as “non-criteria” clinical features of APS, as they were not included in the Sapporo classification criteria. One of these manifestations, the renal involvement is a well-recognized feature of APS, which includes renal artery thrombosis or stenosis, renal vein thrombosis and a renal small vessel vasculopathy, known as “APS nephropathy” (APSN). APS nephropathy is characterized by non-inflammatory occlusion of renal blood vessels. Acute lesions take the form of thrombotic microangiopathy, and chronic lesions are characterized by arteriosclerosis of arteries and arterioles, fibrous intimal hyperplasia, fibrous obliteration of arteries and arterioles and focal cortical atrophy. Controlled studies for the management of APS nephropathy are lacking. Renin angiotensin aldosterone system blockers are frequently used to lower blood pressure, reduce proteinuria and slow the progression of chronic kidney disease. Despite conflicting data about its benefits on kidney outcomes, APSN patients are generally anticoagulated as most of them also suffer from macrovascular thrombotic events. Some studies demonstrated that rituximab, plasmapheresis and eculizumab can be effective on a case level.

The study by Canaud et al, demonstrating the interaction of antiphospholipid antibodies with endothelial cells through mammalian target of rapamycin (mTOR) pathway and the relationship between activation of mTOR complex and proliferation of endothelial cells has suggested a possible mechanism for the efficacy of mTOR inhibitors in APSN. This study provided a new possible pathogenetic mechanism and a new possible therapeutic avenue for APSN. However, there is also data demonstrating that the mTOR inhibitor rapamycin could activate platelets, therefore creating concern for the procoagulant effect of rapamycin in liver and renal transplant recipients. This review aims to cover the expanding data on the role of mTOR pathway and mTOR inhibitors in APS and the available clinical data on the efficacy of mTOR inhibitors in APSN.

Animal Studies and In Vitro Studies Assessing the Role of Mammalian Target of Rapamycin Pathway in Antiphospholipid Syndrome

Animal studies and in vitro studies assessing the role of mTOR pathway in APS are listed in Table-1.

Study (Date) Summary of the Studies
Oaks et al (2016) Animal study demonstrating that antiphospholipid antibody production precedes disease onset and responds to rapamycin in lupus-prone mice
Xia et al (2017) In vitro study demonstrating the mTOR involvement in regulating anti-β2GPI/β2GPI-induced expression of tissue factor and interleukin-8, that is responsive to rapamycin
Müller-Calleja et al (2017) In vitro study demonstrating that antiphospholipid antibodies activate two major proinflammatory signal transduction pathways (endosomal NADPH oxidase and monocyte LDL receptor-related protein 8) depending on their epitope specificity and that hydroxychloroquine and rapamycin, alone or in combination could completely suppress these processes
Hollerbach et al (2019) In vitro study demonstrating that anti-β2GPI aPL-induced platelet activation depended on interaction of aPL with the low affinity Fcγ-receptor IIa on the platelet surface. When rapamycin or everolimus were added to the platelet aggregation assay, they inhibited the platelet aggregation that was induced by anti-β2GPI antibodies
Mu et al (2020) Animal study demonstrating that RapaLink (a third generation mTOR inhibitor) decreased the area of chronic vascular lesions in the animal model of thrombosis by preventing apoptosis and enhancing autophagy of macrophages. In addition Rapa-Link decreased the aPL antibodies in the sera of the mice.
Wei et al (2020) In vitro study demonstrating the effect of anticardiolipin in inducing human umbilical vein endothelial cells injury by inhibiting autophagy and activating mTOR/S6K pathway. Hyperoside reduced anticardiolipin induced secretion of proinflammatory cytokines and endothelial adhesion cytokines, activated autophagy and suppressed mTOR/S6K and TLR4/Myd88/NF-κB pathways.
Wei et al (2020) Animal study demonstrating the rat model of pregnancy loss induced by the anticardiolipin IgG fractions. Hyperoside treatment improved pregnancy outcomes by enhancing autophagy and inhibiting inflammation, demonstrated by downregulation of the expressions of phosphorylated mTOR, phosphorylated p70S6 kinase and inhibition of the expressions of TLR4, MyD88 and NF-κB p-p65 pathways.
Rodríguez et al (2021) In vitro study demonstrating the impact of aPL from different patient populations on endothelial cell mitochondrial function, activation of the mTOR pathway, autophagy and cellular growth. Antibodies from patients with pregnancy morbidity and vascular thrombosis increased activation of the mTOR and autophagic pathways and induced cellular stress which was supported by mitochondrial hyperpolarization.
Zhang et al (2021) In vitro study demonstrating that oxidized LDL/β2GPI/anti-β2GPI complex could induce the foam cell formation of macrophages and vascular smooth muscle cells and the expression of inflammatory cytokines in endothelial cells, that results in the formation of atherosclerotic plaques with APS background. The mTOR inhibitor rapamycin attenuated the oxidized LDL/β2GPI/anti-β2GPI complex induced endothelial inflammation, oxidative stress and apoptosis.
Winans et al (2023) Animal study demonstrating that inactivation of transaldolase-aldose reductase axis results in metabolic stress, which is characterized by reduced mitophagy, enhanced overall autophagy, activation of the mTOR pathway, diminished glycosylation of paraoxonase 1, production of antiphospholipid antibodies, loss of CD161+ NK cells and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo.

