Efficacy of Mammalian Target of Rapamycin Inhibitors in Antiphospholipid Syndrome and Antiphospholipid Syndrome Nephropathy
Main Article Content
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 to cover the increasing number of animal studies, in vitro studies and clinical studies on the role of mTOR pathyway in APS and the available clinical data on the efficacy of mTOR inhibitors in APSN.
Article Details
How to Cite
TORUN, Ege Sinan.
Efficacy of Mammalian Target of Rapamycin Inhibitors in Antiphospholipid Syndrome and Antiphospholipid Syndrome Nephropathy.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6128>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6128.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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5. De Simone E, Sciascia S, Fenoglio R, Oddone V, Barreca A, Roccatello D. Antiphospholipid Syndrome and Kidney Involvement. Kidney Blood Press Res. 2023;48(1):666-677. Doi:10.1159/000529229
6. Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifesta tions of antiphospholipid syndrome. Arthritis Rheumatol. 2013;65: 464–71. https://doi.org/10.1002/art.37759
7. Tsagalis G, Psimenou E, Nakopoulou L, Laggouranis A. Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab. Hippokratia. 2010;14:215–6.
8. Rymarz A, Niemczyk S. The complex treatment including ritux imab in the management ofcatastrophic antiphospholid syndrome with renal involvement. BMC Nephrol. 2018;19:132. https://doi.org/10.1186/s12882-018-0928-z
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10. Kello N, Khoury LE, Marder G, Furie R, Zapantis E, Horowitz DL. Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of com plement and use of eculizumab: case series and review of literature. Semin Arthritis Rheum. 2019;49:74–83. https://doi.org/10.1002/art.40933
11. Sciascia S, Radin M, Yazdany J, Tektonidou M, Cecchi I, Roccatello D, et al. Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence. Rheumatol Int. 2017;37:1249–55. https://doi.org/10.1007/s00296-017-36865
12. Kronbichler A, Frank R, Kirschfink M, Szilágyi Á, Csuka D, Prohászka Z, et al. Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syn drome: acasereport. Medicine (Baltimore). 2014;93:e143. https://doi.org/10.1097/MD.0000000000000143
13. Canaud G, Bienaimé F, Tabarin F, Bataillon G, Seilhean D, Noël LH, Dragon-Durey MA, Snanoudj R, Friedlander G, Halbwachs-Mecarelli L, Legendre C, Terzi F. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014 Jul 24;371(4):303-12. Doi:10.1056/NEJMoa1312890
14. Hollerbach A, Müller-Calleja N, Ritter S, Häuser F, Canisius A, Orning C, Jurk K, Lackner KJ. Platelet Activation by Antiphospholipid Antibodies Depends on Epitope Specificity and is Prevented by mTOR Inhibitors. Thromb Haemost. 2019 Jul;119(7):1147-1153. Doi:10.1055/s-0039-1685453
15. Oaks Z, Winans T, Caza T, Fernandez D, Liu Y, Landas SK, Banki K, Perl A. Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice. Arthritis Rheumatol. 2016 Nov;68(11):2728-2739. Doi:10.1002/art.39791
16. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.
17. Xia L, Zhou H, Wang T, Xie Y, Wang T, Wang X, Yan J. Activation of mTOR is involved in anti-β2GPI/β2GPI-induced expression of tissue factor and IL-8 in monocytes. Thromb Res. 2017 Sep;157:103-110. doi:10.1016/j.thromres.2017.05.023
18. Müller-Calleja N, Hollerbach A, Häuser F, Canisius A, Orning C, Lackner KJ. Antiphospholipid antibody-induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome. J Thromb Haemost. 2017 Dec;15(12):2367-2376. Doi:10.1111/jth.13865
19. Mu F, Jiang Y, Ao F, Wu H, You Q, Chen Z. RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro. Biochem Biophys Res Commun. 2020 Apr 30;525(2):384-391. Doi:10.1016/j.bbrc.2020.02.084
20. Wei A, Xiao H, Xu G, Yu X, Guo J, Jing Z, Shi S, Song Y. Hyperoside Protects Human Umbilical Vein Endothelial Cells Against Anticardiolipin Antibody-Induced Injury by Activating Autophagy. Front Pharmacol. 2020 May 21;11:762. Doi:10.3389/fphar.2020.00762
21. Wei A, Song Y, Ni T, Xiao H, Wan Y, Ren X, Li H, Xu G. Hyperoside attenuates pregnancy loss through activating autophagy and suppressing inflammation in a rat model. Life Sci. 2020 Aug 1;254:117735. Doi:10.1016/j.lfs.2020.117735
22. Rodríguez CM, Velásquez-Berrío M, Rúa C, Viana M, Abrahams VM, Cadavid AP, Alvarez AM. Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy. Front Physiol. 2021 Nov 29;12:706743. Doi:10.3389/fphys.2021.706743
