|
1
|
Larsen ML, Nørgaard L, Linge P, Larsen JB, Langkilde HZ, Hauge EM, Thiel S, Voss A, Bengtsson A, Troldborg A. Molecular mechanisms underlying thrombosis in systemic lupus erythematosus - A Systematic review. Semin Arthritis Rheum 2025; 72:152707. [PMID: 40086157 DOI: 10.1016/j.semarthrit.2025.152707] [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: 10/03/2024] [Revised: 02/13/2025] [Accepted: 02/27/2025] [Indexed: 03/16/2025]
Abstract
Patients with systemic lupus erythematosus (SLE) face an approximately 30 % risk of thrombosis post-diagnosis. However, there remains significant knowledge gaps regarding causative mechanisms, and there is a lack of specific antithrombotic guidelines. This systematic review aims to examine the existing literature regarding the mechanisms contributing to thrombosis risk in SLE, focusing on five predefined procoagulant domains: autoantibodies (including antiphospholipid antibodies (aPL)), the complement system, platelets, the endothelium, and the coagulation system. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statements and searched in PubMed and Embase without time restrictions. Risk of bias assessment was performed using a pre-specified evaluation tool. Out of 3,747 initially identified publications, 30 studies were included, with 28 demonstrating robust methodological quality in the risk of bias assessment. The studies were experimental, involving blood samples from cross-sectional SLE cohorts, except one animal -and one case-control study. We identified six different thrombosis mechanisms of action. Most studies concentrated on autoantibodies, predominantly aPL. Shared mechanisms between aPL and other autoantibodies may account for the increased thrombosis risk in aPL-negative SLE patients. Significant knowledge gaps remain, particularly regarding the role of the complement system in SLE-related thrombosis. Also, most research relies on cross-sectional designs, emphasizing the need for prospective cohort studies to better assess clinical factors. Finally, comprehensive studies examining the interactions between multiple procoagulant factors and their link to thrombosis are lacking. Closing these gaps in future research could improve both preventive and personalized treatment strategies for thrombosis in SLE.
Collapse
Affiliation(s)
- Mads L Larsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
| | - Laura Nørgaard
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Petrus Linge
- Department of Clinical Sciences, Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Julie B Larsen
- Department of Clinical Biochemistry, Regional Hospital Horsens, Horsens, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Henrik Z Langkilde
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Rheumatology, Odense University Hospital, Odense, Denmark
| | - Ellen M Hauge
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Anne Voss
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Rheumatology, Odense University Hospital, Odense, Denmark
| | - Anders Bengtsson
- Department of Clinical Sciences, Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Anne Troldborg
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
2
|
Dernoncourt A, Salle V, Cheloufi M, Kayem G, Mekinian A. [Use of hydroxychloroquine in recurrent immune-mediated obstetric diseases (excluding systemic lupus): Scientific basis and evidence]. Rev Med Interne 2025; 46:220-228. [PMID: 39732523 DOI: 10.1016/j.revmed.2024.12.004] [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: 08/24/2024] [Revised: 11/28/2024] [Accepted: 12/12/2024] [Indexed: 12/30/2024]
Abstract
Hydroxychloroquine (HCQ), a synthetic antimalarial, is recognized for its immunomodulatory, anti-inflammatory and vascular-protective effects. In 20-30% of cases of primary obstetrical antiphospholipid syndrome (APS), the combination of antiplatelet aggregation and prophylactic anticoagulation fails to prevent obstetrical complications, a situation referred to as refractory obstetrical APS. This is partly due to the pro-inflammatory effects of antiphospholipid antibodies (aPL) binding to decidual and trophoblastic cells, which compromise embryonic implantation and placentation. Experimental studies in vitro and in mouse models have shown that HCQ can inhibit the detrimental effect of aPLs on trophoblastic invasion, findings corroborated by retrospective observational clinical studies. However, no randomized controlled trial has evaluated the addition of HCQ to conventional therapy for refractory obstetric APS. The hypothesis of allo-immune and/or autoimmune mechanisms involved in cases of recurrent pregnancy loss (RPL) with no identified cause and in chronic intervillositis of unknown etiology (CIUE) has led to the empirical use of HCQ in these indications. However, current evidence does not support its use in unexplained RPL. A few clinical studies of low scientific evidence suggest a benefit of HCQ in CIUE, but further data are needed. Finally, pre-eclampsia (PE) is another pregnancy-related condition at risk of recurrence, and its pathogenesis also seems to involve an imbalance in immune responses. HCQ's antioxidant properties could have a positive effect on endothelial dysfunction, a key component of PE.
Collapse
Affiliation(s)
- Amandine Dernoncourt
- Service de médecine interne et Réseau d'épidémiologie clinique international francophone (RECIF), centre hospitalo-universitaire Amiens-Picardie, université Picardie Jules-Verne, Amiens, France.
| | - Valéry Salle
- Service de médecine interne et Réseau d'épidémiologie clinique international francophone (RECIF), centre hospitalo-universitaire Amiens-Picardie, université Picardie Jules-Verne, Amiens, France
| | - Meryam Cheloufi
- Service de gynécologie obstétrique, hôpital Armand-Trousseau, AP-HP, Sorbonne université, Paris, France
| | - Gilles Kayem
- Service de gynécologie obstétrique, hôpital Armand-Trousseau, AP-HP, Sorbonne université, Paris, France
| | - Arsène Mekinian
- Service de médecine interne et inflammation, département inflammation-immunopathologie-biothérapie (DMU I3), CEREMAIAA, hôpital Saint-Antoine, AP-HP, Sorbonne université, Paris, France
| |
Collapse
|
|
3
|
Huo R, Wei C, Yang Y, Lin J, Huang X. Hydroxychloroquine: A double‑edged sword (Review). Mol Med Rep 2025; 31:102. [PMID: 39981928 PMCID: PMC11868775 DOI: 10.3892/mmr.2025.13467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
Hydroxychloroquine (HCQ) is an antimalarial drug that has historically been used to treat and prevent malaria. However, its mechanism of action has not yet been fully elucidated. HCQ affects various cellular and molecular pathways through different mechanisms. HCQ has also been shown to be a disease‑improving agent for the treatment of rheumatic diseases, including systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis and primary Sjögren's syndrome. Although generally considered safe, adverse reactions have been reported with the use of HCQ and clinicians should carefully monitor patients with rheumatism when prescribing these drugs. The purpose of the present review is to strengthen the clinical use of HCQ for autoimmune diseases while highlighting the adverse effects that may occur during treatment.
Collapse
Affiliation(s)
- Rongxiu Huo
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Chengcheng Wei
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Yanting Yang
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Jinying Lin
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Xinxiang Huang
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| |
Collapse
|
|
4
|
Bartoloni E, Cacciapaglia F, Erre GL, Gremese E, Manfredi A, Piga M, Sakellariou G, Spinelli FR, Viapiana O, Atzeni F. Immunomodulation for accelerated atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Autoimmun Rev 2025; 24:103760. [PMID: 39894242 DOI: 10.1016/j.autrev.2025.103760] [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: 05/18/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
In the last decades, consisting evidence supported a close relationship between both innate and adaptive immune systems and the accelerated cardiovascular (CV) disease characterizing autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Indeed, several cell lines involved in the pathogenesis of these autoimmune diseases, such as macrophages and dendritic cells, as well as different T and B lymphocyte subsets, and inflammatory cytokines, have been demonstrated to be directly involved in the mechanisms underlying early atherosclerotic arterial wall damage. Traditional CV risk factors play a concomitant role but do not sufficiently account for the increased prevalence of CV disease in these patients. Indeed, the pathophysiological link between RA and SLE and atherosclerosis is based on complex inflammatory pathways that interconnect these conditions and may explain the significant morbidity and mortality rates demonstrated in these patients, with consequent significant negative effects on quality of life and long-term survival. Consequently, it is intriguing to hypothesize that immunosuppressive drugs commonly used in the treatment of these pathologies may also exert an immunomodulatory and anti-inflammatory effect in mitigating the atherosclerotic damage that has been demonstrated to occur early in the initial stages of the disease. Recognizing risk factors, predicting occurrences and early intervention to prevent CV disease development have emerged as critical objectives in RA and SLE treatment. In this review, we aimed to provide an updated overview of the atherogenic effects exerted by the immune and inflammatory pathways involved in the pathogenesis of RA and SLE. Moreover, we examined the available evidence which may support the potential effects of immunosuppressive therapies in reducing CV damage and, consequently, CV disease risk in these patients.
Collapse
Affiliation(s)
- Elena Bartoloni
- Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Italy
| | - Fabio Cacciapaglia
- Rheumatology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DePReMeI), University of Bari, Bari, Italy; Department of Medicine and Surgery, LUM University "Giuseppe De Gennaro" Casamassima & Rheumatology Service "Miulli" General Hospital Acquaviva delle Fonti, Bari, Italy
| | - Gian Luca Erre
- Dipartimento di Scienze Mediche, Chirurgiche e Sperimentali, Università degli Studi di Sassari, Italy
| | - Elisa Gremese
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Andreina Manfredi
- University of Modena and Reggio Emilia,AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - Matteo Piga
- Rheumatology Unit, AOU Cagliari, Department of Medical Sciences and Public Health, University of Cagliari, Italy
| | - Garifallia Sakellariou
- Department of Internal Medicine and Therapeutics, University of Pavia, Istituti Clinici Scientifici Maugeri, Pavia, Italy
| | - Francesca Romana Spinelli
- Reumatology Unit, Department of Internal, Anesthesiological, and Cardiovascular Clinical Sciences, Sapienza University of Rome, Rome, Italy
| | - Ombretta Viapiana
- Rheumatology Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Italy.
| |
Collapse
|
|
5
|
Dobrowolski C, Lao SM, Kharouf F, Croci PP, Wither J, Gladman DD, Garcia LW, Jauhal A, Touma Z. Lupus nephritis II: Treatment and monitoring. Adv Clin Chem 2025; 126:121-154. [PMID: 40185533 DOI: 10.1016/bs.acc.2025.01.001] [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: 04/07/2025]
Abstract
Renal involvement in systemic lupus erythematosus (SLE), lupus nephritis (LN), is common and can result in significant morbidity, including progressive renal dysfunction, and even ultimately leading to death. LN is heterogeneous complicated by the immunologic component, and it is critical to accurately classify LN to direct optimal therapy. Accordingly, identification of objective markers is paramount in reflecting disease stage and monitoring treatment response. In part two of this series, we comprehensively examine LN disease classification, therapies and potential markers to guide therapeutic options.
