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Bitsadze V, Khizroeva J, Lazarchuk A, Salnikova P, Yagubova F, Tretyakova M, Grigoreva K, Gashimova N, Tsibizova V, Karpova A, Mostovoi A, Kapanadze D, Voskresenskaya O, Akinshina S, Di Renzo GC, Gris JC, Elalamy I, Makatsariya A. Pediatric antiphospholipid syndrome: is it the same as an adult? J Matern Fetal Neonatal Med 2024; 37:2390637. [PMID: 39155241 DOI: 10.1080/14767058.2024.2390637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/18/2024] [Accepted: 08/03/2024] [Indexed: 08/20/2024]
Abstract
IMPORTANCE Antiphospholipid syndrome in neonates and children is a rare, but in some cases life-threatening condition with arterial and/or venous thrombosis and/or non-thrombotic neurological, skin, ophthalmological and other manifestations. OBSERVATIONS This review highlights the available information about the features of pediatric APS, including the rare catastrophic form, the differences between pediatric and adult APS, and the role of genetic thrombophilia in APS manifestation. CONCLUSIONS AND RELEVANCE The clinical manifestations and treatment options for APS in children may differ from those in adults, and prescribing therapy can be challenging due to the unique clinical and morphological characteristics of the pediatric patient. Pediatric APS may be a predictor of the development of certain autoimmune diseases and classic manifestations of APS in adulthood, therefore, a revision of the existing criteria for the diagnosis and treatment of APS in children is necessary.
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Affiliation(s)
- Viсtoria Bitsadze
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Jamilya Khizroeva
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Arina Lazarchuk
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Polina Salnikova
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Fidan Yagubova
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Maria Tretyakova
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Kristina Grigoreva
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Nilufar Gashimova
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Valentina Tsibizova
- The PREIS School (International and European School of Perinatal, Neonatal and Reproductive Medicine), Firenze, Italy
| | - Anna Karpova
- Moscow Healthcare Department, Vorokhobov City Clinical Hospital № 67, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Health Ministry of Russian Federation, Moscow, Russia
- Health Ministry of Russian Federation, Yaroslavl State Medical University, Yaroslavl, Russia
| | - Aleksei Mostovoi
- Moscow Healthcare Department, Vorokhobov City Clinical Hospital № 67, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Health Ministry of Russian Federation, Moscow, Russia
- Health Ministry of Russian Federation, Yaroslavl State Medical University, Yaroslavl, Russia
| | | | - Olga Voskresenskaya
- Department of Nervous Diseases and Neurosurgery, N.V. Sklifosovsky Institute of Clinical Medicine, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Svetlana Akinshina
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Gian Carlo Di Renzo
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- The PREIS School (International and European School of Perinatal, Neonatal and Reproductive Medicine), Firenze, Italy
| | - Jean-Christophe Gris
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Montpellier, France
| | - Ismail Elalamy
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Department Hematology and Thrombosis Center, Medicine Sorbonne University, Paris, France
- Hospital Tenon, Paris, France
| | - Alexander Makatsariya
- Department of Obstetrics, Gynecology and Perinatal Medicine, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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Magro CM, Stephan C, Kalomeris T. The utility of the normal thin section skin biopsy in the assessment of systemic/extracutaneous disease and small fiber neuropathy. Clin Dermatol 2024; 42:646-667. [PMID: 39278514 DOI: 10.1016/j.clindermatol.2024.09.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Diseases reflective of multiorgan vascular injury of diverse etiology, peripheral nerve disease, dysautonomia syndromes, and intravascular lymphoma may exhibit abnormalities on a normal skin biopsy that may be instrumental in establishing a diagnosis. A retrospective review of our database was conducted to uncover cases where a normal skin biopsy was performed to rule in or out such systemic diseases as complement-driven thrombotic microvascular disease (including atypical hemolytic uremic syndrome, posttransplant thrombotic microangiopathy, and severe or critical COVID-19), systemic capillary leak syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) intravascular B cell lymphoma, small fiber neuropathy, dysautonomia syndromes, and mast cell activation syndrome. Among the special studies were immunohistochemical staining to detect C5b-9, CD56, and myxovirus resistance protein A, as well as mast cell, B and T cell markers. Characteristic patterns were critical in establishing diagnoses such as : increased C5b-9 microvascular deposition in the deltoid area (atypical hemolytic uremic syndrome, posttransplant thrombotic microangiopathy, catastrophic antiphospholipid antibody syndrome, and severe or critical COVID-19); enhanced type I interferon signaling (systemic capillary leak syndrome); ultrastructural arteriopathic changes (CADASIL); reduced cutaneous autonomic innervation in the lower extremities (small fiber neuropathy and postural orthostatic tachycardia syndrome); presence of intravascular lymphocytes on biopsy of abdominal, thigh, and buttock skin (intravascular B cell lymphoma); and a higher than normal density of mast cells in the absence of other inflammatory cell types (mast cell activation syndrome). The skin is clearly a critical window for understanding extracutaneous disease, a concept well exemplified by the myriad of diseases suggested by the microscopic and/or ultrastructural examination of clinically normal skin and therefore establishing the normal skin biopsy as an important tool for understanding certain extracutaneous reactive, neoplastic and paraneoplastic syndromes as well as small fiber neuropathy.
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Affiliation(s)
- Cynthia M Magro
- Weill Cornell Medicine Department of Pathology & Laboratory Medicine, New York, NY, USA.
| | - Carla Stephan
- New York- Presbyterian/Weill Cornell Medicine Department of Pathology and Laboratory Medicine, New York, NY, USA
| | - Taylor Kalomeris
- New York- Presbyterian/Weill Cornell Medicine Department of Pathology and Laboratory Medicine, New York, NY, USA
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Pala C, Parenti E, Vizzini G, Gianfreda D, Rossi GM. Thrombotic microangiopathy due to primary antiphospholipid syndrome: successful treatment with eculizumab. J Nephrol 2024; 37:1141-1145. [PMID: 37847369 DOI: 10.1007/s40620-023-01789-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/11/2023] [Indexed: 10/18/2023]
Abstract
Antiphospholipid syndrome nephropathy includes a variety of histological lesions, including thrombotic microangiopathy, which is not included among the diagnostic criteria of antiphospholipid syndrome. Whereas in secondary antiphospholipid syndrome, e.g. to systemic lupus erythematosus, there is emerging evidence of a benefit from complement blockade with eculizumab, optimal treatment of primary antiphospholipid syndrome-associated thrombotic microangiopathy is currently unknown. We report the case of a 36-year-old male patient with primary antiphospholipid syndrome-associated thrombotic microangiopathy, presenting with a clinical picture of atypical hemolytic-uremic syndrome with frequent relapses, treated with eculizumab (four 900 mg weekly doses followed by 1200 mg fortnightly infusions) leading to resolution of hemolysis, long-term remission and partial kidney function recovery (peak serum creatinine 3.8 mg/dL, decreased and stabilized around 2.5 mg/dL) over a follow up period of over 2 years.
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Affiliation(s)
- Chiara Pala
- Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma, Italy
| | - Elisabetta Parenti
- Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma, Italy
| | - Giuseppe Vizzini
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma, Italy
- Laboratorio di Immunopatologia Renale "Luigi Migone", Università degli Studi di Parma, Parma, Italy
| | - Davide Gianfreda
- Nefrologia e Dialisi, Ospedale "Santa Caterina Novella", Galatina, Lecce, Italy
| | - Giovanni Maria Rossi
- Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma, Italy.
- Laboratorio di Immunopatologia Renale "Luigi Migone", Università degli Studi di Parma, Parma, Italy.
- Nefrologia e Dialisi, Ospedale "Santa Caterina Novella", Galatina, Lecce, Italy.
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Jacobs L, Wauters N, Lablad Y, Morelle J, Taghavi M. Diagnosis and Management of Catastrophic Antiphospholipid Syndrome and the Potential Impact of the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Antibodies (Basel) 2024; 13:21. [PMID: 38534211 DOI: 10.3390/antib13010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening condition characterized by the persistence of antiphospholipid antibodies and occurrence of multiple vascular occlusive events. CAPS currently remains a diagnostic challenge and requires urgent treatment. The diagnosis of CAPS is made difficult by classification criteria used as diagnostic criteria in clinical practice, knowledge derived from retrospective data and case reports, confounding clinical and biological features, and its rapid onset and mortality. The absence of prospective studies of CAPS limits the strength of evidence for guideline treatment protocols. This comprehensive review summarizes the current understanding of the disease, and discusses how the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria impact the definition and therapeutic management of CAPS, which is considered the most severe form of APS. The correct integration of 2023 ACR/EULAR APS classification criteria is poised to facilitate CAPS diagnosis, particularly in critical situations, offering a promising avenue for improved outcomes.