23. Zhang G, He C, Wu Q, Xu G, Kuang M, Wang T, Xu L, Zhou H, Yuan W. Impaired Autophagy Induced by oxLDL/β2GPI/anti-β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction. Oxid Med Cell Longev. 2021 Jun 14;2021:6662225. Doi:10.1155/2021/6662225
24. Winans T, Oaks Z, Choudhary G, Patel A, Huang N, Faludi T, Krakko D, Nolan J, Lewis J, Blair S, Lai Z, Landas SK, Middleton F, Asara JM, Chung SK, Wyman B, Azadi P, Banki K, Perl A. mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency. J Autoimmun. 2023 Nov;140:103112. Doi:10.1016/j.jaut.2023.103112
25. Mora-Ramírez M, González-Pacheco H, Amezcua-Guerra LM. Stents Coated With Mammalian Target of Rapamycin Inhibitors (mTOR) Appear to Be the Best Choice in Patients With Antiphospholipid Syndrome and Myocardial Infarction. J Clin Rheumatol. 2016 Aug;22(5):281. Doi:10.1097/Rhu.0000000000000409
26. Sartorelli S, De Luca G, Campochiaro C, Peretto G, Sala S, Esposito A, Busnardo E, Basso C, Thiene G, Dagna L. Successful use of sirolimus in a patient with cardiac microangiopathy in primary antiphospholipid syndrome. Scand J Rheumatol. 2019 Nov;48(6):515-516. Doi:10.1080/03009742.2019.1574022. Epub 2019 Feb 22. Erratum in: Scand J Rheumatol. 2019 Nov;48(6):520. Doi:10.1080/03009742.2019.1714880
27. Rodríguez-García ME, Cotrina-Vinagre FJ, Bellusci M, Martínez de Aragón A, Hernández-Sánchez L, Carnicero-Rodríguez P, Martín-Hernández E, Martínez-Azorín F. A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. Eur J Hum Genet. 2019 Sep;27(9):1369-1378. Doi:10.1038/s41431-019-0418-1
28. Sevim E, Siddique S, Chalasani MLS, Chyou S, Shipman WD, O'Shea O, Harp J, Alpan O, Zuily S, Lu TT, Erkan D. Mammalian Target of Rapamycin Pathway Assessment in Antiphospholipid Antibody-Positive Patients with Livedo. J Rheumatol. 2022 Sep;49(9):1026-1030. Doi:10.3899/jrheum.220049
29. Canaud G, Legendre C, Terzi F. AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game. Lupus. 2015 Mar;24(3):227-30. Doi:10.1177/0961203315569336
30. Lai ZW, Marchena-Mendez I, Perl A. Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome. Clin Immunol. 2015 Jun;158(2):148-52. Doi:10.1016/j.clim.2015.03.024
31. Dufour I, Venot Q, Aydin S, Demoulin N, Canaud G, Morelle J. mTORC Pathway Activation and Effect of Sirolimus on Native Kidney Antiphospholipid Syndrome Nephropathy: A Case Report. Am J Kidney Dis. 2020 Aug;76(2):288-291. Doi:10.1053/j.ajkd.2019.08.032
32. Zhang D, Sun F, Ye S. Successful treatment of sirolimus in a Chinese patient with refractory LN and APS: a case report. Ther Adv Musculoskelet Dis. 2022 Feb 28;14:1759720X221079253. Doi:10.1177/1759720X221079253
2. Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, Amoura Z, Andrade D, Andreoli L, Artim-Esen B, Atsumi T, Avcin T, Belmont HM, Bertolaccini ML, Branch DW, Carvalheiras G, Casini A, Cervera R, Cohen H, Costedoat-Chalumeau N, Crowther M, de Jesus G, Delluc A, Desai S, De Sancho M, Devreese KM, Diz-Kucukkaya R, Duarte-Garcia A, Frances C, Garcia D, Gris JC, Jordan N, Leaf RK, Kello N, Knight JS, Laskin C, Lee AI, Legault K, Levine SR, Levy RA, Limper M, Lockshin MD, Mayer-Pickel K, Musial J, Meroni PL, Orsolini G, Ortel TL, Pengo V, Petri M, Pons-Estel G, Gomez-Puerta JA, Raimboug Q, Roubey R, Sanna G, Seshan SV, Sciascia S, Tektonidou MG, Tincani A, Wahl D, Willis R, Yelnik C, Zuily C, Guillemin F, Costenbader K, Erkan D; ACR/EULAR APS Classification Criteria Collaborators. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol. 2023 Oct;75(10):1687-1702. Doi:10.1002/art.42624
3. Xourgia E, Tektonidou MG. Management of Non-criteria Manifestations in Antiphospholipid Syndrome. Curr Rheumatol Rep. 2020 Jul 22;22(9):51. Doi:10.1007/s11926-020-00935-2
4. Tektonidou MG. Antiphospholipid Syndrome Nephropathy: From Pathogenesis to Treatment. Front Immunol. 2018 May 31;9:1181. Doi:10.3389/fimmu.2018.01181
5. De Simone E, Sciascia S, Fenoglio R, Oddone V, Barreca A, Roccatello D. Antiphospholipid Syndrome and Kidney Involvement. Kidney Blood Press Res. 2023;48(1):666-677. Doi:10.1159/000529229
6. Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifesta tions of antiphospholipid syndrome. Arthritis Rheumatol. 2013;65: 464–71. https://doi.org/10.1002/art.37759
7. Tsagalis G, Psimenou E, Nakopoulou L, Laggouranis A. Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab. Hippokratia. 2010;14:215–6.