Animal Study Insights

The animal study by Oaks et al demonstrated that anticardiolipin and anti-beta-2-glycoprotein I (β2GPI) levels were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr and MRL/lpr mice. Treatment with rapamycin selectively blocked mTORC1 activation and aPL production in lupus-prone mice. This study demonstrated that mTORC1 dependent mitochondrial dysfunction contributes to aPL generation, which can be blocked by mTOR inhibitors. The beneficial effect of rapamycin on aPL may be attributed, at least partially, to selective blockade of mTORC1 in the immune system. In their discussion, the authors discuss the possible benefits of inhibition aPL production in APS patients, citing the increased life expectancy that was attributed to rapamycin in an animal study. They also underline the necessity of close monitorization for thrombosis during rapamycin therapy.

In their in vitro study, Xia et al investigated whether mTOR was involved in anti-beta2 glycoprotein1/beta2 glycoprotein1 (anti-β2GPI/β2GPI) complex induced expression of tissue factor and interleukin-8 (IL-8/CXCL8) in monocytes and explored the relationship among toll-like receptor (TLR4), mTOR MAPKs and NF-κB in this process. This study demonstrated that anti-β2GPI/β2GPI complex markedly induces mTOR activation as well as expression of tissue factor and interleukin-8 in THP-1 cells or primary monocytes. The mTOR inhibitor rapamycin could attenuate the elevated TF and IL-8 expression. Rapamycin also decreased the phosphorylation of p38, ERK1/2 and NF-κB p65 stimulated by anti-β2GPI/β2GPI or APS-IgG/ β2GPI complex but it had no effect of JNK. Anti-β2GPI/β2GPI or APS-IgG/ β2GPI complex-induced phosphorylation of mTOR in THP-1 cells was downregulated through inhibition of p38 or ERK rather than inhibition of JNK or NF-κB. In addition, mTOR activation could also be affected by exposure to TLR inhibitor. They concluded that mTOR was involved in regulating anti-β2GPI/β2GPI-induced expression of TF and IL-8, maybe through the phosphorylation of p38, ERK1/2 and NF-κB, in monocytes and that mTOR pathway inhibition might be beneficial for treatment of aP-mediated thrombosis and inflammation in APS patients.

In their in vitro study, Müller-Calleja et al analyzed the effect of three human monoclonal aPLs with different epitope specificities. Expression of tumor necrosis factor-α mRNA by mouse and human monocytes was assessed. Analysis included cells from genetically modified mice and the use of specific inhibitors in monocytes. They validated the data with IgG isolated from 20 APS patients. Cofactor independent anticardiolipin aPLs activated monocytes by induction of endosomal NADPH oxidase, which could be blocked by hydroxychloroquine. Anti-β2GPI aPL activated monocytes by interacting with LDL receptor-related protein 8 (LRP8), which could be blocked by rapamycin. Analysis of 20 APS patients’ IgG demonstrated that all IgG fractions activated the same two pathways as the monoclonal aPL, depending on their epitope patterns as determined by ELISA. Monocyte activation by APS IgG could be blocked by hydroxychloroquine and/or rapamycin, which suggests that in most APS patients there is no other relevant signaling pathway. They concluded that aPLs activate two major proinflammatory signal transduction pathways, depending on their epitope specificity and that hydroxychloroquine and rapamycin, alone or in combination could completely suppress signaling by APS IgG.