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Affiliation(s)
- Lucas Jacobs
- Internal Medicine Department, Brugmann University Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium
- Nephrology and Dialysis Department, Brugmann University Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium
- Internal Medicine Department, Tivoli University Hospital, Université Libre de Bruxelles, 7100 La Louvière, Belgium
| | - Nader Wauters
- Internal Medicine Department, Tivoli University Hospital, Université Libre de Bruxelles, 7100 La Louvière, Belgium
| | - Yahya Lablad
- Internal Medicine Department, Brugmann University Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium
| | - Johann Morelle
- Division of Nephrology, Namur University Hospitals (CHU UCL Namur), 5000 Namur, Belgium
| | - Maxime Taghavi
- Internal Medicine Department, Brugmann University Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium
- Nephrology and Dialysis Department, Brugmann University Hospital, Université Libre de Bruxelles, 1020 Brussels, Belgium
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Frederick R, Zolio L, Romas E, Ierino F. Eculizumab therapy and complement regulation in a case of resistant catastrophic antiphospholipid syndrome. BMJ Case Rep 2024; 17:e254449. [PMID: 38442982 PMCID: PMC10916160 DOI: 10.1136/bcr-2022-254449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024] Open
Abstract
Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of antiphospholipid syndrome characterised by diffuse arterial and venous thrombosis, in the presence of positive antiphospholipid antibodies. The multiple sites of thrombosis in small, medium and large vessels progress to multiorgan failure, accounting for the high mortality rate associated with CAPS. Unregulated complement activation is increasingly recognised as critical to the pathogenesis of CAPS. Early diagnosis is essential to initiate prompt life-saving treatment with the triple therapy of anticoagulation, immunosuppression and either plasmapheresis or intravenous immunoglobulin. Among other immunosuppressive agents, eculizumab, a complement inhibitor has demonstrated efficacy in treatment-resistant cases.We report an instructive case of a woman presenting with both clinical and laboratory findings consistent with primary CAPS, resistant to initial treatment and responsive to eculizumab, with emphasis on genetic testing and implications for future therapy.
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Affiliation(s)
- Rachel Frederick
- Department of Nephrology, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
- Department of General Medicine, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Luigi Zolio
- Department of Rheumatology, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
| | - Evange Romas
- Department of Rheumatology, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
- The University of Melbourne, Melbourne, Victoria, Australia
| | - Frank Ierino
- Department of Nephrology, St Vincent's Hospital Melbourne Pty Ltd, Fitzroy, Victoria, Australia
- The University of Melbourne, Melbourne, Victoria, Australia
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De Simone E, Sciascia S, Fenoglio R, Oddone V, Barreca A, Roccatello D. Antiphospholipid Syndrome and Kidney Involvement. Kidney Blood Press Res 2023; 48:666-677. [PMID: 37734329 DOI: 10.1159/000529229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 01/07/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the development of autoantibodies and the impairment of the coagulation system. Knowledge about this syndrome is increasing over time, but kidney involvement, especially APS nephropathy, still represents a challenge for physicians. SUMMARY A "two hit" model has been hypothesized to explain APS pathophysiology, and the role played by some factors, such as the complement system, is becoming more and more clear. From a clinical point of view, along with thrombosis in any site and/or obstetric morbidities, that are the hallmarks of APS, a constellation of several other clinical symptoms is related to APS. These symptoms alone are not sufficient to fulfill Sydney criteria for APS and this could potentially lead to omitting some diagnoses. The mainstay of management of APS is antithrombotic therapy, but there are expectations for new drugs that regulate the immune system. APS could affect the kidneys in many ways and among them, APS nephropathy is an intriguing entity that has been overlooked in recent years. Novel studies on APS nephropathy are lacking. KEY MESSAGES In this review, we discuss what we currently know about APS and its relationship with the kidney, with an eye toward the future perspectives. Multicenter studies on APS nephropathy are necessary in order to develop targeted therapies.
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Affiliation(s)
- Emanuele De Simone
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) Including the Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital-ASL Città di Torino, University of Turin, Turin, Italy,
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) Including the Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital-ASL Città di Torino, University of Turin, Turin, Italy
| | - Roberta Fenoglio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) Including the Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital-ASL Città di Torino, University of Turin, Turin, Italy
| | - Valentina Oddone
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) Including the Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital-ASL Città di Torino, University of Turin, Turin, Italy
| | - Antonella Barreca
- Division of Pathology, Città Della Salute e Della Scienza Hospital and University of Turin, Turin, Italy
| | - Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) Including the Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital-ASL Città di Torino, University of Turin, Turin, Italy
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Sakowicz A, Bralewska M, Rybak-Krzyszkowska M, Grzesiak M, Pietrucha T. New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations. Int J Mol Sci 2023; 24:12100. [PMID: 37569476 PMCID: PMC10418829 DOI: 10.3390/ijms241512100] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/13/2023] Open
Abstract
Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.
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Affiliation(s)
- Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
| | - Michalina Bralewska
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
| | - Magda Rybak-Krzyszkowska
- Department of Obstetrics and Perinatology, University Hospital in Krakow, 31-501 Krakow, Poland;
| | - Mariusz Grzesiak
- Department of Perinatology, Obstetrics and Gynecology, Polish Mother’s Memorial Hospital-Research Institute in Lodz, 93-338 Lodz, Poland;
- Department of Gynecology and Obstetrics, Medical University of Lodz, 93-338 Lodz, Poland
| | - Tadeusz Pietrucha
- Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (M.B.); (T.P.)
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Yun Z, Duan L, Liu X, Cai Q, Li C. An update on the biologics for the treatment of antiphospholipid syndrome. Front Immunol 2023; 14:1145145. [PMID: 37275894 PMCID: PMC10237350 DOI: 10.3389/fimmu.2023.1145145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/04/2023] [Indexed: 06/07/2023] Open
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Although anticoagulation is the primary treatment for APS, it fails in approximately 20-30% of obstetric APS cases and more than 30% of thrombotic APS cases. Therefore, there is a need for new, targeted treatments beyond anticoagulants. Biologics, such as rituximab and eculizumab, have been recommended for refractory catastrophic APS. This review focuses on the recent advancements in the pathogenesis of APS and explores the potential of targeted treatments, including eculizumab, rituximab, belimumab, daratumumab, obinutuzumab, and anti-TNF-α antibodies, for APS management.
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Affiliation(s)
- Zelin Yun
- Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People’s Hospital, Beijing, China
| | - Lizhi Duan
- Department of Rheumatology and Immunology, Gangkou Hospital of Hebei Port Group Company Limited, Qinhuangdao, Hebei, China
| | - Xiangjun Liu
- Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People’s Hospital, Beijing, China
| | - Qingmeng Cai
- Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People’s Hospital, Beijing, China
| | - Chun Li
- Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China
- Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People’s Hospital, Beijing, China
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Trambas IA, Coughlan MT, Tan SM. Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease. Int J Mol Sci 2023; 24:ijms24108758. [PMID: 37240105 DOI: 10.3390/ijms24108758] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) affects 30-40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of diabetes and its complications. The potent anaphylatoxin C5a is a critical effector of complement-mediated inflammation. Excessive activation of the C5a-signalling axis promotes a potent inflammatory environment and is associated with mitochondrial dysfunction, inflammasome activation, and the production of reactive oxygen species. Conventional renoprotective agents used in the treatment of diabetes do not target the complement system. Mounting preclinical evidence indicates that inhibition of the complement system may prove protective in DKD by reducing inflammation and fibrosis. Targeting the C5a-receptor signaling axis is of particular interest, as inhibition at this level attenuates inflammation while preserving the critical immunological defense functions of the complement system. In this review, the important role of the C5a/C5a-receptor axis in the pathogenesis of diabetes and kidney injuries will be discussed, and an overview of the status and mechanisms of action of current complement therapeutics in development will be provided.
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Affiliation(s)
- Inez A Trambas
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Sih Min Tan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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11
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El Hasbani G, Saliba AN, Uthman I, Taher AT. Hematological manifestations of antiphospholipid syndrome: Going beyond thrombosis. Blood Rev 2023; 58:101015. [PMID: 36175215 DOI: 10.1016/j.blre.2022.101015] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/30/2022]
Abstract
Thrombotic complications are a hallmark of antiphospholipid syndrome (APS). These vascular - arterial, venous, and/or small vessel - complications are well described and known to hematologists and healthcare providers caring for patients with this disease. In this review, we shed light on other hematological manifestations of the disease, including bleeding, thrombocytopenia, autoimmune hemolytic anemia, and thrombotic microangiopathy syndromes. While these manifestations are not bona fide clinical criteria for the diagnosis of APS, they frequently interact and contribute to the complexity of clinical management of APS.
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Affiliation(s)
- Georges El Hasbani
- Department of Internal Medicine, Hartford Healthcare, St. Vincent's Medical Center, Bridgeport, CT 06606, USA
| | - Antoine N Saliba
- Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Imad Uthman
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon..