8. Rymarz A, Niemczyk S. The complex treatment including ritux imab in the management ofcatastrophic antiphospholid syndrome with renal involvement. BMC Nephrol. 2018;19:132. https://doi.org/10.1186/s12882-018-0928-z
9. Diószegi Á, Tarr T, Nagy-Vincze M, Nánásy-Vass M, Veisz R, Bidiga L, et al. Microthrombotic renal involvement in an SLE patient with concomitant catastrophic antiphospholipid syndrome: the beneficial effect of rituximab treatment. Lupus. 2018;27: 1552–8. https://doi.org/10.1177/0961203318768890
10. Kello N, Khoury LE, Marder G, Furie R, Zapantis E, Horowitz DL. Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of com plement and use of eculizumab: case series and review of literature. Semin Arthritis Rheum. 2019;49:74–83. https://doi.org/10.1002/art.40933
11. Sciascia S, Radin M, Yazdany J, Tektonidou M, Cecchi I, Roccatello D, et al. Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence. Rheumatol Int. 2017;37:1249–55. https://doi.org/10.1007/s00296-017-36865
12. Kronbichler A, Frank R, Kirschfink M, Szilágyi Á, Csuka D, Prohászka Z, et al. Efficacy of eculizumab in a patient with immunoadsorption-dependent catastrophic antiphospholipid syn drome: acasereport. Medicine (Baltimore). 2014;93:e143. https://doi.org/10.1097/MD.0000000000000143
13. Canaud G, Bienaimé F, Tabarin F, Bataillon G, Seilhean D, Noël LH, Dragon-Durey MA, Snanoudj R, Friedlander G, Halbwachs-Mecarelli L, Legendre C, Terzi F. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014 Jul 24;371(4):303-12. Doi:10.1056/NEJMoa1312890
14. Hollerbach A, Müller-Calleja N, Ritter S, Häuser F, Canisius A, Orning C, Jurk K, Lackner KJ. Platelet Activation by Antiphospholipid Antibodies Depends on Epitope Specificity and is Prevented by mTOR Inhibitors. Thromb Haemost. 2019 Jul;119(7):1147-1153. Doi:10.1055/s-0039-1685453
15. Oaks Z, Winans T, Caza T, Fernandez D, Liu Y, Landas SK, Banki K, Perl A. Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice. Arthritis Rheumatol. 2016 Nov;68(11):2728-2739. Doi:10.1002/art.39791
16. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392–5.