Collapse
Affiliation(s)
- Chrisanna Dobrowolski
- Division of Rheumatology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, United States
| | - Shu Min Lao
- Division of Rheumatology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, United States
| | - Fadi Kharouf
- Centre for Prognosis Studies in Rheumatic Diseases, University of Toronto Lupus Clinic, Toronto Western Hospital, Toronto, ON, Canada
| | - Paula Parnizari Croci
- Hospital Manuel Quintela, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Joan Wither
- Centre for Prognosis Studies in Rheumatic Diseases, University of Toronto Lupus Clinic, Toronto Western Hospital, Toronto, ON, Canada
| | - Dafna D Gladman
- Centre for Prognosis Studies in Rheumatic Diseases, University of Toronto Lupus Clinic, Toronto Western Hospital, Toronto, ON, Canada
| | - Laura Whitall Garcia
- Centre for Prognosis Studies in Rheumatic Diseases, University of Toronto Lupus Clinic, Toronto Western Hospital, Toronto, ON, Canada
| | - Arenn Jauhal
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Zahi Touma
- Centre for Prognosis Studies in Rheumatic Diseases, University of Toronto Lupus Clinic, Toronto Western Hospital, Toronto, ON, Canada.
| |
Collapse
|
|
6
|
Jayasinghe M, Rashidi F, Gadelmawla AF, Pitton Rissardo J, Rashidi M, Elendu CC, Fornari Caprara AL, Khalil I, Hmedat KI, Atef M, Moharam H, Prathiraja O. Neurological Manifestations of Systemic Lupus Erythematosus: A Comprehensive Review. Cureus 2025; 17:e79569. [PMID: 40151747 PMCID: PMC11947500 DOI: 10.7759/cureus.79569] [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] [Accepted: 02/24/2025] [Indexed: 03/29/2025] Open
Abstract
Neurological involvement in systemic lupus erythematosus (SLE) poses significant challenges, impacting patient morbidity, mortality, and quality of life. This narrative review provides an update on the pathogenesis, clinical presentation, diagnosis, and management of neurological SLE. The multifaceted pathophysiology involves immune-mediated and vascular mechanisms such as autoantibodies, neuroinflammation, complement dysregulation, and genetic factors. Neuropsychiatric SLE (NPSLE) manifests in a variety of ways, including cognitive dysfunction, mood disorders, psychosis, cerebrovascular disease, demyelinating syndromes, and neuropathies. Diagnosing neurological SLE is complicated by nonspecific and fluctuating symptoms, requiring comprehensive neurological examination, neuroimaging, autoantibody profiling, and cerebrospinal fluid analysis. Current management strategies include corticosteroids, immunosuppressive agents, and emerging biologics targeting specific immune pathways. Managing neuropsychiatric symptoms, seizures, and neuropathic pain remains a complex aspect of treatment. This review highlights the importance of early recognition and tailored management approaches to improve patient outcomes in neurological SLE.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Ibrahim Khalil
- Neurological Surgery, Faculty of Medicine, Alexandria University, Alexandria, EGY
| | - Khalil I Hmedat
- Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, EGY
| | | | | | | |
Collapse
|
|
7
|
Al-Jedai AH, Almudaiheem HY, Al-Homood IA, Almaghlouth I, Bahlas SM, Alolaiwi AM, Fatani M, Eshmawi MT, AlOmari BA, Alenzi KA, Albarakati RG, Al Ghanim N. Saudi National Clinical Practice Guidelines for Management of Adult Systemic Lupus Erythematosus. Curr Rheumatol Rev 2025; 21:70-96. [PMID: 38693734 DOI: 10.2174/0115733971275638240429063041] [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: 11/27/2023] [Revised: 03/04/2024] [Accepted: 03/10/2024] [Indexed: 05/03/2024]
Abstract
OBJECTIVE To provide evidence-based clinical practice recommendations for managing Systemic Lupus Erythematosus (SLE) in Saudi Arabia. METHODS This EULAR-adapted national guideline in which a multidisciplinary task force utilized the modified Delphi method to develop 31 clinical key questions. A systematic literature review was conducted to update the evidence since the EULAR publication. After reaching a consensus agreement, two rounds of voting and group discussion were conducted to generate consolidated recommendations/ statements. RESULTS A significant number of patients in Saudi Arabia experience delays in accessing rheumatologists, highlighting the significance of timely referral to SLE specialists or rheumatologists to ensure accurate diagnosis and prompt treatment. The primary goal of Glucocorticoid (GC) therapy in SLE patients is to establish disease control with a minimum dose and duration. Steroid-sparing agent utilization facilitates steroid-sparing goals. Hydroxychloroquine is recommended for all SLE patients, though physicians must carefully monitor toxicity and prioritize regular medication adherence assessment. SLE management during pregnancy starts from preconception time by assessing disease activity, major organ involvement, hypercoagulability status, and concomitant diseases that may negatively impact maternal and fetal outcomes. Multidisciplinary care with close monitoring may optimize both maternal and fetal outcomes. For patients with antiphospholipid antibodies, low-dose aspirin prophylaxis is recommended. Also, Long-term anticoagulant medications are fundamental to prevent secondary antiphospholipid syndrome due to high thrombosis recurrence. CONCLUSION This Saudi National Clinical Practice guidelines for SLE management provide evidence- based recommendations and guidance for healthcare providers in Saudi Arabia who are managing patients with SLE. These guidelines will help to standardize healthcare service, improve provider education, and perhaps lead to better treatment outcomes for SLE patients.
Collapse
Affiliation(s)
- Ahmed H Al-Jedai
- Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
- Colleges of Medicine and Pharmacy, Al Faisal University, Riyadh, Saudi Arabia
| | | | - Ibrahim A Al-Homood
- Medical Specialties Department, King Fahad Medical City, Riyadh, Saudi Arabia
- Medicine Department, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia
| | - Ibrahim Almaghlouth
- Department of Medicine, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
- College of Medicine Research Center, King Saud University, Riyadh 11461, Saudi Arabia
| | - Sami M Bahlas
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdulaziz Mohammed Alolaiwi
- Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
- Department of Rheumatology, King Saud Medical City, Riyadh, Saudi Arabia
| | - Mohammad Fatani
- Hera General Hospital, Ministry of Health, Makkah, Saudi Arabia
| | - Maysa Tariq Eshmawi
- King Abdullah Medical Complex, Jeddah, Saudi Arabia
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Bedor A AlOmari
- Department of Pharmaceutical Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | | | - Rayan G Albarakati
- Department of Obstetrics and Gynecology, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Nayef Al Ghanim
- Department of Rheumatology, King Saud Medical City, Riyadh, Saudi Arabia
| |
Collapse
|
|
8
|
Legge AC, Hanly JG. Recent advances in the diagnosis and management of neuropsychiatric lupus. Nat Rev Rheumatol 2024; 20:712-728. [PMID: 39358609 DOI: 10.1038/s41584-024-01163-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2024] [Indexed: 10/04/2024]
Abstract
Neuropsychiatric manifestations of systemic lupus erythematosus (SLE) are common and frequently associated with a substantial negative impact on health outcomes. The pathogenesis of neuropsychiatric SLE (NPSLE) remains largely unknown, but a single pathogenic mechanism is unlikely to be responsible for the heterogeneous array of clinical manifestations, and a combination of inflammatory and ischaemic mechanistic pathways have been implicated. Currently, valid and reliable biomarkers for the diagnosis of NPSLE are lacking, and differentiating NPSLE from nervous system dysfunction not caused by SLE remains a major challenge for clinicians. However, correct attribution is essential to ensure timely institution of appropriate treatment. In the absence of randomized clinical trials on NPSLE, current treatment strategies are derived from clinical experience with different therapeutic modalities and their efficacy in the management of other manifestations of SLE or of neuropsychiatric disease in non-SLE populations. This Review describes recent advances in the understanding of NPSLE that can inform diagnosis and management, as well as unanswered questions that necessitate further research.
Collapse
Affiliation(s)
- Alexandra C Legge
- Division of Rheumatology, Department of Medicine, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
- Arthritis Research Canada, Vancouver, British Columbia, Canada
| | - John G Hanly
- Division of Rheumatology, Department of Medicine, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
| |
Collapse
|
|
9
|
Atzeni F, Rodríguez-Pintó I, Cervera R. Cardiovascular disease risk in systemic lupus erythematous: Certainties and controversies. Autoimmun Rev 2024; 23:103646. [PMID: 39321952 DOI: 10.1016/j.autrev.2024.103646] [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: 06/09/2024] [Revised: 09/19/2024] [Accepted: 09/21/2024] [Indexed: 09/27/2024]
Abstract
Patients with systemic lupus erythematosus (SLE) experience greater cardiovascular morbidity and mortality compared to the general population. It is known that endothelial dysfunction, an early indicator of atherosclerosis development, can arise even without the presence of conventional cardiovascular risk factors. In fact, the risk factors contributing to cardiovascular disease can be classified into traditional risk factors and those uniquely associated with SLE such as disease activity, autoantibodies, etc.Furthermore, the pathogenesis of cardiovascular disease in SLE is linked to the activation of both the innate and adaptive immune systems. Given these findings, it is essential for clinicians to acknowledge the heightened CVD risk in SLE patients, perform comprehensive screenings for cardiovascular risk factors, and implement aggressive treatment strategies for those who exhibit signs of clinical CVD. The aim of this review is to summarize the findings on cardiovascular disease in SLE and to examine potential screening and therapeutic strategies for clinical practice.
Collapse
Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | - Ignasi Rodríguez-Pintó
- Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERNReCONNET, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
| | - Ricard Cervera
- Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERNReCONNET, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
| |
Collapse
|
|
10
|
Hiraoka D, Ishizaki J, Yamanouchi J, Honda T, Niiya T, Horimoto E, Horie K, Yamasaki H, Matsumoto T, Suemori K, Hasegawa H, Takenaka K. Antiplatelet effects of hydroxychloroquine in patients with systemic lupus erythematosus evaluated by the total thrombus-formation analysis system (T-TAS). Lupus Sci Med 2024; 11:e001223. [PMID: 38977356 PMCID: PMC11256038 DOI: 10.1136/lupus-2024-001223] [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: 04/08/2024] [Accepted: 06/18/2024] [Indexed: 07/10/2024]
Abstract
OBJECTIVES Hydroxychloroquine (HCQ) has been shown to reduce thrombotic events in patients with SLE. However, the antiplatelet effects of HCQ are only supported by the platelet aggregation assay, which is a non-physiological test. The total thrombus-formation analysis system (T-TAS) is a microchip-based flow chamber system that mimics physiological conditions and allows for the quantitative analysis of thrombogenicity. The present study investigated the antiplatelet effects of HCQ using T-TAS. METHODS This was a single-centre cross-sectional study on 57 patients with SLE. We measured the area under the pressure curve for 10 min (PL-AUC10) and the time to 10 kPa (T10) in patients with SLE using T-TAS and examined their relationships with the use of HCQ. PL-AUC10 and platelet aggregation were also measured at several HCQ concentrations using blood samples from healthy donors. RESULTS PL-AUC10 was significantly lower in the HCQ/real body weight (RBW) ≥5 mg/kg group than in the <5 mg/kg group, while T10 was similar, indicating that HCQ inhibited overall thrombus formation rather than the initiation of thrombus formation. The antiplatelet effects of HCQ were initially detected at HCQ/RBW of approximately 4 mg/kg and reached a plateau at around 5.5 mg/kg. The administration of HCQ/RBW >4.6 mg/kg clearly exerted antiplatelet effects. Additionally, HCQ inhibited thrombus formation in T-TAS and the platelet aggregation response to epinephrine in a dose-dependent manner. CONCLUSIONS We demonstrated the antiplatelet effects of HCQ under conditions simulating the physiological environment by using T-TAS and identified the range of doses at which HCQ exerted antiplatelet effects.