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12
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Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum. Obstet Gynecol 2023; 141:85-108. [PMID: 36455925 DOI: 10.1097/aog.0000000000005024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/04/2022] [Indexed: 12/05/2022]
Abstract
The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidence-based recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternal-fetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital.
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13
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Rousselin C, Amoura Z, Faguer S, Bataille P, Boffa JJ, Canaud G, Guerrot D, Jourde-Chiche For The Gclr N, Karras A, Auxenfants E, Chapelet A, Lambert M, Behal H, Nochy D, Jean-Paul DVH, Brocheriou For The Cfpr I, Gnemmi V, Quemeneur T. Renal and vascular outcomes in patients with isolated antiphospholipid syndrome nephropathy. J Autoimmun 2022; 132:102889. [PMID: 35987174 DOI: 10.1016/j.jaut.2022.102889] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/24/2022] [Accepted: 07/24/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Antiphospholipid syndrome (APS) nephropathy (APSN) is a rare pattern with specific features resulting from microvascular lesions. The prognosis of APSN, outside of lupus nephritis, is unknown. The aim of this study was to describe the renal, vascular and overall outcomes of patients with APSN. METHODS Retrospective multicenter study of patients with antiphospholipid antibodies (aPL) associated with histological APSN lesions and no other nephropathy, identified through a national call for medical records. End-stage renal disease (ESRD)-free survival, thrombosis recurrence-free survival and overall survival were assessed. RESULTS Thirty patients were included (19 women) with a median age of 40 years (34-52 years). Fifteen patients had APS, 26/28 had lupus anticoagulant, and 15/26 had triple positivity for aPL. Median eGFR was 50 (31-60) mL/min/1.73 m2. Glomerular thrombotic microangiopathy was found in 12/24 cases, fibrous intimal hyperplasia in 12/22 cases and focal cortical atrophy in 17/29 cases. Nineteen patients had moderate to severe interstitial fibrosis (>25%). Six patients developed ESRD at a median follow-up of 6.2 (1.8-9.1) years. The ESRD-free survival rates at 5 and 10 years were 80.0% (95% CI 57.6%-91.4%) and 72.7% (95% CI, 46.9%-87.4%) respectively. None of the histological factors considered was significantly associated with a decrease in eGFR at 12 months. Thrombosis recurrence-free survival was 77.8% (95% CI 48.2%-91.6%) at 10 years. Overall survival was 94% at 10 years (95% CI 65.0%-99.2%). CONCLUSIONS The renal prognosis of isolated APSN is poor. The severe fibrotic lesions observed are suggestive of late diagnosis.
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Affiliation(s)
| | - Zahir Amoura
- Médecine Interne 2, French National Reference Center for SLE and APS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Stanislas Faguer
- Département de Néphrologie et Transplantation D'Organes, Centre de Référence des Maladies Rénales Rares, CHU de Toulouse, F-31000 Toulouse, France
| | | | | | | | | | | | | | | | | | | | - Hélène Behal
- Univ. Lille, CHU Lille, ULR 2694 - METRICS: Évaluation des Technologies de Santé et des Pratiques Médicales, F-59000 Lille, France
| | - Dominique Nochy
- Anatomo-pathologie, Hôpital Européen Georges Pompidou, Paris, France
| | | | | | | | - Thomas Quemeneur
- Néphrologie et Médecine Interne, Hôpital de Valenciennes, France
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14
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Treatment advances in antiphospholipid syndrome: 2022 update. Curr Opin Pharmacol 2022; 65:102212. [DOI: 10.1016/j.coph.2022.102212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 03/11/2022] [Indexed: 12/22/2022]
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15
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Fernandez-Ruiz R, Belmont HM. The role of anticomplement therapy in lupus nephritis. Transl Res 2022; 245:1-17. [PMID: 35158097 DOI: 10.1016/j.trsl.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 10/19/2022]
Abstract
The complement system plays crucial roles in homeostasis and host defense against microbes. Deficiency of early complement cascade components has been associated with increased susceptibility to systemic lupus erythematosus (SLE), whereas excessive complement consumption is a hallmark of this disease. Although enhanced classical pathway activation by immune complexes was initially thought to be the main contributor to lupus nephritis (LN) pathogenesis, an increasing body of evidence has suggested the alternative and the lectin pathways are also involved. Therapeutic agents targeting complement activation have been used in LN patients and clinical trials are ongoing. We review the mechanisms by which complement system dysregulation contributes to renal injury in SLE and summarize the latest evidence on the use of anticomplement agents to manage this condition.
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Affiliation(s)
- Ruth Fernandez-Ruiz
- Division of Rheumatology, NYU Grossman School of Medicine, New York, New York
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16
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol 2022; 44:347-362. [PMID: 35122116 PMCID: PMC8816310 DOI: 10.1007/s00281-022-00916-w] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.
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Affiliation(s)
- Jason S Knight
- Division of Rheumatology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
| | - Yogendra Kanthi
- Division of Intramural Research National Heart, Lung, and Blood Institute, Bethesda, MD, USA
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18
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Sevim E, Zisa D, Andrade D, Sciascia S, Pengo V, Tektonidou MG, Ugarte A, Gerosa M, Michael Belmont H, Zamorano MAA, Fortin PR, Ji L, Efthymiou M, Cohen H, Ware Branch D, de Jesus GR, Andreoli L, Petri M, Rodriguez E, Cervera R, Knight JS, Atsumi T, Willis R, Roubey R, Bertolaccini ML, Erkan D, Barbhaiya M. Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository. Arthritis Care Res (Hoboken) 2022; 74:324-335. [PMID: 32986935 PMCID: PMC10725727 DOI: 10.1002/acr.24468] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 09/04/2020] [Accepted: 09/22/2020] [Indexed: 12/19/2023]
Abstract
OBJECTIVE To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes. METHODS The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-β2 -glycoprotein I [anti-β2 GPI]) antibodies by aPL profiles (LAC only, single, double, and triple aPL positivity). RESULTS The 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-β2 GPI only. CONCLUSION Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.
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Affiliation(s)
- Ecem Sevim
- Ecem Sevim, MD: Hospital for Special Surgery, New York, New York, and Montefiore Medical Center, Bronx, New York
| | - Diane Zisa
- Diane Zisa, MD, Doruk Erkan, MD, MPH, Medha Barbhaiya, MD, MPH: Hospital for Special Surgery and Weill Cornell Medicine, New York, New York
| | - Danieli Andrade
- Danieli Andrade, MD, PhD: University of Sao Paulo, Sao Paulo, Brazil
| | | | - Vittorio Pengo
- Vittorio Pengo, MD: University Hospital Padova, Padova, Italy
| | - Maria G. Tektonidou
- Maria G. Tektonidou, MD: National and Kapodistrian University of Athens, Athens, Greece
| | - Amaia Ugarte
- Amaia Ugarte, MD: Hospital Universitario Cruces, Barakaldo, País Vasco, Spain
| | - Maria Gerosa
- Maria Gerosa, MD, PhD: University of Milan, Milan, Italy
| | - H. Michael Belmont
- H. Michael Belmont, MD: New York University Langone Medical Center, New York, New York
| | | | - Paul R. Fortin
- PaulR. Fortin, MD, PhD: CHU de Québec and Université Laval, Quebec City, Canada
| | - Lanlan Ji
- Lanlan Ji, MD: Peking University First Hospital, Beijing, China
| | - Maria Efthymiou
- MariaEfthymiou, PhD, Hannah Cohen, MD: University College London, London, UK
| | - Hannah Cohen
- MariaEfthymiou, PhD, Hannah Cohen, MD: University College London, London, UK
| | - D. Ware Branch
- D. Ware Branch, MD: University of Utah and Intermountain Healthcare, Salt Lake City, Utah
| | | | - Laura Andreoli
- Laura Andreoli, MD, PhD: University of Brescia, Brescia, Italy
| | - Michelle Petri
- Michelle Petri, MD, MPH: Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Esther Rodriguez
- Esther Rodriguez, MD: Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Ricard Cervera
- Ricard Cervera, MD, PhD, FRCP: Hospital Clínic Institut d’Investigacions Biomèdiques August Pi i Sunyer(IDIBAPS), Barcelona, Catalonia, Spain
| | | | - Tatsuya Atsumi
- Tatsuya Atsumi, MD, PhD: Hokkaido University Hospital, Sapporo, Japan
| | - Rohan Willis
- Rohan Willis, MD: University of Texas Medical Branch, Galveston
| | - Robert Roubey
- Robert Roubey, MD: University of North Carolina, Chapel Hill
| | | | - Doruk Erkan
- Diane Zisa, MD, Doruk Erkan, MD, MPH, Medha Barbhaiya, MD, MPH: Hospital for Special Surgery and Weill Cornell Medicine, New York, New York
| | - Medha Barbhaiya
- Diane Zisa, MD, Doruk Erkan, MD, MPH, Medha Barbhaiya, MD, MPH: Hospital for Special Surgery and Weill Cornell Medicine, New York, New York
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Nobata H, Katsuno T, Kachi A, Kinashi H, Banno S, Ito Y. Diversity of Renal Involvement in Antiphospholipid Syndrome Based on Pathological Findings and Treatment Responses. J Clin Rheumatol 2021; 27:S495-S497. [PMID: 31714303 DOI: 10.1097/rhu.0000000000001173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Hironobu Nobata
- Department of Nephrology and Rheumatology Aichi Medical University Nagakute, Aichi, Japan
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20
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Stanescu C, Andronesi AG, Jurcut C, Gherghiceanu M, Vornicu A, Burcea FA, Andronesi TD, Lupusoru GE, Iliuta L, Sorohan BM, Obrisca B, Ismail G. Successful Treatment of Catastrophic Antiphospholipid Syndrome Using Rituximab: Case Report and Review of the Literature. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:912. [PMID: 34577835 PMCID: PMC8470109 DOI: 10.3390/medicina57090912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Kidney involvement is a frequent complication of systemic lupus erythematosus (SLE) and kidney biopsy is essential in differentiating lupus nephritis (LN) from thrombotic microangiopathy (TMA) secondary to antiphospholipid autoantibodies (aPL). Association between antiphospholipid syndrome (APS) and acquired hemophilia due to inhibitors was very rarely described in SLE patients. CASE PRESENTATION We present the case of a 61-year-old male diagnosed with SLE who acquired deficiency of clotting factor VIII due to circulating inhibitors, admitted for acute kidney injury (AKI), microangiopathic hemolytic anemia, thrombocytopenia, and diplopia. Kidney biopsy showed TMA due to APS, but no signs of LN. Head computed tomography identified low dense areas in the white matter, suggesting small blood vessels' involvement. A diagnosis of probable catastrophic antiphospholipid syndrome (CAPS) was established and treatment with low molecular weight heparin, intravenous methylprednisolone, plasmapheresis, and rituximab was initiated, followed by resolution of AKI, diplopia, and TMA with complete depletion of CD19+B-lymphocytes (CD19+B-Ly) after one month. We further review the current knowledge regarding pathogenesis and management of CAPS in SLE patients. CONCLUSIONS Targeted therapy was possible after kidney biopsy, improving renal and general prognosis. CD19+B-Ly repopulation preceded biological relapse, so monitoring of CD19+B-Ly may serve as a tool to predict relapses and guide rituximab therapy.