The in vitro study of Hollerbach et al analyzed the ability of three human monoclonal aPL with distinctly different antigenic specificities to activate platelets in vitro. They demonstrated that a co-factor-independent human monoclonal anti cardiolipin aPL had no discernible effect on human platelets. Two monoclonal aPL reactive against β2GPI induced platelet aggregation, integrin αIIbβ3 activation and P-selectin surface expression. These data were confirmed with APS patient IgG fractions which could only induce aggregation, if they had anti-β2GPI activity. Anti-β2GPI aPL-induced platelet activation depended on interaction of aPL with the low affinity Fcγ-receptor IIa on the platelet surface. When the mTOR inhibitors rapamycin or everolimus was added to the platelet aggregation assay, they inhibited that platelet aggregation that was induced by β2GPI antibodies but it did not affect ADP-induced platelet aggregation. The authors discussed that the reported effects of mTOR inhibitors on platelet aggregation are variable and appear to depend on the experimental conditions, concluding that the role of mTOR signaling in platelets is explored incompletely and requires further research.

Clinical Studies Assessing the Role of Mammalian Target of Rapamycin Pathway in Non-Renal Manifestations of Antiphospholipid Syndrome

Clinical studies assessing the role of mTOR pathway in non-renal manifestations of APS are listed in Table-2.

Study (Date) Summary
Mora-Ramírez et al (2016) Case report demonstrating the efficacy of sirolimus eluting stents in preventing stent stenosis, thrombosis or neointimal hyperplasia in an antiphospholipid syndrome patient
Sartorelli et al (2019) Case report demonstrating that efficacy of sirolimus treatment enabling dramatic clinical, echocardiographic and laboratory improvements in cardiac function in an antiphospholipid syndrome patient with cardiac microangiopathy.
Rodríguez-García et al (2019) Case report demonstrating a patient with Smith-Kingsmore syndrome and antiphospholipid syndrome that had a gain-of-function variant, treated with sirolimus
Sevim et al (2022) Study investigating the mTOR activation in the skin of aPL-positive patients with livedo. This study demonstrated increased mTOR activity in livedoid lesions of aPL-positive patients with or without SLE compared to aPL-negative patients with SLE.

Clinical Studies Assessing the Role of Mammalian Target of Rapamycin Pathway in Antiphospholipid Syndrome Nephropathy

Clinical studies assessing the role of mTOR pathway in APS nephropathy are listed in Table-3.

Study (Date) Summary
Canaud et al (2014) The pivotal study demonstrating the activation of mTORC pathway in vascular endothelium of proliferating intrarenal vessels from APSN patients. In cultured vascular endothelial cells, IgG antibodies from patients with APS stimulated mTORC through the phosphatidylinositol 3-kinase-AKT pathway. Patients with APSN who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy compared to patients with aPL antibodies who were not receiving sirolimus. Activation of mTORC was also found in the vessels of autopsy specimens from CAPS patients.
Canaud et al (2015) Editorial underlining the importance of the previous study and identifying mTORC pathway as a novel molecular pathway critically involved in the development of intimal hyperplasia which accompanies the most severe variants of APS. This editorial is also presenting the novel therapeutic strategy of mTOR inhibition as a potential treatment that can prevent kidney loss.
Lai et al (2015) Study examining the mitochondrial mass, superoxide production, mTOR and FoxP3 expression in 72 SLE patients (12 of them had accompanying APS) and 54 healthy controls by flow cytometry. There was a similar mTOR activity between SLE patients with or without APS. Authors concluded that oxidative stress and Treg depletion rather than mTOR activation underlie APS in patients with SLE.
Dufour et al (2020) Case report demonstrating an APS patient with thrombotic microangiopathy lesions in native kidney biopsy that were characteristic of APS nephropathy. After demonstration of endothelial mTORC activation at the molecular level, this patient was successfully treated with sirolimus that was added to anticoagulant and angiotensin converting enzyme inhibitor therapy.
Zhang (2022) Case report demonstrating a patient with SLE and APS who had class III lupus nephritis. This patient was refractory to cyclophosphamide and mycophenolate. Immunofluorescence of the kidney biopsy showed the activation of the mTOR pathway. Sirolimus was added to warfarin. Patient had complete remission in the sixth month, discontinued sirolimus 1 year later and remained in remission even after discontinuation of sirolimus for another 3.5 years.

Conclusion

The accumulating data from animal studies, in vitro studies and clinical studies indicate that mTOR pathway may play a significant role in the pathogenesis of pregnancy morbidities and vasculopathy in APS, while also providing a rationale for use of mTOR inhibitors for the treatment of patients that have APS nephropathy and other clinical findings of APS such as cardiac involvement and livedoid skin lesions. Use of mTOR inhibitors as an add-on treatment to anticoagulation will also offset the possible concerns about the procoagulant effects of mTOR inhibitors. Prospective randomized controlled studies that will include a large number of patients with APS nephropathy will improve our understanding of the role of mTOR pathway in APS and APSN pathogenesis and clarify its place in the future within treatment algorithms.

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