Collapse
Affiliation(s)
- Daisuke Hiraoka
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | - Jun Ishizaki
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | - Jun Yamanouchi
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
- Division of Blood Transfusion and Cell Therapy, Ehime University Hospital, Toon, Japan
| | - Takatsugu Honda
- Clinical Laboratory Department, Ehime University Hospital, Toon, Japan
| | - Toshiyuki Niiya
- Clinical Laboratory Department, Ehime University Hospital, Toon, Japan
| | - Erika Horimoto
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kenta Horie
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | | | - Takuya Matsumoto
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | - Koichiro Suemori
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| | | | - Katsuto Takenaka
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan
| |
Collapse
|
|
11
|
Unal D, Cam V, Emreol HE, Özen S. Diagnosis and Management of Pediatric Neuropsychiatric Systemic Lupus Erythematosus: An Update. Paediatr Drugs 2024; 26:381-395. [PMID: 38805115 DOI: 10.1007/s40272-024-00632-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2024] [Indexed: 05/29/2024]
Abstract
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a potentially serious and life-threatening complication of SLE. The presentation and severity of neuropsychiatric involvement in SLE may show considerable variability. The disease can affect the neural tissue directly or may be associated with vascular involvement, mainly associated with anti-phospholipid (aPL) antibodies. A direct causal link with SLE may sometimes be challenging since there are many confounding factors and the symptoms may be non-specific. Despite its remarkable sensitivity in detecting hemorrhagic and ischemic stroke, transverse myelitis and ischemic infarction, magnetic resonance imaging (MRI) lacks the spatial resolution required to identify microvascular involvement. When standard MRI fails to detect a suspicious lesion, it is advisable to use advanced imaging modalities such as positron emission tomography (PET), single photon emission computed tomography (SPECT) or quantitative MRI, if available. Even with these advanced modalities, the specificity of neuroimaging in NPSLE remains inadequate (60-82% for MRI). Neuropsychiatric syndromes, such as cerebrovascular events, seizures and cognitive impairments appear to be associated with serum aPL antibodies. Some studies have shown that anti-ribosomal P antibodies have a low sensitivity for NPSLE and a limited contribution to the differentiation of different clinical entities. Treatment has two main goals: symptomatic relief and treatment of the disease itself. Commonly used immunosuppressants for NPSLE include cyclophosphamide (CYC), azathioprine (AZA), and mycophenolate mofetil (MMF). According to EULAR's current recommendation, strong immunosuppressants such as CYC and rituximab (RTX) should be preferred. Biologics have also been used in NPSLE. Fingolimod, eculizumab, and JAK inhibitors are potential drugs in the pipeline. Developing targeted therapies will be possible by a better understanding of the pathological mechanisms.
Collapse
Affiliation(s)
- Dilara Unal
- Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Sihhiye Campus, 06100, Ankara, Turkey
| | - Veysel Cam
- Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Sihhiye Campus, 06100, Ankara, Turkey
| | - Hulya Ercan Emreol
- Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Sihhiye Campus, 06100, Ankara, Turkey
| | - Seza Özen
- Department of Pediatric Rheumatology, Hacettepe University Medical Faculty, Sihhiye Campus, 06100, Ankara, Turkey.
| |
Collapse
|
|
12
|
Peng-Cheng L, Meng-Na L, Jian-Bin L, Shu-Jiao Y, Wu R. Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus. Heliyon 2024; 10:e30393. [PMID: 38711668 PMCID: PMC11070867 DOI: 10.1016/j.heliyon.2024.e30393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/08/2024] Open
Abstract
Hydroxychloroquine (HCQ) has gained significant attention as a therapeutic option for systemic lupus erythematosus (SLE) because of its multifaceted mechanism of action. It is a lipophilic, lysosomotropic drug, that easily traverses cell membranes and accumulates in lysosomes. Once accumulated, HCQ alkalizes lysosomes within the cytoplasm, thereby disrupting their function and interfering with processes like antigen presentation. Additionally, HCQ has shown potential in modulating T-cell responses, inhibiting cytokine production, and influencing Toll-like receptor signaling. Its immunomodulatory effects have generated interest in its application for autoimmune disorders. Despite its established efficacy, uncertainties persist regarding the optimal therapeutic concentrations and their correlation with adverse effects such as retinal toxicity. Therefore, standardized dosing and monitoring guidelines are crucial. In this study, we provide a comprehensive review of the mechanisms, efficacy, dosing variations, and retinal toxicity profiles of HCQ, which are essential to optimize SLE treatment protocols and ensure patient safety.
Collapse
Affiliation(s)
- Liu Peng-Cheng
- Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Lv Meng-Na
- The First Clinical Medical College of Nanchang University, Nanchang, China
| | - Li Jian-Bin
- Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yu Shu-Jiao
- Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Rui Wu
- Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| |
Collapse
|
|
13
|
King PT, Dousha L. Neutrophil Extracellular Traps and Respiratory Disease. J Clin Med 2024; 13:2390. [PMID: 38673662 PMCID: PMC11051312 DOI: 10.3390/jcm13082390] [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: 02/28/2024] [Revised: 03/26/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Extracellular traps made by neutrophils (NETs) and other leukocytes such as macrophages and eosinophils have a key role in the initial immune response to infection but are highly inflammatory and may contribute to tissue damage. They are particularly relevant to lung disease, with the pulmonary anatomy facilitating their ability to fully extend into the airways/alveolar space. There has been a rapid expansion in the number of published studies demonstrating their role in a variety of important respiratory diseases including chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, pneumonia, COVID-19, rhinosinusitis, interstitial lung disease and lung cancer. The expression of NETs and other traps is a specific process, and diagnostic tests need to differentiate them from other inflammatory pathways/causes of cell death that are also characterised by the presence of extracellular DNA. The specific targeting of this pathway by relevant therapeutics may have significant clinical benefit; however, current clinical trials/evidence are at a very early stage. This review will provide a broad overview of the role of NETs and their possible treatment in respiratory disease.
Collapse
Affiliation(s)
- Paul T. King
- Monash Lung, Sleep, Allergy and Immunology, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, VIC 3168, Australia;
- Department of Medicine, Monash University, Clayton, Melbourne, VIC 3168, Australia
| | - Lovisa Dousha
- Monash Lung, Sleep, Allergy and Immunology, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, VIC 3168, Australia;
- Department of Medicine, Monash University, Clayton, Melbourne, VIC 3168, Australia
| |
Collapse
|
|
14
|
Manabe A, Sada RM, Miyake H, Akebo H, Tsugihashi Y, Hatta K. An observational study to identify causative factors for not using hydroxychloroquine in systemic lupus erythematosus. Sci Rep 2024; 14:7750. [PMID: 38565930 PMCID: PMC10987587 DOI: 10.1038/s41598-024-58463-3] [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: 12/08/2023] [Accepted: 03/29/2024] [Indexed: 04/04/2024] Open
Abstract
Hydroxychloroquine (HCQ) use is indicated for patients with systemic lupus erythematosus (SLE). Nevertheless, reports discussing the reasons for not prescribing HCQ are limited. We identified the factors that interfere with HCQ use in patients with SLE. This observational, single-center study included data from 265 patients with SLE in 2019. The patients were categorized into groups with and without a history of HCQ use. Between these groups, clinical characteristics were compared using univariate analysis and logistic regression models. Among the 265 patients, 133 (50.2%) had a history of HCQ use. Univariate analysis identified older age; longer disease duration; lower prednisolone dose, clinical SLE disease activity index 2000, and estimated glomerular filtration rate; higher C3 level; and lower anti-double-stranded DNA antibody concentration as HCQ non-use-related variables. Logistic regression models identified a positive association between HCQ non-use and longer disease duration (odds ratio [OR] 1.08), prednisolone dose ≤ 7.5 mg/day (OR 4.03), C3 level ≥ 73 mg/dL (OR 2.15), and attending physician having graduated > 10 years prior (OR 3.19). In conclusion, a longer disease duration, lower prednisolone dose, higher C3 level, and longer time since attending physicians' graduation correlated with HCQ non-use. Physicians and patients should be educated to facilitate HCQ use despite these factors.
Collapse
Affiliation(s)
- Atsushi Manabe
- Department of General Internal Medicine, Tenri Hospital, Tenri, Japan
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryuichi Minoda Sada
- Department of General Internal Medicine, Tenri Hospital, Tenri, Japan.
- Department of Infection Control, Graduate School of Medicine, Osaka University, Suita, Japan.
- Department of Transformative Protection to Infectious Disease, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Hirofumi Miyake
- Department of General Internal Medicine, Tenri Hospital, Tenri, Japan
| | - Hiroyuki Akebo
- Department of General Internal Medicine, Tenri Hospital, Tenri, Japan
| | - Yukio Tsugihashi
- Medical Home Care Centre, Tenri Hospital, Shirakawa Branch, Tenri, Japan
| | - Kazuhiro Hatta
- Department of General Internal Medicine, Tenri Hospital, Tenri, Japan
| |
Collapse
|
|
15
|
Chighizola CB, Willis R, Maioli G, Sciascia S, Andreoli L, Amengual O, Radin M, Gerosa M, Atsumi T, de Jesus G, Trespidi L, Branch DW, Caporali R, Andrade D, Roubey R, Petri M, Bertolaccini ML. Deciphering the clinical significance of longitudinal antiphospholipid antibody titers. Autoimmun Rev 2024; 23:103510. [PMID: 38171447 DOI: 10.1016/j.autrev.2023.103510] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024]
Abstract
In antiphospholipid syndrome (APS), the risk of clinical manifestations increases with higher titers of antiphospholipid antibodies (aPL). Despite the adoption of aPL titers in the classification approach to aPL-positive subjects, the value of longitudinal monitoring of those titers in the follow-up is still debated, being well studied only in systemic lupus erythematosus (SLE). The literature suggests that the rate of aPL positivity decreases during follow-up in primary APS, estimating that seroconversion occurs in between 8.9 and 59% of patients over time. Negativisation of aPL occurs more frequently in asymptomatic aPL carriers than in patients with full-blown APS as well as in subjects with single aPL positivity or low aPL antibody titers. In patients with SLE, aPL typically behave fluctuating from positive to negative and back again in the course of follow-up. The few studies assessing the longitudinal course of aPL positivity with no associated systemic connective tissue disease reported a progressive decrement of aPL titers over time, in particular of antibodies against β2 glycoprotein I (antiβ2GPI) and cardiolipin (aCL) of IgG isotype. After a thrombotic event, aPL titers tend to decrease, as emerged from cohorts of both primary and secondary APS. Hydroxychloroquine has been identified as the most effective pharmacological agent to reduce aPL titers, with multiple studies demonstrating a parallel reduction in thrombosis rate. This review addresses available evidence on the significance of aPL titer fluctuation from clinical, therapeutic and pathogenic perspectives.