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Affiliation(s)
- Cristina Stanescu
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
| | - Andreea Gabriella Andronesi
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
- Nephrology Department, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania; (B.M.S.); (B.O.)
| | - Ciprian Jurcut
- Internal Medicine Department, “Carol Davila” Military Emergency Hospital, 010225 Bucharest, Romania;
| | - Mihaela Gherghiceanu
- “Victor Babes” National Institute for Research and Development in Pathology and Biomedical Sciences, 050097 Bucharest, Romania;
| | - Alexandra Vornicu
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
| | - Florentina Andreea Burcea
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
| | - Toader Danut Andronesi
- Department of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Gabriela Elena Lupusoru
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
- Nephrology Department, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania; (B.M.S.); (B.O.)
| | - Luminita Iliuta
- Department of Biostatistics, Marketing and Medical Technology, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania;
| | - Bogdan Marian Sorohan
- Nephrology Department, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania; (B.M.S.); (B.O.)
| | - Bogdan Obrisca
- Nephrology Department, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania; (B.M.S.); (B.O.)
| | - Gener Ismail
- Nephrology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.S.); (A.V.); (F.A.B.); (G.E.L.); (G.I.)
- Nephrology Department, “Carol Davila” University of Medicine and Pharmacy, 050471 Bucharest, Romania; (B.M.S.); (B.O.)
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21
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Erkan D. Expert Perspective: Management of Microvascular and Catastrophic Antiphospholipid Syndrome. Arthritis Rheumatol 2021; 73:1780-1790. [PMID: 34114366 DOI: 10.1002/art.41891] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 06/01/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Doruk Erkan
- Hospital for Special Surgery and Weill Cornell Medicine, New York, New York
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22
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Uludag G, Onghanseng N, Tran ANT, Hassan M, Halim MS, Sepah YJ, Do DV, Nguyen QD. Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations. J Ophthalmic Inflamm Infect 2021; 11:11. [PMID: 33834305 PMCID: PMC8032459 DOI: 10.1186/s12348-021-00240-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 03/02/2021] [Indexed: 12/18/2022] Open
Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder associated with obstetrical complications, thrombotic complications involving both arteries and veins, and non-thrombotic manifestations affecting multiple other systems presenting in various clinical forms. Diagnosis requires the presence of antiphospholipid antibodies. The exact pathogenesis of APS is not fully known. However, it has recently been shown that activation of different types of cells by antiphospholipid antibodies plays an important role in thrombosis formation. Ocular involvement is one of the important clinical manifestations of APS and can vary in presentations. Therefore, as an ophthalmologist, it is crucial to be familiar with the ocular findings of APS to prevent further complications that can develop. Furthermore, the ongoing identification of new and specific factors contributing to the pathogenesis of APS may provide new therapeutic options in the management of the disease in the future.
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Affiliation(s)
- Gunay Uludag
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA
| | - Neil Onghanseng
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA
| | - Anh N T Tran
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA
| | - Muhammad Hassan
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA
| | - Muhammad Sohail Halim
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA.,Ocular Imaging Research and Reading Center, Sunnyvale, CA, USA
| | - Yasir J Sepah
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA.,Ocular Imaging Research and Reading Center, Sunnyvale, CA, USA
| | - Diana V Do
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA
| | - Quan Dong Nguyen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford University, 2370 Watson Court, Suite 200, Palo Alto, CA, 94303, USA.
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23
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Ávila A, Gavela E, Sancho A. Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front Med (Lausanne) 2021; 8:642864. [PMID: 33898482 PMCID: PMC8063690 DOI: 10.3389/fmed.2021.642864] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/22/2021] [Indexed: 01/25/2023] Open
Abstract
Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy. De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.
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Affiliation(s)
- Ana Ávila
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Eva Gavela
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Asunción Sancho
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
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Non-Criteria Manifestations of Juvenile Antiphospholipid Syndrome. J Clin Med 2021; 10:jcm10061240. [PMID: 33802787 PMCID: PMC8002433 DOI: 10.3390/jcm10061240] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 01/07/2023] Open
Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder mainly characterised by increased risks of thrombosis and pregnancy morbidity and persistent positive test results for antiphospholipid antibodies (aPLs). The criteria for diagnosing juvenile APS have yet to be validated, while the Sydney classification criteria do not contain several non-thrombotic clinical manifestations associated with the presence of aPLs. As such, difficulties have been encountered in the diagnosis of patients who have no certain thrombotic occlusions. Moreover, extra-criteria manifestations (i.e., clinical manifestations not listed in the classification criteria), including neurologic manifestations (chorea, myelitis and migraine), haematologic manifestations (thrombocytopenia and haemolytic anaemia), livedo reticularis, nephropathy and valvular heart disease have been reported, which suggests that the clinical spectrum of aPL-related manifestations extends beyond that indicated in the classification criteria. Studies have demonstrated that more than 40% of children with aPLs demonstrated non-thrombotic aPL-related clinical manifestations alone. Moreover, our results showed that the pathogenesis of non-criteria manifestations is characterised by “APS vasculopathy”. The present review introduces the characteristics and findings of non-criteria manifestations observed in juvenile APS.
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Chaturvedi S, Braunstein EM, Brodsky RA. Antiphospholipid syndrome: Complement activation, complement gene mutations, and therapeutic implications. J Thromb Haemost 2021; 19:607-616. [PMID: 32881236 PMCID: PMC8080439 DOI: 10.1111/jth.15082] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/13/2022]
Abstract
Antiphospholipid syndrome (APS) is an acquired thromboinflammatory disorder characterized by the presence of antiphospholipid antibodies as well as an increased frequency of venous or arterial thrombosis and/or obstetrical morbidity. The spectrum of disease varies from asymptomatic to a severe form characterized by widespread thrombosis and multiorgan failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients, often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy. Animal models have implicated complement in the pathophysiology of thrombosis in APS, with more recent data from human studies confirming the interaction between the coagulation and complement pathways. Activation of the complement cascade via antiphospholipid antibodies can cause cellular injury and promote coagulation via multiple mechanisms. Finally, analogous to classic complement-mediated diseases such as atypical hemolytic uremic syndrome, a subset of patients with APS may be at increased risk for development of CAPS because of the presence of germline variants in genes crucial for complement regulation. Together, these data make complement inhibition an attractive and potentially lifesaving therapy to mitigate morbidity and mortality in severe thrombotic APS and CAPS.