17. Xia L, Zhou H, Wang T, Xie Y, Wang T, Wang X, Yan J. Activation of mTOR is involved in anti-β2GPI/β2GPI-induced expression of tissue factor and IL-8 in monocytes. Thromb Res. 2017 Sep;157:103-110. doi:10.1016/j.thromres.2017.05.023
18. Müller-Calleja N, Hollerbach A, Häuser F, Canisius A, Orning C, Lackner KJ. Antiphospholipid antibody-induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome. J Thromb Haemost. 2017 Dec;15(12):2367-2376. Doi:10.1111/jth.13865
19. Mu F, Jiang Y, Ao F, Wu H, You Q, Chen Z. RapaLink-1 plays an antithrombotic role in antiphospholipid syndrome by improving autophagy both in vivo and vitro. Biochem Biophys Res Commun. 2020 Apr 30;525(2):384-391. Doi:10.1016/j.bbrc.2020.02.084
20. Wei A, Xiao H, Xu G, Yu X, Guo J, Jing Z, Shi S, Song Y. Hyperoside Protects Human Umbilical Vein Endothelial Cells Against Anticardiolipin Antibody-Induced Injury by Activating Autophagy. Front Pharmacol. 2020 May 21;11:762. Doi:10.3389/fphar.2020.00762
21. Wei A, Song Y, Ni T, Xiao H, Wan Y, Ren X, Li H, Xu G. Hyperoside attenuates pregnancy loss through activating autophagy and suppressing inflammation in a rat model. Life Sci. 2020 Aug 1;254:117735. Doi:10.1016/j.lfs.2020.117735
22. Rodríguez CM, Velásquez-Berrío M, Rúa C, Viana M, Abrahams VM, Cadavid AP, Alvarez AM. Antiphospholipid Antibodies From Women With Pregnancy Morbidity and Vascular Thrombosis Induce Endothelial Mitochondrial Dysfunction, mTOR Activation, and Autophagy. Front Physiol. 2021 Nov 29;12:706743. Doi:10.3389/fphys.2021.706743
23. Zhang G, He C, Wu Q, Xu G, Kuang M, Wang T, Xu L, Zhou H, Yuan W. Impaired Autophagy Induced by oxLDL/β2GPI/anti-β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction. Oxid Med Cell Longev. 2021 Jun 14;2021:6662225. Doi:10.1155/2021/6662225
24. Winans T, Oaks Z, Choudhary G, Patel A, Huang N, Faludi T, Krakko D, Nolan J, Lewis J, Blair S, Lai Z, Landas SK, Middleton F, Asara JM, Chung SK, Wyman B, Azadi P, Banki K, Perl A. mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency. J Autoimmun. 2023 Nov;140:103112. Doi:10.1016/j.jaut.2023.103112
25. Mora-Ramírez M, González-Pacheco H, Amezcua-Guerra LM. Stents Coated With Mammalian Target of Rapamycin Inhibitors (mTOR) Appear to Be the Best Choice in Patients With Antiphospholipid Syndrome and Myocardial Infarction. J Clin Rheumatol. 2016 Aug;22(5):281. Doi:10.1097/Rhu.0000000000000409
26. Sartorelli S, De Luca G, Campochiaro C, Peretto G, Sala S, Esposito A, Busnardo E, Basso C, Thiene G, Dagna L. Successful use of sirolimus in a patient with cardiac microangiopathy in primary antiphospholipid syndrome. Scand J Rheumatol. 2019 Nov;48(6):515-516. Doi:10.1080/03009742.2019.1574022. Epub 2019 Feb 22. Erratum in: Scand J Rheumatol. 2019 Nov;48(6):520. Doi:10.1080/03009742.2019.1714880
27. Rodríguez-García ME, Cotrina-Vinagre FJ, Bellusci M, Martínez de Aragón A, Hernández-Sánchez L, Carnicero-Rodríguez P, Martín-Hernández E, Martínez-Azorín F. A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. Eur J Hum Genet. 2019 Sep;27(9):1369-1378. Doi:10.1038/s41431-019-0418-1
28. Sevim E, Siddique S, Chalasani MLS, Chyou S, Shipman WD, O'Shea O, Harp J, Alpan O, Zuily S, Lu TT, Erkan D. Mammalian Target of Rapamycin Pathway Assessment in Antiphospholipid Antibody-Positive Patients with Livedo. J Rheumatol. 2022 Sep;49(9):1026-1030. Doi:10.3899/jrheum.220049
29. Canaud G, Legendre C, Terzi F. AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game. Lupus. 2015 Mar;24(3):227-30. Doi:10.1177/0961203315569336
30. Lai ZW, Marchena-Mendez I, Perl A. Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome. Clin Immunol. 2015 Jun;158(2):148-52. Doi:10.1016/j.clim.2015.03.024
31. Dufour I, Venot Q, Aydin S, Demoulin N, Canaud G, Morelle J. mTORC Pathway Activation and Effect of Sirolimus on Native Kidney Antiphospholipid Syndrome Nephropathy: A Case Report. Am J Kidney Dis. 2020 Aug;76(2):288-291. Doi:10.1053/j.ajkd.2019.08.032
32. Zhang D, Sun F, Ye S. Successful treatment of sirolimus in a Chinese patient with refractory LN and APS: a case report. Ther Adv Musculoskelet Dis. 2022 Feb 28;14:1759720X221079253. Doi:10.1177/1759720X221079253