Collapse
Affiliation(s)
- Cecilia B Chighizola
- Department of Clinical Sciences and Community Health, University of Milan, Pediatric Rheumatology Unit, ASST G. Pini - CTO, Milan, Italy.
| | - Rohan Willis
- University of Texas Medical Branch, Internal Medicine, Galveston, USA
| | - Gabriella Maioli
- Department of Clinical Sciences and Community Health, University of Milan, Clinical Rheumatology Unit, ASST G. Pini - CTO, Milan, Italy
| | - Savino Sciascia
- University of Turin, Department of Clinical and Biological Sciences, Turin, Italy
| | - Laura Andreoli
- Rheumatology and Clinical Immunology Unit - ERN ReCONNET, ASST Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Olga Amengual
- Hokkaido University, Department of Rheumatology, Endocrinology and Nephrology Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Massimo Radin
- University of Turin, Department of Clinical and Biological Sciences, Turin, Italy
| | - Maria Gerosa
- Department of Clinical Sciences and Community Health, University of Milan, Clinical Rheumatology Unit, ASST G. Pini - CTO, Milan, Italy
| | - Tatsuya Atsumi
- Hokkaido University, Department of Rheumatology, Endocrinology and Nephrology Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Guilherme de Jesus
- Universidade do Estado do Rio de Janeiro, Department of Obstetrics, Rio de Janeiro, Brazil
| | - Laura Trespidi
- Department of Obstetrics and Gynaecology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - D Ware Branch
- Department of Obstetrics and Gynecology, University of Utah Health, Salt Lake City, UT, USA
| | - Roberto Caporali
- Department of Clinical Sciences and Community Health, University of Milan, Pediatric Rheumatology Unit, ASST G. Pini - CTO, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Clinical Rheumatology Unit, ASST G. Pini - CTO, Milan, Italy
| | | | - Robert Roubey
- Department of Rheumatology, University of North Carolina, Chapel Hill, NC, USA
| | - Michelle Petri
- Johns Hopkins University School of Medicine, Rheumatology, Baltimore, MD, USA
| | | |
Collapse
|
|
16
|
Ramdani I, Bouazza B. Hydroxychloroquine and COVID-19 story: is the low-dose treatment the missing link? A comprehensive review and meta-analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1181-1188. [PMID: 37639021 DOI: 10.1007/s00210-023-02688-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 08/22/2023] [Indexed: 08/29/2023]
Abstract
Hydroxychloroquine (HCQ) has been repurposed and used for the treatment of COVID-19 patients; however, its efficacy remains controversial, maybe partly due to the dosage, ranging from 200 to 800 mg/day, reported in different studies. Indeed, HCQ low dose (≤ 2.4 g/5 days) showed a lower risk of side effects compared to high doses. In this study, we performed a systematic review and meta-analysis to investigate the effect of low-dose HCQ used alone on three outcomes including in-hospital mortality, the need for mechanical ventilation, and ICU admission in COVID-19 patients. A systematic review of English literature was conducted from January 2020 to April 2022, in PubMed, Cochrane Library, and Google Scholar. Studies reporting a dosage of 400 mg twice the first day, followed by 200 mg twice for four days were included. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models. Eleven studies (12,503 patients) were retained in the quantitative analysis, four observational cohort studies, and seven RCTs. When pooling both observational and RCTs, low-dose HCQ was associated with decreased mortality (OR = 0.73, 95% CI: [0.55-0.97], I2 = 58%), but not with mechanical ventilation need (OR = 1.03, 95% CI: [0.56-1.89], I2 = 67%) and ICU admission rate (OR = 0.70, 95% CI: [0.42-1.17], I2 = 47%). However, no effect was observed when pooling only RCTs. Despite RCTs limitations, treatment with low-dose HCQ was not associated with improvement in mortality, mechanical ventilation need and ICU admission rate in COVID-19 patients.
Collapse
Affiliation(s)
- Idir Ramdani
- Ecology, Biotechnology and Health Lab. Faculty of Biological and Agricultural Sciences, Mouloud Mammeri University of Tizi-Ouzou, Route de Hasnaoua, 15000, Tizi-Ouzou, Algeria
| | - Belaid Bouazza
- Ecology, Biotechnology and Health Lab. Faculty of Biological and Agricultural Sciences, Mouloud Mammeri University of Tizi-Ouzou, Route de Hasnaoua, 15000, Tizi-Ouzou, Algeria.
- National Center for Biotechnology Research, Constantine, Algeria.
| |
Collapse
|
|
17
|
Taha AM, Hassan WS, Elmasry MS, Sayed RA. A validated eco-friendly HPLC-FLD for analysis of the first approved antiviral remdesivir with other potential add-on therapies for COVID-19 in human plasma and pharmaceuticals. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2023; 15:6666-6678. [PMID: 38031474 DOI: 10.1039/d3ay01562a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
It is crucial to have a reliable and sensitive method for separating common drugs used in SARS-CoV-2 pneumonia treatment protocols for ongoing treatment and upcoming investigations. This study presents an HPLC-FLD approach to analyze three co-administered medicines - remdesivir (RDV), hydroxychloroquine sulphate (HCQ), and levofloxacin hemihydrate (LVX) - in their pure forms, pharmaceutical preparations, and spiked human plasma. The HPLC-FLD analysis was conducted using a Symmetry® C18 column (100 mm × 4.6 mm ID, 3.5 μm particle size) at 40 °C, with (A) an aqueous mixture of 0.02 M phosphate buffer and 0.2% heptane-1-sulphonic acid sodium solutions (50 : 50) adjusted to pH 3, (B) acetonitrile, and (C) methanol as the mobile phase. The injection volume was 10 μL, and the flow rate was 1.5 mL min-1. The detection was done using a multi-wavelength excitation and emission fluorescence detector, with individual optimization for each drug. The drug separation time was less than 10 minutes, and the method showed sensitive and wide linearity ranges for all medicines, with r2 values of more than 0.999. The impact of the mobile phase pH and flow rate on suitability parameters (retention time and number of theoretical plates) was studied. The method was found to be environmentally friendly based on GAPI and AGREE metrics. The validity of the method was evaluated following ICH and FDA guidelines.
Collapse
Affiliation(s)
- Asmaa M Taha
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Wafaa S Hassan
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Manal S Elmasry
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Rania A Sayed
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| |
Collapse
|
|
18
|
Bartels CM, Jorge A, Feldman CH, Zell J, Bermas B, Barber CEH, Duarte-García A, Garg S, Haseley L, Jatwani S, Johansson T, Limanni A, Rodgers W, Rovin BH, Santiago-Casas Y, Suter LG, Barnado A, Ude J, Aguirre A, Li J, Schmajuk G, Yazdany J. Development of American College of Rheumatology Quality Measures for Systemic Lupus Erythematosus: A Modified Delphi Process With Rheumatology Informatics System for Effectiveness (RISE) Registry Data Review. Arthritis Care Res (Hoboken) 2023; 75:2295-2305. [PMID: 37165898 PMCID: PMC10615706 DOI: 10.1002/acr.25143] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/04/2023] [Indexed: 05/12/2023]
Abstract
OBJECTIVE We aimed to develop readily measurable digital quality measure statements for clinical care in systemic lupus erythematosus (SLE) using a multistep process guided by consensus methods. METHODS Using a modified Delphi process, an American College of Rheumatology (ACR) workgroup of SLE experts reviewed all North American and European guidelines from 2000 to 2020 on treatment, monitoring, and phenotyping of patients with lupus. Workgroup members extracted quality constructs from guidelines, rated these by importance and feasibility, and generated evidence-based quality measure statements. The ACR Rheumatology Informatics System for Effectiveness (RISE) Registry was queried for measurement data availability. In 3 consecutive Delphi sessions, a multidisciplinary Delphi panel voted on the importance and feasibility of each statement. Proposed measures with consensus on feasibility and importance were ranked to identify the top 3 measures. RESULTS Review of guidelines and distillation of 57 quality constructs resulted in 15 quality measure statements. Among these, 5 met high consensus for importance and feasibility, including 2 on treatment and 3 on laboratory monitoring measures. The 3 highest-ranked statements were recommended for further measure specification as SLE digital quality measures: 1) hydroxychloroquine use, 2) limiting glucocorticoid use >7.5 mg/day to <6 months, and 3) end-organ monitoring of kidney function and urine protein excretion at least every 6 months. CONCLUSION The Delphi process selected 3 quality measures for SLE care on hydroxychloroquine, glucocorticoid reduction, and kidney monitoring. Next, measures will undergo specification and validity testing in RISE and US rheumatology practices as the foundation for national implementation and use in quality improvement programs.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Shivani Garg
- University of Wisconsin School of Medicine and Public Health, Madison
| | | | | | | | | | - Wendy Rodgers
- Lupus Foundation Care and Support Services, Los Angeles, California
| | - Brad H Rovin
- Ohio State University Wexner Medical Center, Columbus
| | | | - Lisa G Suter
- Yale School of Medicine, New Haven, and Veterans Administration Medical Center, West Haven, Connecticut
| | - April Barnado
- Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jennifer Ude
- American College of Rheumatology, Atlanta, Georgia
| | | | - Jing Li
- University of California San Francisco
| | | | | |
Collapse
|
|
19
|
Jimenez AL, Valle A, Mustehsan MH, Wang S, Law J, Guerrero MS, Mowrey WB, Horton DB, Briceno D, Broder A. Association of Hydroxychloroquine Dose With Adverse Cardiac Events in Patients With Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken) 2023; 75:1673-1680. [PMID: 36331104 PMCID: PMC10156898 DOI: 10.1002/acr.25052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 09/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To determine whether hydroxychloroquine (HCQ) dose is associated with adverse cardiac outcomes in patients with systemic lupus erythematosus (SLE). METHODS Patients with SLE taking HCQ and with ≥1 echocardiogram followed at a tertiary care center in the Bronx, New York between 2005 and 2021 were included. The HCQ weight-based dose at the HCQ start date was the main exposure of interest. The outcome was incident all-cause heart failure with reduced ejection fraction (HFrEF), life-threatening arrhythmia, or cardiac death. We used Fine-Gray regression models with death as a competing event to study the association of HCQ dose with the outcome. Due to a significant interaction between smoking and HCQ exposure, models were stratified by smoking status. Propensity score analysis was performed as a secondary analysis. RESULTS Of 294 patients, 37 (13%) developed the outcome over a median follow-up time of 7.9 years (interquartile range [IQR] 4.2-12.3 years). In nonsmokers (n = 226), multivariable analysis adjusted for age, body mass index, hypertension, chronic kidney disease, diabetes mellitus, and thromboembolism showed that higher HCQ weight-based doses were not associated with an increased risk of the outcome (subdistribution hazard ratio [HR] 0.62 [IQR 0.41-0.92], P = 0.02). Similarly, higher baseline HCQ doses were not associated with a higher risk of the outcome among smokers (n = 68) (subdistribution HR 0.85 [IQR 0.53-1.34] per mg/kg, P = 0.48). Propensity score analysis showed comparable results. CONCLUSION Higher HCQ doses were not associated with an increased risk of HFrEF, life-threatening arrhythmia, or cardiac death among patients with SLE and may decrease the risk among nonsmokers.