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Affiliation(s)
- Shruti Chaturvedi
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Evan M Braunstein
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Brodsky
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Mormile I, Granata F, Punziano A, de Paulis A, Rossi FW. Immunosuppressive Treatment in Antiphospholipid Syndrome: Is It Worth It? Biomedicines 2021; 9:biomedicines9020132. [PMID: 33535377 PMCID: PMC7911562 DOI: 10.3390/biomedicines9020132] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/18/2021] [Accepted: 01/26/2021] [Indexed: 11/16/2022] Open
Abstract
The antiphospholipid syndrome (APS) is characterized by the development of venous and/or arterial thrombosis and pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of APS occurring in about 1% of cases. Lifelong anticoagulation with vitamin K antagonists remains the cornerstone of the therapy for thrombotic APS, but frequently the use of anticoagulation may be problematic due to the increased risk of bleeding, drug interactions, or comorbidities. Immunosuppressant drugs are widely used to treat several autoimmune conditions, in which their safety and effectiveness have been largely demonstrated. Similar evidence in the treatment of primary APS is limited to case reports or case series, and studies on a large scale lack. Immunomodulatory drugs may be an emerging tool in managing such particular situations, like refractory obstetrical complications, CAPS, or so-called APS non-criteria manifestations. In addition, immunomodulatory drugs may be useful in patients experiencing recurrent thromboembolic events despite optimized anticoagulant therapy. We did a comprehensive review of literature analyzing the possible role of immunomodulation in primary APS to provide a broad overview of potentially safe and effective target treatments for managing this devastating disease.
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Affiliation(s)
- Ilaria Mormile
- Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (I.M.); (F.G.); (A.P.); (A.d.P.)
| | - Francescopaolo Granata
- Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (I.M.); (F.G.); (A.P.); (A.d.P.)
| | - Alessandra Punziano
- Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (I.M.); (F.G.); (A.P.); (A.d.P.)
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (I.M.); (F.G.); (A.P.); (A.d.P.)
- Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, 80131 Naples, Italy
| | - Francesca Wanda Rossi
- Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; (I.M.); (F.G.); (A.P.); (A.d.P.)
- Center for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, 80131 Naples, Italy
- Correspondence: ; Tel.: +39-81-7464513
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Abstract
PURPOSE OF REVIEW Antiphospholipid syndrome (APS), more common than once believed, is an autoimmune disease best known for its high risk of incident and recurrent thrombotic events. The approach to treatment potentially differs from treatment of thrombosis in the general population, and this article endeavors to review the latest updates on this topic. RECENT FINDINGS The epidemiology of APS is being increasingly elucidated by large population-based studies, with APS perhaps affecting as many as 1 in 2000 individuals. Vitamin K antagonists, aspirin, and heparinoids continue to have obvious roles in the management of patients with APS. There has recently been intensive study of direct oral anticoagulants in APS, with the most recent randomized studies raising concerns about their inferiority to vitamin K antagonists, at least in some subgroups. Other approaches to treating APS beyond anticoagulants and antiaggregants are also receiving increased attention in mechanistic and preclinical studies with an eye toward future roles in patients with refractory and/or microvascular disease. Pediatric APS is identified as an area in desperate need of additional prospective research. SUMMARY Progress continues to be made in pursuit of improving the lives of individuals afflicted with APS. The most important future directions would seem to involve leveraging modern molecular technologies in order to improve subphenotyping of antiphospholipid antibody-positive individuals. This will help personalize risk profiles and ideally define the optimal approach to therapy based on future risk, rather than past morbid events.
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Nauseef JT, Lim HI, DeSancho MT. Successful outcome with eculizumab treatment in a patient with antiphospholipid syndrome presenting with an unusual thrombotic storm. J Thromb Thrombolysis 2020; 52:597-600. [PMID: 33222114 DOI: 10.1007/s11239-020-02343-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2020] [Indexed: 12/26/2022]
Abstract
Catastrophic Antiphospholipid Syndrome (CAPS) is a life-threatening complication of APS requiring complex management to optimize patient outcome. We describe a 54-year-old man with APS with history of splanchnic vein thrombosis, a Factor II G20210A heterozygote, autoimmune hemolytic anemia and thrombocytopenia. He developed sudden onset of severe flank pain due to spontaneous bilateral adrenal hemorrhage while on warfarin with a therapeutic INR. Despite unfractionated heparin and initial clinical improvement, severe thrombocytopenia developed requiring dexamethasone, rituximab, and romiplostim. Hospitalization was complicated further by thrombosis of the inferior vena cava, pulmonary embolism, and painful violaceous patches on his neck and ear cartilages. Punch biopsy of lesions revealed C5b-C9 deposition of small vessel thromboses. Although the inciting event for his thrombotic storm remains uncertain, anti-complement therapy with eculizumab provided rapid and durable lesion resolution. Eculizumab was discontinued after 6 months and patient remains in remission without recurrent thrombosis. This case provides insight on the management of CAPS, including the use of eculizumab.
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Affiliation(s)
- Jones T Nauseef
- Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA
| | - Hana I Lim
- Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA
| | - Maria T DeSancho
- Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA.
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Management of Antiphospholipid Syndrome. Biomedicines 2020; 8:biomedicines8110508. [PMID: 33212808 PMCID: PMC7696303 DOI: 10.3390/biomedicines8110508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/09/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023] Open
Abstract
Antiphospholipid syndrome (APS), is an acquired autoimmune disorder characterised by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL). Although venous thromboembolism is the most common manifestation, thrombotic events in APS may also occur in virtually any vascular bed, with cerebral circulation being the arterial territory most commonly affected. As APS is a heterogeneous condition, its management should be tailored with a patient-centred approach based on individual risk assessment, which includes the aPL profile, concomitant auto-immune diseases, and traditional cardiovascular risk factors. Although literature data are conflicting regarding primary prophylaxis, there is some evidence indicating that antiplatelet agents may reduce the risk of a first thrombotic event in individuals with a high-risk profile. In patients with thrombotic APS, current evidence-based guidelines recommend lifelong vitamin K antagonists (VKAs), preferably warfarin. The optimal intensity of anticoagulation following arterial thrombosis remains controversial. Arterial thrombosis should be treated either with high-intensity warfarin at a target INR > 3.0, or low-dose aspirin (LDA) combined with moderate-intensity warfarin (INR 2.0-3.0). It is recommended to avoid direct oral anticoagulants (DOACs) in patients with high-risk APS, mainly those with triple-positive PL and previous arterial events. They would only be used exceptionally in selected patients with low-risk venous thromboembolism (VTE). In low-risk VTE patients currently treated with a DOAC due to warfarin intolerance or a previous unstable International Normalized Ratio on warfarin, the decision of continuing DOACs would be taken in carefully selected patients. In women with obstetric APS, the combination therapy with LDA plus heparin remains the conventional strategy.
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Yang B, Zhao M, Wu H, Lu Q. A Comprehensive Review of Biological Agents for Lupus: Beyond Single Target. Front Immunol 2020; 11:539797. [PMID: 33123125 PMCID: PMC7573553 DOI: 10.3389/fimmu.2020.539797] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/01/2020] [Indexed: 12/29/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cells. Due to its complex pathogenesis, the effectiveness of traditional treatment methods is limited. Many patients have developed resistance to conventional treatment or are not sensitive to steroid and immunosuppressant therapy, and so emerging therapeutic antibodies have become an alternative and have been shown to work well in many patients with moderate and severe SLE. This review summarizes the biological agents that are in the preclinical and clinical trial study of SLE. In addition to the various monoclonal antibodies that have been studied for a long time, such as belimumab and rituximab, we focused on another treatment for SLE, bispecific antibodies (BsAbs) such as tibulizumab, which simultaneously targets multiple pathogenic cytokines or pathways. Although the application of BsAbs in cancer has been intensively studied, their application in autoimmune diseases is still in the infant stage. This unique combined mechanism of action may provide a novel therapeutic strategy for SLE.