Collapse
Affiliation(s)
| | - Ana Valle
- Albert Einstein College of Medicine/Montefiore Medical Center, the Bronx, New York
| | | | - Shudan Wang
- Albert Einstein College of Medicine/Montefiore Medical Center, the Bronx, New York
| | - Jammie Law
- Albert Einstein College of Medicine/Montefiore Medical Center, the Bronx, New York
| | | | - Wenzhu B Mowrey
- Albert Einstein College of Medicine/Montefiore Medical Center, the Bronx, New York
| | - Daniel B Horton
- Rutgers Center for Pharmacoepidemiology and Treatment Science and Institute for Health, Health Care Policy, and Aging Research, New Brunswick, New Jersey
| | | | - Anna Broder
- Hackensack University Hospital, Hackensack, New Jersey
| |
Collapse
|
|
20
|
Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications. Int J Mol Sci 2023; 24:ijms24055034. [PMID: 36902466 PMCID: PMC10003347 DOI: 10.3390/ijms24055034] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases.
Collapse
|
|
21
|
Nevras V, Milaras N, Katsioulis C, Sotiriou Z, Tsalamandris S, Gkounti G, Skevos S. Acute Coronary Syndromes in Antiphospholipid Syndrome-above Suspicion: A Systematic Review. Curr Probl Cardiol 2023; 48:101503. [PMID: 36402221 DOI: 10.1016/j.cpcardiol.2022.101503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022]
Abstract
Antiphospholipid syndrome(APS) is an autoimmune disorder characterized clinically by vascular thrombosis and/or pregnancy morbidity, associated with persistently elevated titers of antiphospholipid antibodies on at least two measurements over 12 weeks apart. In this study, we conducted a systematic review of the literature utilizing the Pubmed platform, in order to acquire clinical information about acute coronary syndromes in patients with APS. The obtained articles were reviewed in order to register the clinical characteristics, the rate of occurrence, the prognosis and the therapeutic approach of these patients. APS should be considered in young patients with acute myocardial infarction, even in patients with normal coronary arteries. The pharmaceutical approach is mainly based on the vitamin K antagonists, and in certain occasions aspirin, without any definite guidelines on the subject. Further randomized clinical trials are imperative for a better understanding of the particular characteristics of this group of patients, so that a more complete therapeutic approach to be obtained.
Collapse
Affiliation(s)
- Vasileios Nevras
- Cardiology Department, General Hospital of Thessaloniki G.Gennimatas, Thessaloniki, Thessaloniki, Greece
| | - Nikias Milaras
- Cardiology Department, General Hospital of Athens Hippokration, Athens, Athens, Greece.
| | - Christos Katsioulis
- Cardiology Department, General Hospital of Thessaloniki G.Gennimatas, Thessaloniki, Thessaloniki, Greece
| | - Zoi Sotiriou
- Pediatrics Department, General Hospital of Karditsa, Karditsa, Karditsa, Greece
| | - Sotirios Tsalamandris
- Cardiology Department, General Hospital of Athens Hippokration, Athens, Athens, Greece
| | - Georgia Gkounti
- Cardiology Department, General Hospital of Thessaloniki G.Gennimatas, Thessaloniki, Thessaloniki, Greece
| | - Sideris Skevos
- Cardiology Department, General Hospital of Athens Hippokration, Athens, Athens, Greece
| |
Collapse
|
|
22
|
Hurst C, Soto M, Vina ER, Rodgers KE. Renin-Angiotensin System-Modifying Antihypertensive Drugs Can Reduce the Risk of Cardiovascular Complications in Lupus: A Retrospective Cohort Study. Am J Med 2023; 136:284-293.e4. [PMID: 36495935 PMCID: PMC9957968 DOI: 10.1016/j.amjmed.2022.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Patients with systemic lupus erythematosus have a higher incidence of cardiovascular disease than the general population. Antihypertensive drugs that modify the renin-angiotensin system (RAS) are used to protect renal function in lupus nephritis and may also have extrarenal effects that lower cardiovascular disease risk due to their anti-inflammatory properties. In this study, we compared the effects of RAS vs non-RAS antihypertensive drugs on cardiovascular disease incidence in patients with lupus. METHODS Using a medical insurance claims dataset, 220,168 patients with lupus were identified, of which 31,647 patients (4018 patients prescribed RAS drugs, 27,629 patients prescribed non-RAS drugs) were eligible for the study. Patients had a mean age of 46.1 years, were 93.0% female, and healthy (96.9% Charlson Comorbidity Index score 0-4). Patients in the 2 drug groups were propensity score matched using demographic data, risk factors, and comorbidities. RESULTS Use of RAS vs non-RAS drugs lowered the relative risk (RR) of diagnosis of cardiovascular disease (RR 0.80; 95% confidence interval [CI], 0.74-0.87), which was more pronounced after propensity score matching (RR 0.62; 95% CI, 0.57-0.68). The decreased risk in cardiovascular disease occurred regardless of lupus nephritis status (with lupus nephritis: RR 0.51; 95% CI, 0.39-0.65; without lupus nephritis: RR 0.65; 95% CI, 0.59-0.72). RAS-modifying therapies significantly increased cardiovascular disease-free survival probability over a 5-year period (86.0% vs 78.3% probability). CONCLUSIONS RAS-modifying drugs reduced the risk of cardiovascular disease in patients with systemic lupus erythematosus in this dataset. These findings have the potential to impact clinical decision-making with regards to hypertension management in patients with lupus.
Collapse
Affiliation(s)
- Chelsie Hurst
- Department of Pharmacology, Center for Innovation in Brain Science, College of Medicine, University of Arizona, Tucson
| | - Maira Soto
- Department of Pharmacology, Center for Innovation in Brain Science, College of Medicine, University of Arizona, Tucson
| | - Ernest R Vina
- Section of Rheumatology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pa
| | - Kathleen E Rodgers
- Department of Pharmacology, Center for Innovation in Brain Science, College of Medicine, University of Arizona, Tucson.
| |
Collapse
|
|
23
|
Hydroxychloroquine in children with proliferative lupus nephritis: a randomized clinical trial. Eur J Pediatr 2023; 182:1685-1695. [PMID: 36752895 PMCID: PMC10167107 DOI: 10.1007/s00431-023-04837-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/14/2023] [Accepted: 01/20/2023] [Indexed: 02/09/2023]
Abstract
UNLABELLED Hydroxychloroquine (HCQ) is an antimalarial agent used to treat mucocutaneous, musculoskeletal, constitutional manifestations of systemic lupus erythematosus (SLE). This study assessed the efficacy and side effects of HCQ in children with proliferative lupus nephritis (LN). This double-blind, randomized, placebo-controlled trial study was conducted on 60 children with proliferative LN classes III and IV treated with steroids and a mycophenolate (MMF) regimen. Patients were categorized into two groups, the HCQ group (n = 30) and the placebo group (n = 30). They were evaluated initially at 6- and a 12-month follow-up by mucocutaneous, ophthalmological examination, and investigations (BUN, creatinine, 24 h proteinuria, triglycerides (TG), cholesterol, Antids-DNA, C3, C4). Disease activity was assessed using the SLE disease activity index (SLEDAI-2 k). After 12 months, TG, cholesterol, 24 h proteinuria, Antids-DNA, and SLEDAI score were significantly decreased in the HCQ group (P: 0.002, 0.012, 0.031, 0.001, respectively). After 12 months, the cumulative probabilities of developing primary end-points (LN partial and complete remission) were 40% and 60% in the HCQ group versus 53.3% and 36.7% in the placebo group (P: 0.002). After 12 months, the HCQ group experienced mucocutaneous alopecia (3.3%), hyperpigmentation (10%), and ophthalmological mild retinal changes (6.7%), but they did not differ significantly from the placebo group. Cunclusion: HCQ improved the disease and LN activity in children with proliferative LN, with documented skin hyperpigmentation and mild retinal changes following HCQ use in a few cases. This study was registered on http://www. CLINICALTRIALS gov/ with trial registration number (TRN): NCT03687905, September 2018 "retrospectively registered." WHAT IS KNOWN • Hydroxychloroquine (HCQ) is documented as an adjunctive treatment in children with systemic lupus erythematosus (c-SLE) LN with efficacy in improving lupus musculoskeletal and mucocutaneous manifestations. • Due to the paucity of studies, its effects and side effects in children with LN remain unclear. WHAT IS NEW • This pilot randomized clinical trial assessed the efficacy and adverse effects of HCQ in children with proliferative LN. • HCQ had numerous advantages for LN, including rapid and sustained remission, antilipidemic effect, and rapid improvement of kidney functions.
Collapse
|
|
24
|
Huang J, Hong W, Wan M, Zheng L. Molecular mechanisms and therapeutic target of NETosis in diseases. MedComm (Beijing) 2022; 3:e162. [PMID: 36000086 PMCID: PMC9390875 DOI: 10.1002/mco2.162] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/03/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web-like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: "suicidal" NETosis and "vital" NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell-free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small-vessel vasculitis, inflammatory bowel disease, cancer, COVID-19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll-like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis-induced diseases, and NETosis-targeted therapy.
Collapse
Affiliation(s)
- Jiayu Huang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Meihua Wan
- Department of Integrated Traditional Chinese and Western MedicineWest China HospitalSichuan UniversityChengduSichuanChina
| | - Limin Zheng
- Guangdong Province Key Laboratory of Pharmaceutical Functional GenesMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouChina
- State Key Laboratory of Oncology in Southern ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐Sen University Cancer CenterGuangzhouChina
| |
Collapse
|
|
25
|
Wang M, Wang Z, Zhang S, Wu Y, Zhang L, Zhao J, Wang Q, Tian X, Li M, Zeng X. Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus. J Clin Med 2022; 11:4955. [PMID: 36078885 PMCID: PMC9456588 DOI: 10.3390/jcm11174955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 11/16/2022] Open
Abstract
Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improving understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. In this review, we aimed to present the latest pathogenetic mechanisms of NPSLE and discuss the progress in its management.
Collapse
Affiliation(s)
| | | | - Shangzhu Zhang
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | | | | | | | | | | | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
| | | |
Collapse
|
|
26
|
Thrombosis and Anticoagulation Therapy in Systemic Lupus Erythematosus. Autoimmune Dis 2022; 2022:3208037. [PMID: 35795725 PMCID: PMC9252713 DOI: 10.1155/2022/3208037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/24/2022] [Accepted: 06/06/2022] [Indexed: 11/17/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease in which pathogenic autoantibodies and immune complexes are formed and mediate multiple organ and tissue damage. Thrombosis is one of the most common causes of death in patients with SLE. Anticoagulant therapy blocks the vicious cycle between inflammation and thrombosis, which may greatly improve the long-term prognosis of patients with SLE. However, the etiology and pathogenesis of this disease are very complicated and have not yet been fully clarified. Therefore, in the present review, we will highlight the characteristics and mechanisms of thrombosis and focus on the anticoagulant drugs commonly used in clinical practice, thus, providing a theoretical basis for scientific and reasonable anticoagulant therapy in clinical practice.
Collapse
|
|
27
|
Petri M. Drug monitoring in systemic lupus erythematosus. Curr Opin Pharmacol 2022; 64:102225. [PMID: 35490454 DOI: 10.1016/j.coph.2022.102225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022]
Abstract
Therapeutic drug monitoring (TDM) is not yet accepted by systemic lupus erythematosus (SLE) treatment guidelines. Studies in SLE, however, have proven benefit in three areas: identification of non-adherence or poor adherence; targets for clinical benefit; and ranges of toxicity. This review covers the data on three medications commonly used for SLE, drawing on studies from both the SLE and non-SLE literature.
Collapse
Affiliation(s)
- Michelle Petri
- Johns Hopkins University School of Medicine, Department of Medicine, Division of Rheumatology, 1830 E. Monument Street, Suite 7500, Baltimore, MD, 21205, USA.
| |
Collapse
|
|
28
|
Burroway B, Lin DA, Miteva M. SnapshotDx Quiz: April 2022. J Invest Dermatol 2022; 142:e37-e41. [DOI: 10.1016/j.jid.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 01/10/2023]
|
|
29
|
Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis 2022; 14:1759720X211073001. [PMID: 35186126 PMCID: PMC8848057 DOI: 10.1177/1759720x211073001] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ’s effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.
Collapse
Affiliation(s)
- Alina Dima
- Department of Rheumatology, Colentina Clinical Hospital, Bucharest, Romania
| | - Ciprian Jurcut
- Department of Internal Medicine, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest, Romania
| | - François Chasset
- Department of Dermatology and Allergology, Hôpital Tenon, Paris, France; Faculté de Médecine, Sorbonne Université, Paris, France
| | - Renaud Felten
- National Reference Center for Rare Auto-immune and Systemic Diseases Est Sud-Est (RESO), Strasbourg, France
- Department of Rheumatology, Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Laurent Arnaud
- National Reference Center for Rare Auto-immune and Systemic Diseases Est Sud-Est (RESO), Strasbourg, France
- Department of Rheumatology, Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Université de Strasbourg, Inserm UMR-S 1109, Strasbourg, France
- Service de Rhumatologie, Hôpital de Hautepierre, 1, avenue Molière BP 83049, 67098 Strasbourg Cedex, France
| |
Collapse
|
|
30
|
Jha SB, Rivera AP, Flores Monar GV, Islam H, Puttagunta SM, Islam R, Kundu S, Sange I. Systemic Lupus Erythematosus and Cardiovascular Disease. Cureus 2022; 14:e22027. [PMID: 35282557 PMCID: PMC8910778 DOI: 10.7759/cureus.22027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
|
|
31
|
Abstract
Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes. In this Review, the authors provide an overview of the immune cells involved in atherosclerosis, discuss preclinical research and published and ongoing clinical trials assessing the therapeutic potential of targeting the immune system in atherosclerosis, highlight emerging therapeutic targets from preclinical studies and identify challenges for successful clinical translation.
Inflammation is an important component of the pathophysiology of cardiovascular disease; an imbalance between pro-inflammatory and anti-inflammatory processes drives chronic inflammation and the formation of atherosclerotic plaques in the vessel wall. Clinical trials assessing canakinumab and colchicine therapies in atherosclerotic cardiovascular disease have provided proof-of-principle of the benefits associated with therapeutic targeting of the immune system in atherosclerosis. The immunosuppressive adverse effects associated with the systemic use of anti-inflammatory drugs can be minimized through targeted delivery of anti-inflammatory drugs to the atherosclerotic plaque, defining the window of opportunity for treatment and identifying more specific targets for cardiovascular inflammation. Implementing immunophenotyping in clinical trials in patients with atherosclerotic cardiovascular disease will allow the identification of immune signatures and the selection of patients with the highest probability of deriving benefit from a specific therapy. Clinical stratification via novel risk factors and discovery of new surrogate markers of vascular inflammation are crucial for identifying new immunotherapeutic targets and their successful translation into the clinic.
Collapse
|
|
32
|
Chamardani TM, Amiritavassoli S. Inhibition of NETosis for treatment purposes: friend or foe? Mol Cell Biochem 2022; 477:673-688. [PMID: 34993747 PMCID: PMC8736330 DOI: 10.1007/s11010-021-04315-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/25/2021] [Indexed: 12/29/2022]
Abstract
Active neutrophils participate in innate and adaptive immune responses through various mechanisms, one of the most important of which is the formation and release of neutrophil extracellular traps (NETs). The NETs are composed of network-like structures made of histone proteins, DNA and other released antibacterial proteins by activated neutrophils, and evidence suggests that in addition to the innate defense against infections, NETosis plays an important role in the pathogenesis of several other non-infectious pathological states, such as autoimmune diseases and even cancer. Therefore, targeting NET has become one of the important therapeutic approaches and has been considered by researchers. NET inhibitors or other molecules involved in the NET formation, such as the protein arginine deiminase 4 (PAD4) enzyme, an arginine-to-citrulline converter, participate in chromatin condensation and NET formation, is the basis of this therapeutic approach. The important point is whether complete inhibition of NETosis can be helpful because by inhibiting this mechanism, the activity of neutrophils is suppressed. In this review, the biology of NETosis and its role in the pathogenesis of some important diseases have been summarized, and the consequences of treatment based on inhibition of NET formation have been discussed.
Collapse
|
|
33
|
Sarhan RM, Harb HS, Abou Warda AE, Salem-Bekhit MM, Shakeel F, Alzahrani SA, Madney YM, Boshra MS. Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 Patients. J Infect Public Health 2022; 15:116-122. [PMID: 34764044 PMCID: PMC8562044 DOI: 10.1016/j.jiph.2021.10.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The effectiveness of the best combination between different antiviral and anti-inflammatory drugs stills an interest in the treatment of COVID19 infection. PATIENTS AND METHODS A prospective randomized cohort study comprised 108 adult patients with confirmed PCR COVID 19 infection with systemic hyper inflammation state, divided into two groups according to the treatment regimen, 56 in the tocilizumab- hydroxychloroquine (TCZ-HCQ) treatment, and 52 in the tocilizumab-remdesivir (TCZ-RMV) treatment. The first group received a combination of I.V. TCZ (400-800 mg every 24 h for only two doses) and HCQ (400 mg twice in the first day then 200 mg twice for 5 days) while the second group of patients received I.V. RMV of 200 mg on day 1 followed by 100 mg once daily infused over 60 min for 5 days with the same TCZ regimen used in the first group. All clinical parameters and laboratory investigations were assessed before and after treatment. RESULTS The CRP was significantly decreased while PaO2/FiO2 (P/F) ratio post-treatment was significantly improved in both treatment groups. TCZ-HCQ group showed a significant decrease in the ferritin, LDH, and D. Dimer levels. The median days of hospitalization with interquartile range (IQR) were 10 (6-16) and 8 (5-12) for TCZ-HCQ and TCZ-RMV groups, respectively. The numbers of mechanically ventilated patients were 25 and 43 for TCZ-HCQ and TCZ-RMV groups, respectively. Therapeutic failure was about 26.8% in the TCZ-HCQ group and 30.8% in the TCZ-RMV group but there was no significant difference between both groups. Some complications were recognized only in TCZ-RMV following treatment including secondary bacterial infections (42.3%), myocarditis (15.4%), and finally pulmonary embolism (7.7%). CONCLUSION Efficacy of both TCZ-RMV and TCZ-HCQ combinations are observed in the treatment of severe COVID-19 patients; however the increased need for ICU or mechanical ventilation in the TCZ-RMV arm contributed to the appearance of cardiac and thrombotic events. The study was registered at the Clinical Trials registry (ClinicalTrials.gov; NCT04779047).
Collapse
Affiliation(s)
- Rania M Sarhan
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-suef, Egypt.
| | - Hadeer S Harb
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-suef, Egypt
| | - Ahmed E Abou Warda
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza, Egypt
| | - Mounir M Salem-Bekhit
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Faiyaz Shakeel
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Sami Ali Alzahrani
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Yasmin M Madney
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-suef, Egypt
| | - Marian S Boshra
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-suef, Egypt
| |
Collapse
|
|
34
|
Keyes E, Grinnell M, Jacoby D, Vazquez T, Diaz D, Werth VP, Williams KJ. Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis. Int J Womens Dermatol 2021; 7:560-575. [PMID: 35024413 PMCID: PMC8721062 DOI: 10.1016/j.ijwd.2021.08.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 01/05/2023] Open
Abstract
For patients with lupus erythematosus (LE) or dermatomyositis (DM), there is an urgent need to address a heightened risk of clinical events, chiefly heart attacks and strokes, caused by atherosclerotic cardiovascular disease (ASCVD). Patients with LE or DM frequently exhibit high levels of conventional risk factors for ASCVD events, particularly dyslipoproteinemia and hypertension; an amplified burden of atherosclerotic plaques; and increased age- and sex-adjusted rates of ASCVD events compared with the general population. The rate of ASCVD events exceeds what would be expected from conventional risk factors, suggesting that disease-specific autoimmune processes exacerbate specific, known pathogenic steps in atherosclerosis. Importantly, despite their heightened risk, patients with LE or DM are often undertreated for known causative agents and exacerbators of ASCVD. Herein, we propose an approach to assess and manage the heightened risk of ASCVD events in patients with LE or DM. Our approach is modeled in large part on established approaches to patients with diabetes mellitus or stage 3 or 4 chronic kidney disease, which are well-studied conditions that also show heightened risk for ASCVD events and have been explicitly incorporated into standard clinical guidelines for ASCVD. Based on the available evidence, we conclude that patients with LE or DM require earlier and more aggressive screening and management of ASCVD. We suggest that physicians consider implementing multipliers of conventional risk calculators to trigger earlier initiation of lifestyle modifications and medical therapies in primary prevention of ASCVD events, employ vascular imaging to quantify the burden of subclinical plaques, and treat to lower lipid targets using statins and newer therapies, such as PCSK9 inhibitors, that decrease ASCVD events in nonautoimmune cohorts. More clinical vigilance is needed regarding surveillance, prevention, risk modification, and treatment of dyslipidemias, hypertension, and smoking in patients with LE or DM. All of these goals are achievable.