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Affiliation(s)
- Bingyi Yang
- Department of Dermatology, The Second Xiangya Hospital of Central South University; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ming Zhao
- Department of Dermatology, The Second Xiangya Hospital of Central South University; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haijing Wu
- Department of Dermatology, The Second Xiangya Hospital of Central South University; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qianjin Lu
- Department of Dermatology, The Second Xiangya Hospital of Central South University; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China
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The clinical and serological associations of hypocomplementemia in a longitudinal sle cohort. Semin Arthritis Rheum 2020; 50:1081-1086. [PMID: 32916558 DOI: 10.1016/j.semarthrit.2020.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 04/24/2020] [Accepted: 06/17/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND In SLE, low complement is an important serological manifestation. Recent classification criteria include hypocomplementemia and one gives additional weight if both C3 and C4 are low. We evaluated patients with a history of, and those with persistently, low complement. As complement activation occurs in the antiphospholipid antibody syndrome, an analysis was also performed on those with positive antiphospholipid antibodies to evaluate thrombotic outcomes. METHODS In a longitudinal SLE cohort, organ manifestations, damage, C3, C4 and antiphospholipid antibodies were assessed quarterly. Using univariate and multivariate methods we compared those with and without a history of low C3, low C4 and both. We evaluated those who had a history of low complement at any time point, and those who had persistent hypocomplementemia. Further analysis considered thrombotic outcomes in patients with positive antiphospholipid antibodies and a history of low complement. RESULTS 2399 patients were evaluated. Fifty-five percent had a history of low C3 and 47% low C4; 83 (4%) had persistently low C3 and 65 (3.2%) had persistently low C4. Hematological, renal and serological abnormalities associated with a history of low C3 but not low C4. With anticardiolipin antibodies, a history of hypocomplementemia (both C3 and C4 low) associated with stroke and deep venous thrombosis. CONCLUSION Low C4 was a weak marker in terms of the associated clinical and serological manifestations. Low C3 associated with renal involvement and poor renal outcomes. A history of both low C3 and C4 associated with stroke in the presence of lupus anticoagulant or anticardiolipin antibodies, and low C4 with digital gangrene (with lupus anticoagulant).
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Nasonov EL, Reshetnyak TM, Alekberova ZS. [Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity]. TERAPEVT ARKH 2020; 92:4-14. [PMID: 32598770 DOI: 10.26442/00403660.2020.05.000697] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Indexed: 12/16/2022]
Abstract
Uncontrolled hypercoagulation and inflammation (thromboinflammation), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of thromboinflammatory pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of critical hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.
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Abstract
The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.
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Affiliation(s)
- Eleni Gavriilaki
- Hematology Department, G. Papanicolaou Hospital, Thessaloniki, Greece
| | - Robert A. Brodsky
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Atypical hemolytic uremic syndrome and complement blockade: established and emerging uses of complement inhibition. Curr Opin Nephrol Hypertens 2020; 28:278-287. [PMID: 30865166 DOI: 10.1097/mnh.0000000000000499] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Atypical hemolytic uremic syndrome (aHUS) is a diagnosis that has captured the interest of specialists across multiple fields. The hallmark features of aHUS are microangiopathic hemolysis and thrombocytopenia, which creates a diagnostic dilemma because of the occurrence of these findings in a wide variety of clinical disorders. RECENT FINDINGS In most of the instances, aHUS is a diagnosis of exclusion after ruling out causes such as Shigella toxin, acquired or genetic a disintegrin and metalloproteinase thrombospondin motif 13 deficiency (thrombotic thrombocytopenic purpura), and vitamin B12 deficiency. In the purest sense, aHUS is a genetic condition that is activated (or unmasked) by an environmental exposure. However, it is now evident that complement activation is a feature of many diseases. Variants in complement regulatory genes predispose to microangiopathic hemolysis in many rheumatologic, oncologic, and drug-induced vascular, obstetric, peritransplant, and infectious syndromes. SUMMARY Many 'hemolysis syndromes' overlap clinically with aHUS, and we review the literature on the treatment of these conditions with complement inhibition. New reports on the treatment of C3 glomerulopathy, Shiga toxin-related classic hemolytic uremic syndrome, and medication-related thrombotic microangiopathy will be reviewed as well.
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Cáliz Cáliz R, Díaz Del Campo Fontecha P, Galindo Izquierdo M, López Longo FJ, Martínez Zamora MÁ, Santamaria Ortiz A, Amengual Pliego O, Cuadrado Lozano MJ, Delgado Beltrán MP, Ortells LC, Pérez ECC, Rego GDC, Corral SG, Varela CF, López MM, Nishishinya B, Navarro MN, Testa CP, Pérez HS, Silva-Fernández L, Taboada VMM. Recommendations of the Spanish Rheumatology Society for Primary Antiphospholipid Syndrome. Part II: Obstetric Antiphospholipid Syndrome and Special Situations. REUMATOLOGIA CLINICA 2020; 16:133-148. [PMID: 30686569 DOI: 10.1016/j.reuma.2018.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 10/31/2018] [Accepted: 11/09/2018] [Indexed: 06/09/2023]
Abstract
OBJECTIVE The difficulty in diagnosis and the spectrum of clinical manifestations that can determine the choice of treatment for antiphospholipid syndrome (APS) has fostered the development of recommendations by the Spanish Society of Rheumatology (SER), based on the best possible evidence. These recommendations can serve as a reference for rheumatologists and other specialists involved in the management of APS. METHODS A panel of 4rheumatologists, a gynaecologist and a haematologist with expertise in APS was created, previously selected by the SER through an open call or based on professional merits. The stages of the work were: identification of the key areas for the document elaboration, analysis and synthesis of the scientific evidence (using the Scottish Intercollegiate Guidelines Network, SIGN levels of evidence) and formulation of recommendations based on this evidence and formal assessment or reasoned judgement techniques (consensus techniques). RESULTS Forty-six recommendations were drawn up, addressing 5main areas: diagnosis and evaluation, measurement of primary thromboprophylaxis, treatment for APS or secondary thromboprophylaxis, treatment for obstetric APS and special situations. These recommendations also include the role of novel oral anticoagulants, the problem of recurrences or the key risk factors identified in these subjects. This document reflects the last 25, referring to the areas of: obstetric APS and special situations. The document provides a table of recommendations and treatment algorithms. CONCLUSIONS Update of SER recommendations on APS is presented. This document corresponds to part II, related to obstetric SAF and special situations. These recommendations are considered tools for decision-making for clinicians, taking into consideration both the decision of the physician experienced in APS and the patient. A part I has also been prepared, which addresses aspects related to diagnosis, evaluation and treatment.
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Affiliation(s)
- Rafael Cáliz Cáliz
- Servicio de Reumatología, Hospital Universitario Virgen de las Nieves, Facultad de Medicina, Universidad de Granada, España.
| | | | | | | | - María Ángeles Martínez Zamora
- Unidad de Ginecología y Obstetricia, Hospital Clinic, Barcelona, España; Representante de la Sociedad Española de Ginecología y Obstetricia (SEGO), Madrid, España
| | - Amparo Santamaria Ortiz
- Unidad de Hemostasia y Trombosis, Servicio de Hematología. Hospital Vall d́Hebron, Barcelona, España; Representante de la Sociedad Española de Trombosis y Hemostasia (SETH), Madrid, España
| | - Olga Amengual Pliego
- Departamento de Reumatología, Endocrinología y Nefrología. Facultad de Medicina. Universidad de Hokkaido, Sapporo, Japón
| | | | | | | | | | | | | | - Clara Fuego Varela
- Servicio de Reumatología. Hospital Regional Universitario de Málaga. Hospital Civil, Málaga, España
| | - María Martín López
- Servicio de Reumatología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Betina Nishishinya
- Servicio de Reumatología y Medicina del deporte. Medicina del Deporte. Clínica Quirón, Barcelona, España
| | | | | | - Hiurma Sánchez Pérez
- Servicio de Reumatología, Hospital Universitario de Canarias, Santa Cruz de Tenerife, España
| | - Lucia Silva-Fernández
- Servicio de Reumatología. Complexo Hospitalario Universitario de Ferrol, Ferrol, A Coruña, España
| | - Víctor Manuel Martínez Taboada
- Facultad de Medicina, Universidad de Cantabria, Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, Santander, España
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36
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Abstract
Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the setting of documented persistent antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2Glycoprotein I antibodies. Associated clinical manifestations include livedo reticularis, cutaneous ulcerations, thrombocytopenia, hemolytic anemia, valvular heart disease, and nephropathy. The degree of risk associated with antiphospholipid antibody depends on the characteristics of the antiphospholipid antibody profile and on the presence of additional thrombotic risk factors. Current standard treatment for unprovoked thrombosis is long-term warfarin or other vitamin K antagonist therapy. Treatment to prevent recurrent obstetric complications is low-dose aspirin and prophylactic heparin, usually low-molecular-weight heparin. Optimal treatment for standard therapy failures or for certain nonthrombotic manifestations is uncertain, although nonanticoagulation therapies that address multiple demonstrated mechanisms of disease are being explored.