Collapse
Affiliation(s)
- Emily Keyes
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Madison Grinnell
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Douglas Jacoby
- Cardiovascular Division, Department of Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania
| | - Thomas Vazquez
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - DeAnna Diaz
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Victoria P. Werth
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania
| | - Kevin Jon Williams
- Department of Cardiovascular Sciences, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| |
Collapse
|
|
35
|
Park E, Giles JT, Perez-Recio T, Pina P, Depender C, Gartshteyn Y, Askanase AD, Bathon J, Geraldino-Pardilla L. Hydroxychloroquine use is not associated with QTc length in a large cohort of SLE and RA patients. Arthritis Res Ther 2021; 23:271. [PMID: 34715924 PMCID: PMC8554185 DOI: 10.1186/s13075-021-02646-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Background Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, reports of its use and subsequent fatal arrhythmias in patients with coronavirus disease 19 (COVID-19) have raised concern regarding its cardiovascular (CV) safety. Therefore, we examined the relationship between HCQ use and corrected QT (QTc) length in SLE and RA patients without clinical CV disease (CVD). Methods SLE patients from the Columbia University Lupus Cohort registry (n = 352) and two RA cohorts (n = 178; ESCAPE-RA and RHYTHM-RA) with electrocardiograms (ECGs) collected as part of study data were analyzed. RA cohort participants were recruited from tertiary referral centers with additional referrals from community rheumatologists, while SLE subjects originated from the Columbia University Lupus Cohort. All patients met American College of Rheumatology (ACR) classification criteria for SLE or RA and lacked known CVD. The exposure of interest was HCQ use and main outcome measure was QTc length [continuous or categorical (≥ 440 ms and ≥ 500 ms)]. Results Of the combined SLE and RA cohorts (n = 530), 70% were HCQ users and 44% had a QTc ≥ 440 ms. The adjusted mean QTc length was comparable between HCQ users vs non-users (438 ms vs 437 ms). In multivariable logistic models, HCQ use was not a significant predictor of a QTc ≥ 440 ms for the entire cohort (OR 0.77; 95% CI 0.48–1.23; p = 0.27). Importantly, a QTc ≥ 500 ms was inversely associated with HCQ use and not associated with arrhythmias or deaths. A significant interaction was found between HCQ use and use of anti-psychotics. Ultimately, the use of HCQ combined with any QTc prolonging medication as a group was associated with a QTc length (434 ms; 95% CI 430, 439) which was comparable to that of use of HCQ alone (433 ms; 95% CI 429-437). Conclusion In a combined cohort of SLE and RA patients without clinical CVD, adjusted QTc length was comparable between HCQ and non-HCQ users, supporting its CV safety in patients with rheumatic diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-021-02646-0.
Collapse
Affiliation(s)
- Elizabeth Park
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA.
| | - Jon T Giles
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Thania Perez-Recio
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Paloma Pina
- Cardiac Electrophysiology, Northwestern Medicine, Chicago, IL, USA
| | - Christopher Depender
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Yevgeniya Gartshteyn
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Anca D Askanase
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Joan Bathon
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| | - Laura Geraldino-Pardilla
- Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, 630 W 168th St, P&S 3-450, New York, NY, 10032, USA
| |
Collapse
|
|
36
|
Tedesco Silva LM, Cortes A, Rossi B, Boll L, Waclawovsky G, Eibel B, Cadaval Gonçalves S, Irigoyen MC, Martinez D. Effects of Hydroxychloroquine on endOthelial function in eLDerly with sleep apnea (HOLD): study protocol for a randomized clinical trial. Trials 2021; 22:638. [PMID: 34535165 PMCID: PMC8447592 DOI: 10.1186/s13063-021-05610-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 09/07/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Sleep apnea and coronary artery disease are prevalent and relevant diseases. The mechanism by which sleep apnea leads to coronary artery disease remains unclear. Intermittent hypoxia, caused by sleep apnea, leads to inflammation and consequent endothelial dysfunction. Endothelial dysfunction precedes the development of atherosclerotic disease and the occurrence of cardiovascular events. Agents that potentially act to improve endothelial function can help prevent cardiovascular events. Patients using immunomodulators due to rheumatic diseases have a lower prevalence of cardiovascular diseases. However, the potential cardioprotective effect of these drugs in patients without autoimmune diseases is not clear. Hydroxychloroquine (HCQ) is an immunomodulator used to treat rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol and blood glucose levels and has antithrombotic effects. The drug is inexpensive and widely available. Adverse effects of HCQ are rare and occur more frequently with high doses. OBJECTIVE In this randomized clinical trial, the effect of HCQ treatment on endothelial function will be tested in seniors with sleep apnea. METHODS We will recruit participants over the age of 65 and with moderate-severe sleep apnea from an ongoing cohort. We chose to use this sample already evaluated for sleep apnea for reasons of convenience, but also because the elderly with sleep apnea are vulnerable to heart disease. Endothelial function will be assessed by examining flow-mediated dilation of the brachial artery, the gold standard method, considered an independent predictor of cardiovascular events in the general population and by peripheral arterial tonometry, the most recent and most easily obtained method. Hydroxychloroquine will be used at a dose of 400 mg/daily for 8 weeks. DISCUSSION Our study aims to obtain evidence, albeit preliminary, of the efficacy of hydroxychloroquine in improving endothelial function and reducing cardiovascular risk markers. If the improvement occurs, we plan to design a randomized multicenter clinical trial to confirm the findings. TRIAL REGISTRATION ClinicalTrials.gov NCT04161339 . Registered on November 2019.
Collapse
Affiliation(s)
| | - Antonio Cortes
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Beatriz Rossi
- Instituto de Cardiologia - Fundação Universitária de Cardiologia (IC-FUC), Porto Alegre, Brazil
| | - Liliana Boll
- Instituto de Cardiologia - Fundação Universitária de Cardiologia (IC-FUC), Porto Alegre, Brazil
| | - Gustavo Waclawovsky
- Instituto de Cardiologia - Fundação Universitária de Cardiologia (IC-FUC), Porto Alegre, Brazil
| | - Bruna Eibel
- Instituto de Cardiologia - Fundação Universitária de Cardiologia (IC-FUC), Porto Alegre, Brazil
| | | | - Maria Claudia Irigoyen
- Instituto de Cardiologia - Fundação Universitária de Cardiologia (IC-FUC), Porto Alegre, Brazil
- Universidade de São Paulo, São Paulo, Brazil
| | - Denis Martinez
- Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| |
Collapse
|
|
37
|
McMahon M, Seto R, Skaggs BJ. Cardiovascular disease in systemic lupus erythematosus. RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2021; 2:157-172. [PMID: 35880242 PMCID: PMC9242526 DOI: 10.2478/rir-2021-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 11/21/2022]
Abstract
There is a well-known increased risk for cardiovascular disease that contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Major adverse cardiovascular events and subclinical atherosclerosis are both increased in this patient population. While traditional cardiac risk factors do contribute to the increased risk that is seen, lupus disease-related factors, medications, and genetic factors also impact the overall risk. SLE-specific inflammation, including oxidized lipids, cytokines, and altered immune cell subtypes all are likely to play a role in the pathogenesis of atherosclerotic plaques. Research is ongoing to identify biomarkers that can help clinicians to predict which SLE patients are at the greatest risk for cardiovascular disease (CVD). While SLE-specific treatment regimens for the prevention of cardiovascular events have not been identified, current strategies include minimization of traditional cardiac risk factors and lowering of overall lupus disease activity.
Collapse
Affiliation(s)
- Maureen McMahon
- UCLA David Geffen School of Medicine, Division of Rheumatology, 32-59 Rehab Center, 1000 Veteran Avenue, Los Angeles, CA90095, USA
| | - Richard Seto
- UCLA David Geffen School of Medicine, Division of Rheumatology, 32-59 Rehab Center, 1000 Veteran Avenue, Los Angeles, CA90095, USA
| | - Brian J. Skaggs
- UCLA David Geffen School of Medicine, Division of Rheumatology, 32-59 Rehab Center, 1000 Veteran Avenue, Los Angeles, CA90095, USA
| |
Collapse
|
|
38
|
Mok CC, Hamijoyo L, Kasitanon N, Chen DY, Chen S, Yamaoka K, Oku K, Li MT, Zamora L, Bae SC, Navarra S, Morand EF, Tanaka Y. The Asia-Pacific League of Associations for Rheumatology consensus statements on the management of systemic lupus erythematosus. THE LANCET. RHEUMATOLOGY 2021; 3:e517-e531. [PMID: 38279404 DOI: 10.1016/s2665-9913(21)00009-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
Systemic lupus erythematosus (SLE) is prevalent in Asia and carries a variable prognosis among patients across the Asia-Pacific region, which could relate to access to health care, tolerability of medications, and adherence to therapies. Because many aspects of SLE are unique among patients from this region, the Asia-Pacific League of Associations for Rheumatology developed the first set of consensus recommendations on the management of SLE. A core panel of 13 rheumatologists drafted a set of statements through face-to-face meeting and teleconferences. A literature review was done for each statement to grade the quality of evidence and strength of recommendation. 29 independent specialists and three patients with SLE were then recruited for a modified Delphi process to establish consensus on the statements through an online voting platform. A total of 34 consensus recommendations were developed. Panellists agreed that patients with SLE should be referred to a specialist for the formulation of a treatment plan through shared decision making between patients and physicians. Remission was agreed to be the goal of therapy, but when it cannot be achieved, a low disease activity state should be aimed for. Patients should be screened for renal disease, and hydroxychloroquine is recommended for all Asian people with SLE. Major organ manifestations of SLE should be treated with induction immunosuppression and subsequently maintenance; options include cyclophosphamide, mycophenolate mofetil, azathioprine, and calcineurin inhibitors, in combination with glucocorticoids. Biologics, combination regimens, plasma exchange, and intravenous immunoglobulins should be reserved for cases of refractory or life-threatening disease. Anticoagulation therapy with warfarin is preferred to the direct oral anticoagulants for thromboembolic SLE manifestations associated with a high-risk antiphospholipid antibody profile.
Collapse
Affiliation(s)
- Chi Chiu Mok
- Division of Rheumatology, Department of Medicine, Tuen Mun Hospital, Hong Kong Special Administrative Region, China.
| | - Laniyati Hamijoyo
- Rheumatology Division, Department of Internal Medicine, Padjadjaran University, Jawa Barat, Indonesia
| | - Nuntana Kasitanon
- Division of Rheumatology, Department of Internal Medicine, Chiang Mai University, Thailand
| | - Der Yuan Chen
- Rheumatology and Immunology Centre, China Medical University, Taichung, Taiwan
| | - Sheng Chen
- Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Kunihiro Yamaoka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Kenji Oku
- Department of Rheumatology, Endocrinology and Nephrology Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Meng Tao Li
- Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China; Chinese Academy of Medical Science, National Clinical Research Centre for Dermatological and Immunological Diseases, Beijing, China
| | - Leonid Zamora
- Section of Rheumatology, University of Santo Tomas, Manila, Philippines
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Sandra Navarra
- Section of Rheumatology, University of Santo Tomas, Manila, Philippines
| | - Eric F Morand
- Centre for Inflammatory Diseases, Monash University School of Clinical Sciences, Monash Medical Centre, Melbourne, Australia
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| |
Collapse
|
|
39
|
Costa R, Castagna A, Torchia C, Ruberto C, Vespertini V, Cosco L, Ruotolo G. Proarrhythmia assessment in treatment with hydroxychloroquine and azithromycin hospitalized elderly COVID-19 patients - our experience. GERIATRIC CARE 2021. [DOI: 10.4081/gc.2021.9536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of our study was to characterize the repolarization disorders propensity induced by drug-drug interaction. In this observational retrospective study, we report our experience on all elderly patients with ascertained diagnosis of coronavirus disease 2019 through nasopharyngeal swab with real time-polymerase chain reaction at our Pugliese-Ciaccio hospital in Catanzaro, who received hydroxychloroquine (HCQ), with or without azithromycin (AZY). 33 hospitalized patients were examined. We calculated QT value, cQT, QT dispersion, and cQT dispersion and examined possible progression on the basal electrocardiogram (T0) and after the insertion of the drug (T1). The QT value is increased by T0 vs T1 (370±40.74 vs 420±36.91 ms; P=0.000), as well as the cQT value (408±25.40 vs 451.54±58.81; P=0.003), the QT dispersion (QTd: 36.36±14.53 vs 50.90±13.12 ms; P=0.000); the dispersion of cQTc (cQTd 46.27±18.72 vs 63.18±21.93 ms; P=0.001). The ΔQT was 37.44±44.09 while the ΔcQT was 32.01±56.47). The main determinant of QTc prolongation is the number of drug at risk of prolongation of the QT that could influence the ventricular repolarization phase. The use of HCQ in combination with AZY, in patients suffering from severe acute respiratory syndrome-related coronavirus-2, can favor the onset of serious side effects, even potentially fatal. Finally, the measures of QTd and cQTd confirmed additional electrocardiographic parameters useful in identifying patients being treated with drugs at risk of potential adverse arrhythmic events following drug interaction.