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Affiliation(s)
- Lisa R Sammaritano
- Associate Professor of Clinical Medicine, Weill Cornell Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
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37
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Kotzen ES, Roy S, Jain K. Antiphospholipid Syndrome Nephropathy and Other Thrombotic Microangiopathies Among Patients With Systemic Lupus Erythematosus. Adv Chronic Kidney Dis 2019; 26:376-386. [PMID: 31733722 DOI: 10.1053/j.ackd.2019.08.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 06/07/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023]
Abstract
Antiphospholipid syndrome (APS) and other causes of thrombotic microangiopathy (TMA) negatively impact the renal outcomes of patients with systemic lupus erythematosus (SLE) and lupus nephritis. Here we review the diagnosis and management of occlusive renal vascular lesions due to APS and other TMAs, with a focus on patients with SLE and lupus nephritis. The presence of a thrombotic event, unexplained hypertension, thrombocytopenia, or hemolytic anemia should prompt consideration for TMA syndromes. The differential diagnosis of a TMA in a patient with SLE includes APS, thrombocytopenic purpura, complement-mediated or infection-associated hemolytic uremic syndrome, drug-mediated TMA (particularly due to calcineurin inhibitor toxicity), and malignant hypertension. Treatment of APS with a documented thrombotic event focuses on anticoagulation to reduce the risk for further thrombotic events. Treatment of classic presentations of thrombocytopenic purpura and hemolytic uremic syndrome in the SLE population is the same as in patients without SLE. Treatment of APS nephropathy or TMA when it is diagnosed by biopsy with concomitant lupus nephritis presents a challenge to clinicians because there is no clear standard of care. Small and retrospective studies suggest potential benefit of complement inhibition, mammalian target of rapamycin (mTOR) inhibition, B cell depleting therapy, and plasma exchange therapy for patients with lupus nephritis and TMA, and prospective investigation of these therapies should be a research priority.
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Bada-Bosch T, Redondo B, Sevillano AM, Alonso M, Trujillo H, Auñón P, Polanco N, Rodríguez L, Gonzalez E, Andrés A. Primary antiphospholipid syndrome presented as thrombotic microangiopathy in renal transplantation. Nefrologia 2019; 40:108-110. [PMID: 31431303 DOI: 10.1016/j.nefro.2019.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 11/28/2022] Open
Affiliation(s)
- Teresa Bada-Bosch
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España.
| | - Beatriz Redondo
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Angel M Sevillano
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Marina Alonso
- Servicio de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, España
| | - Hernando Trujillo
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Pilar Auñón
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Natalia Polanco
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Lucía Rodríguez
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Esther Gonzalez
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Amado Andrés
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
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Abstract
Dysregulation of lymphocyte function, accumulation of autoantibodies and defective clearance of circulating immune complexes and apoptotic cells are hallmarks of systemic lupus erythematosus (SLE). Moreover, it is now evident that an intricate interplay between the adaptive and innate immune systems contributes to the pathogenesis of SLE, ultimately resulting in chronic inflammation and organ damage. Platelets circulate in the blood and are chiefly recognized for their role in the prevention of bleeding and promotion of haemostasis; however, accumulating evidence points to a role for platelets in both adaptive and innate immunity. Through a broad repertoire of receptors, platelets respond promptly to immune complexes, complement and damage-associated molecular patterns, and represent a major reservoir of immunomodulatory molecules in the circulation. Furthermore, evidence suggests that platelets are activated in patients with SLE, and that they could contribute to the circulatory autoantigenic load through the release of microparticles and mitochondrial antigens. Herein, we highlight how platelets contribute to the immune response and review evidence implicating platelets in the pathogenesis of SLE.
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Eculizumab in refractory catastrophic antiphospholipid syndrome: a case report and systematic review of the literature. Clin Exp Med 2019; 19:281-288. [PMID: 31214910 DOI: 10.1007/s10238-019-00565-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 06/12/2019] [Indexed: 10/26/2022]
Abstract
Catastrophic antiphospholipid syndrome (CAPS) is a rare disorder, characterized by the development of multiple vascular thrombosis over a short period of time, in patients with persistently detectable antiphospholipid antibodies (aPLs). The vascular occlusions predominantly affect small vessels. The overall mortality is 36.9%, despite the recent progress in the therapeutic approach. It has been shown that aPLs are able to induce a hypercoagulability state through different mechanisms of action, including complement activation, which in turn plays a key role in the pathogenesis of some thrombotic microangiopathies. Consequently, complement inhibition may be proposed as a targeted intervention to effectively prevent the progression of the microthrombotic storm. The employment of the complement inhibitor eculizumab has been proposed in CAPS on the basis of occasional reports and expert opinion. We report the case of a 54-year-old woman with a CAPS refractory to conventional therapies, who was successfully treated with eculizumab. The administration of this anti-C5 monoclonal antibody aborted the acute progressive thrombotic events and prevented further clinical episodes of thrombosis in the following year. We also faced our case to a systematic literature review, by analyzing all reported cases of CAPS in which eculizumab was added to conventional therapy. Even if further investigation is needed, our results suggest that the inhibition of one mechanism of aPL-induced organ damage may be an add-on treatment for this condition.
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Thurman JM, Yapa R. Complement Therapeutics in Autoimmune Disease. Front Immunol 2019; 10:672. [PMID: 31001274 PMCID: PMC6456694 DOI: 10.3389/fimmu.2019.00672] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/12/2019] [Indexed: 12/17/2022] Open
Abstract
Many autoimmune diseases are characterized by generation of autoantibodies that bind to host proteins or deposit within tissues as a component of immune complexes. The autoantibodies can activate the complement system, which can mediate tissue damage and trigger systemic inflammation. Complement inhibitory drugs may, therefore, be beneficial across a large number of different autoimmune diseases. Many new anti-complement drugs that target specific activation mechanisms or downstream activation fragments are in development. Based on the shared pathophysiology of autoimmune diseases, some of these complement inhibitory drugs may provide benefit across multiple different diseases. In some antibody-mediated autoimmune diseases, however, unique features of the autoantibodies, the target antigens, or the affected tissues may make it advantageous to block individual components or pathways of the complement system. This paper reviews the evidence that complement is involved in various autoimmune diseases, as well as the studies that have examined whether or not complement inhibitors are effective for treating these diseases.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Roshini Yapa
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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42
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Chaturvedi S, Brodsky RA, McCrae KR. Complement in the Pathophysiology of the Antiphospholipid Syndrome. Front Immunol 2019; 10:449. [PMID: 30923524 PMCID: PMC6426753 DOI: 10.3389/fimmu.2019.00449] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 02/19/2019] [Indexed: 12/16/2022] Open
Abstract
The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Complement is a system of enzymes and regulatory proteins of the innate immune system that plays a key role in the inflammatory response to pathogenic stimuli. The complement and coagulation pathways are closely linked, and expanding data indicate that complement may be activated in patients with aPL and function as a cofactor in the pathogenesis of aPL-associated clinical events. Complement activation by aPL generates C5a, which induces neutrophil tissue factor-dependent procoagulant activity. Beta-2-glycoprotein I, the primary antigen for pathogenic aPL, has complement regulatory effects in vitro. Moreover, aPL induce fetal loss in wild-type mice but not in mice deficient in specific complement components (C3, C5). Antiphospholipid antibodies also induce thrombosis in wild type mice and this effect is attenuated in C3 or C6 deficient mice, or in the presence of a C5 inhibitor. Increased levels of complement activation products have been demonstrated in sera of patients with aPL, though the association with clinical events remains unclear. Eculizumab, a terminal complement inhibitor, has successfully been used to treat catastrophic APS and prevent APS-related thrombotic microangiopathy in the setting of renal transplant. However, the mechanisms of complement activation in APS, its role in the pathogenesis of aPL related complications in humans, and the potential of complement inhibition as a therapeutic target in APS require further study.
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Affiliation(s)
- Shruti Chaturvedi
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Robert A Brodsky
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Keith R McCrae
- Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland, OH, United States.,Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, United States
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44
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Uthman I, Noureldine MHA, Ruiz-Irastorza G, Khamashta M. Management of antiphospholipid syndrome. Ann Rheum Dis 2019; 78:155-161. [PMID: 30282668 DOI: 10.1136/annrheumdis-2018-213846] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/21/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
Antiphospholipid syndrome, also known as 'Hughes Syndrome', is an autoimmune disease characterised by a set of clinical manifestations, almost all of which are direct or indirect sequelae of a hypercoagulable state involving the venous, and to a lesser extent the arterial vasculature. The incidence and prevalence of antiphospholipid syndrome are estimated at approximately 5 de novo cases per 100 000 per year and 40-50 cases per 100 000 individuals, respectively. The clinical spectrum of antiphospholipid syndrome involves haematological (thrombocytopaenia, venous thrombosis), obstetrical (recurrent pregnancy loss), neurological (stroke, transient ischaemic attack, migraine, seizures, cognitive dysfunction, chorea, transverse myelitis, multiple sclerosis), cardiovascular (cardiac valve disease), dermatological (livedo reticularis and racemosa, skin ulceration and necrosis), renal (glomerulonephritis, renal thrombotic microangiopathy) and orthopaedic (avascular necrosis of bones, non-traumatic fractures) manifestations, among others. In addition to the classical antiphospholipid antibodies, namely anticardiolipin antibodies and lupus anticoagulant, new autoantibodies and antibody complexes of different immunoglobulin subtypes (IgA, IgG, IgM) are now recognised as significant contributors to the pathogenesis of antiphospholipid syndrome. Anticoagulation remains the cornerstone in the management of antiphospholipid syndrome; nevertheless, new drugs and therapeutic strategies are being tested, and some have been found effective for the primary and secondary thromboprophylaxis in antiphospholipid syndrome.
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Affiliation(s)
- Imad Uthman
- Division of Rheumatology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Guillermo Ruiz-Irastorza
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Health Research Institute, Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
| | - Munther Khamashta
- Department of Rheumatology, Dubai Hospital, Dubai, United Arab Emirates
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45
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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 complement and use of eculizumab: Case series and review of literature. Semin Arthritis Rheum 2018; 49:74-83. [PMID: 30598332 DOI: 10.1016/j.semarthrit.2018.11.005] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 10/25/2018] [Accepted: 11/26/2018] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Thrombotic microangiopathy (TMA) is a life-threatening, albeit infrequent, complication of systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). Recommendations for the treatment of SLE- and APS-related secondary TMA are currently based solely on case reports and expert opinion. Unfortunately, interventions may not yield timely results or effectively halt the progression of TMA. Since complement activation plays a key role in the pathogenesis of secondary TMA due to SLE, APS, a therapy that targets the complement pathway is an attractive intervention. Eculizumab, a recombinant, fully humanized IgG2/IgG4 monoclonal antibody inhibits C5 activation and is FDA-approved for PNH and atypical HUS (aHUS). However, limited case reports are available on its use in treatment of secondary TMA. CASE PRESENTATION AND RESULTS We present the largest case series to date that includes 9 patients with SLE and/or APS who were successfully treated with eculizumab for refractory secondary TMA. In this case series, we report significant responses in hematology values, renal function and other organs following treatment with eculizumab. At 4 weeks, 75% improvement in platelet counts was observed in 78% of patients. Two-thirds of patients demonstrated >75% improvement of haptoglobin and LDH at four weeks. At 4 weeks, eGFR improved by 25% in half of the patients, and 43% had reductions in proteinuria. Two of 3 patients that required hemodialysis were able to be taken off hemodialysis. CONCLUSION Based on these observations, we suggest that eculizumab may be a potential treatment option for acutely ill patients with secondary TMA due to SLE and/or APS who have failed standard of care. A collective approach is needed to better elucidate the role and optimal timing of eculizumab use in the management of TMA complicating SLE and/or APS.
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Affiliation(s)
- Nina Kello
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA.
| | - Lara El Khoury
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA
| | - Galina Marder
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA
| | - Richard Furie
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA
| | - Ekaterini Zapantis
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA
| | - Diane Lewis Horowitz
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 865 Northern Boulevard, Suite 302, Great Neck, NY 11021, USA
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Fleetwood T, Cantello R, Comi C. Antiphospholipid Syndrome and the Neurologist: From Pathogenesis to Therapy. Front Neurol 2018; 9:1001. [PMID: 30534110 PMCID: PMC6275383 DOI: 10.3389/fneur.2018.01001] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/06/2018] [Indexed: 12/16/2022] Open
Abstract
Antiphospholipid syndrome (APS) is an autoimmune antibody-mediated condition characterized by thrombotic events and/or pregnancy morbidity in association with persistent positivity to antiphospholipid antibodies (aPL). The nervous system is frequently affected, as intracranial vessels are the most frequent site of arterial pathology. Over the course of years, many other neurological conditions not included in the diagnostic criteria, have been associated with APS. The pathogenic mechanisms behind the syndrome are complex and not fully elucidated. aPL enhance thrombosis, interfering with different pathways. Nevertheless, ischemic injury is not always sufficient to explain clinical features of the syndrome and immune-mediated damage has been advocated. This may be particularly relevant in the context of neurological complications. The reason why only a subgroup of patients develop non-criteria nervous system disorders and what determines the clinical phenotype are questions that remain open. The double nature, thrombotic and immunologic, of APS is also reflected by therapeutic strategies. In this review we summarize known neurological manifestations of APS, revisiting pathogenesis and current treatment options.
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Affiliation(s)
- Thomas Fleetwood
- Section of Neurology, Department of Translational Medicine University of Eastern Piedmont, Novara, Italy
| | - Roberto Cantello
- Section of Neurology, Department of Translational Medicine University of Eastern Piedmont, Novara, Italy
| | - Cristoforo Comi
- Section of Neurology, Department of Translational Medicine University of Eastern Piedmont, Novara, Italy.,Interdisciplinary Research Centre of Autoimmune Diseases University of Eastern Piedmont, Novara, Italy
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Abstract
Abstract. Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called “thrombotic APS”) and pregnancy complications (“obstetric APS”). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option. Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication
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Affiliation(s)
- Birgit Linnemann
- Division of Angiology, East Bavarian Center of Vascular Medicine, University Hospital Regensburg, Regensburg, Germany
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48
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The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: A comprehensive review. J Autoimmun 2018; 92:1-11. [DOI: 10.1016/j.jaut.2018.05.007] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 05/10/2018] [Indexed: 01/13/2023]
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Román E, Mendizábal S, Jarque I, de la Rubia J, Sempere A, Morales E, Praga M, Ávila A, Górriz JL. Secondary thrombotic microangiopathy and eculizumab: A reasonable therapeutic option. Nefrologia 2018; 37:478-491. [PMID: 28946961 DOI: 10.1016/j.nefro.2017.01.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/03/2017] [Accepted: 01/14/2017] [Indexed: 12/16/2022] Open
Abstract
Understanding the role of the complement system in the pathogenesis of atypical haemolytic uraemic syndrome and other thrombotic microangiopathies (TMA) has led to the use of anti-complement therapy with eculizumab in these diseases, in addition to its original use in patients with paroxysmal nocturnal haemoglobinuria andatypical haemolytic uraemic syndrome. Scientific evidence shows that both primary and secondary TMAs with underlying complement activation are closely related. For this reasons, control over the complement system is a therapeutic target. There are 2scenarios in which eculizumab is used in patients with TMA: primary or secondary TMA that is difficult to differentiate (including incomplete clinical presentations) and complement-mediated damage in various processes in which eculizumab proves to be efficacious. This review summarises the evidence on the role of the complement activation in the pathophysiology of secondary TMAs and the efficacy of anti-complement therapy in TMAs secondary to pregnancy, drugs, transplant, humoral rejection, systemic diseases and glomerulonephritis. Although experience is scarce, a good response to eculizumab has been reported in patients with severe secondary TMAs refractory to conventional treatment. Thus, the role of the anti-complement therapy as a new treatment option in these patients should be investigated.
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Affiliation(s)
- Elena Román
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España.
| | - Santiago Mendizábal
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Isidro Jarque
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Javier de la Rubia
- Servicio de Hematología, Hospital Universitario Dr. Peset, Valencia, España
| | - Amparo Sempere
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Enrique Morales
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Manuel Praga
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Ana Ávila
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
| | - José Luis Górriz
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
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50
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Tektonidou MG. Antiphospholipid Syndrome Nephropathy: From Pathogenesis to Treatment. Front Immunol 2018; 9:1181. [PMID: 29904380 PMCID: PMC5990608 DOI: 10.3389/fimmu.2018.01181] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 05/11/2018] [Indexed: 11/13/2022] Open
Abstract
Kidney damage is a well-recognized complication of the antiphospholipid syndrome (APS), either primary or systemic lupus erythematosus (SLE)-associated APS. Kidney involvement in APS involves a variety of manifestations, such as renal artery thrombosis or stenosis, renal vein thrombosis, allograft loss due to thrombosis after kidney transplantation, and injury to the renal microvasculature, also known as APS nephropathy. Biopsy in patients with APS nephropathy includes acute thrombotic microangiopathy lesions and chronic intrarenal vascular lesions such as interlobular fibrous intimal hyperplasia, arterial and arteriolar recanalizing thrombosis, fibrous arterial occlusion, and focal cortical atrophy. The most frequent clinical features are hypertension, microscopic hematuria, proteinuria (ranging from mild to nephritic levels), and renal insufficiency. It is uncertain whether antiphospholipid antibodies or other factors are implicated in the development of APS nephropathy, and whether it is driven mainly by thrombotic or by inflammatory processes. Experimental models and clinical studies of thrombotic microangiopathy lesions implicate activation of the complement cascade, tissue factor, and the mTORC pathway. Currently, the management of APS nephropathy relies on expert opinion, and consensus is lacking. There is limited evidence about the effect of anticoagulants, and their use remains controversial. Treatment approaches in patients with APS nephropathy lesions may include the use of heparin based on its role on complement activation pathway inhibition or the use of intravenous immunoglobulin and/or plasma exchange. Targeted therapies may also be considered based on potential APS nephropathy pathogenetic mechanisms such as B-cell directed therapies, complement inhibition, tissue factor inhibition, mTOR pathway inhibition, or anti-interferon antibodies, but prospective multicenter studies are needed to address their role.
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Affiliation(s)
- Maria G Tektonidou
- Joint Rheumatology Academic Program, First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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