Collapse
|
|
40
|
Petri M, Konig MF, Li J, Goldman DW. Association of Higher Hydroxychloroquine Blood Levels With Reduced Thrombosis Risk in Systemic Lupus Erythematosus. Arthritis Rheumatol 2021; 73:997-1004. [PMID: 33403833 DOI: 10.1002/art.41621] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/23/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hydroxychloroquine (HCQ) has a primary role in the prophylaxis and treatment of systemic lupus erythematosus (SLE) and may be protective against thrombosis in SLE. Optimal weight-based dosing of HCQ is unknown. This study was undertaken to examine the usefulness of HCQ blood monitoring in predicting thrombosis risk in a longitudinal SLE cohort. METHODS HCQ levels were serially quantified from EDTA whole blood by liquid chromatography-tandem mass spectrometry. The mean HCQ blood levels calculated prior to thrombosis or until the last visit were compared using t-tests between patients with and those without thrombosis. Pooled logistic regression was used to analyze the association between rates of thrombosis and HCQ blood level. Rate ratios (RRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%). The mean ± SD HCQ blood level was lower in patients who developed thrombosis versus those who did not develop thrombosis (720 ± 489 ng/ml versus 935 ± 580 ng/ml; P = 0.025). Thrombosis rates were reduced by 13% for every 200-ng/ml increase in the most recent HCQ blood level (RR 0.87 [95% CI 0.78-0.98], P = 0.025) and by 13% for mean HCQ blood level (RR 0.87 [95% CI 0.76-1.00], P = 0.056). Thrombotic events were reduced by 69% in patients with mean HCQ blood levels ≥1,068 ng/ml versus those with levels <648 ng/ml (RR 0.31 [95% CI 0.11-0.86], P = 0.024). This remained significant after adjustment for confounders (RR 0.34 [95% CI 0.12-0.94], P = 0.037). CONCLUSION Low HCQ blood levels are associated with thrombotic events in SLE. Longitudinal measurement of HCQ levels may allow for personalized HCQ dosing strategies. Recommendations for empirical dose reduction may reduce or eliminate the benefits of HCQ in this high-risk population.
Collapse
Affiliation(s)
- Michelle Petri
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Jessica Li
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daniel W Goldman
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
41
|
Tian Z, Zhang H, Shang C. Farrerol ameliorate adjuvant-induced ankle injury via alteration of PPAR-γ signal pathway. J Food Biochem 2021; 45:e13585. [PMID: 33844304 DOI: 10.1111/jfbc.13585] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/31/2020] [Accepted: 11/01/2020] [Indexed: 12/15/2022]
Abstract
This study evaluated the anti-inflammatory activity against lipopolysaccharide (LPS)-mediated mouse macrophages (in vitro) and assessed the protective effect of farrerol on arthritis caused by complete freund adjuvant (CFA) in rats. For the evaluation of the pharmacological effect of farrerol on the activity of nitric oxide (NO) and cyclooxygenase, pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β, RAW 264.7 cells were used. A 0.1 ml CFA was injected subcutaneously for the induction of arthritis. The paw volume, body weight and arthritic score were estimated at regular intervals. Pro-inflammatory cytokines, inflammatory mediators, and antioxidant parameters were also estimated. Farrerol suppressed NO production and COX-catalyzed prostaglandin (PGE2 ) in RAW 264.7. Farrerol also downregulated the p-p65, p-IκBα expression and upregulated the PPAR-γ expression in RAW 264.7 cells. Treatment of farrerol increased body weight substantially, and reduced paw edema and arthritic score. Farrerol treatment also significantly improved the level of hemoglobin (Hb), count of red blood cells (RBC), and decreased the rate of erythrocyte sedimentation (ESR), white blood cell (WBC) parameters, while the generation of pro-inflammatory cytokines inhibited. Together, farrerol also suppressed the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Obtained results directed that the farrerol exerted its therapeutic effect against CFA-induced arthritic rats through anti-inflammatory mechanism by regulation of the PPAR-γ. PRACTICAL APPLICATIONS: Increase the arthritis disease worldwide day-by-day. The current research study showed the anti-arthritic effect of farrerol (flavonoid phytoconstituent) of Rhododendron dauricum Linn. In this study, farrerol considerably inhibited the NF-κB to show the anti-arthritic effect. The finding showed the potential effect against acute and chronic inflammation via inhibition of inflammatory mediators and oxidative stress. The result suggests the anti-inflammatory and antioxidant effect of farrerol. On the basis of result, we can say that farrerol can be the beneficial drug to treat the arthritis.
Collapse
Affiliation(s)
- Zhao Tian
- Department of Hand Surgery, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, 710054, China
| | - Hongxing Zhang
- Department of Hand Surgery, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, 710054, China
| | - Chi Shang
- Department of Hand Surgery, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, 710054, China
| |
Collapse
|
|
42
|
Understanding Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Toward Better Treatment and Prevention. Inflammation 2021; 44:1663-1682. [PMID: 33821395 DOI: 10.1007/s10753-021-01455-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/01/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022]
Abstract
Systemic lupus erythematosus (SLE) carries a significant risk of cardiovascular disease (CVD). The prevalence of premature CVD is especially noteworthy because it occurs in premenopausal women with SLE who would otherwise have very low rates of CVD. While traditional risk factors likely play a role in development of CVD in the setting of SLE, they do not fully explain the excess risk. The pathogenesis of CVD in SLE is not fully understood, but the inflammatory nature of SLE is believed to be a key factor in accelerating atherosclerosis. Systemic inflammation may lead to an abnormal lipid profile with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol and dysfunctional high-density lipoprotein cholesterol. Additionally, the inflammatory milieu of SLE plasma promotes endothelial dysfunction and vascular injury, early steps in the progression of atherosclerotic CVD. Despite the overall headway that has been achieved in treating lupus, innovative therapeutics specifically targeting the progression of atherosclerosis within the lupus population are currently lacking. However, there have been advancements in the development of promising modalities for diagnosis of subclinical atherosclerosis and detection of high CVD risk patients. Due to the significant impact of CVD on morbidity and mortality, research addressing prevention and treatment of CVD in SLE needs to be prioritized. This review explores the intricate interplay of SLE-specific properties that contribute to atherosclerosis and CVD within this population, as well as screening methods and possible therapies.
Collapse
|
|
43
|
Garg S, Unnithan R, Hansen KE, Costedoat-Chalumeau N, Bartels CM. Clinical Significance of Monitoring Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken) 2021; 73:707-716. [PMID: 32004406 DOI: 10.1002/acr.24155] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 01/21/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Despite the pivotal role that hydroxychloroquine (HCQ) plays in treating systemic lupus erythematosus (SLE), less than 50% of patients take HCQ as prescribed. Measurement of HCQ blood levels can help clinicians distinguish nonadherence versus lack of efficacy of HCQ. Our objective was to systematically review publications and perform a meta-analysis to examine the correlation between HCQ levels and 1) nonadherence and 2) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, in SLE. METHODS A comprehensive search was performed. We included observational and interventional studies that measured HCQ levels and assessed adherence or SLEDAI scores in adults with SLE. Forest plots compared pooled estimates of correlations between HCQ levels and reported nonadherence or SLEDAI scores. RESULTS Among 604 studies screened, 17 were reviewed. We found 3-times higher odds of reported nonadherence in patients with low HCQ levels (odds ratio 2.95 [95% confidence interval (95% CI) 1.63, 5.35], P < 0.001). The mean SLEDAI score was 3.14 points higher in groups with below-threshold HCQ levels on a priori analysis (δ = 3.14 [95% CI -0.05, 6.23], P = 0.053), and 1.4 points higher in groups with HCQ levels of <500 ng/ml (δ = 1.42 [95% CI 0.07, 2.76], P = 0.039). Among 1,223 patients, those with HCQ levels ≥750 ng/ml had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower. CONCLUSION We found a strong association between low HCQ levels and reported nonadherence. Our results suggest that HCQ levels of ≥750 ng/ml might be a potential therapeutic target.
Collapse
Affiliation(s)
- Shivani Garg
- University of Wisconsin School of Medicine and Public Health, Madison
| | - Rachna Unnithan
- University of Wisconsin School of Medicine and Public Health, Madison
| | - Karen E Hansen
- University of Wisconsin School of Medicine and Public Health, Madison
| | | | | |
Collapse
|
|
44
|
The neurology of lupus. J Neurol Sci 2021; 424:117419. [PMID: 33832774 DOI: 10.1016/j.jns.2021.117419] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 10/30/2020] [Accepted: 03/24/2021] [Indexed: 12/19/2022]
|
|
45
|
Ugarte A, Garcia de Bustos A, Ruiz-Arruza I, Soto-Peleteiro A, Martin-Iglesias D, Gonzalez-Echavarri C, Ruiz-Irastorza G. ANTIPHOSPHOLIPID ANTIBODIES DO NOT PREDICT DAMAGE IN SLE PATIENTS IN THE XXI CENTURY. AN OBSERVATIONAL STUDY FROM THE LUPUS-CRUCES COHORT. Rheumatology (Oxford) 2021; 61:249-257. [PMID: 33769455 DOI: 10.1093/rheumatology/keab307] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE To compare the influence of antiphospholipid antibodies (aPL) on global and cardiovascular damage in patients with systemic lupus erythematosus (SLE) diagnosed before and after year 2000. METHODS 286 patients from the Lupus-Cruces cohort with a minimum follow-up of 5 years, divided into two sub-cohorts according to the date of diagnosis, before 2000 (<2000) and from 2000 on (≥2000). We compared the mean SDI score and global and cardiovascular damage-free survival rates in the presence/absence of aPL in both sub-cohorts. Variables potentially modulating damage among aPL-positive patients were analysed. RESULTS The sub-cohorts were comparable for demographic and lupus-related variables except for treatment variables: the ≥2000 sub-cohort received lower doses of prednisone and more hydroxychloroquine, low-dose aspirin, statins, immunosuppressive agents and Vitamin D. aPL-positive patients in the <2000, but not in the ≥2000 sub-cohort, accrued more damage compared with aPL-negative. In the <2000 sub-cohort, the adjusted HRs for global and cardiovascular damage in aPL-positive vs. aPL-negative patients were 1.98 (95% CI 1.24-3.14) and 9.3 (95% CI 3.24-26.92), respectively. No differences in damage were seen between aPL-positive and aPL-negative patients in the ≥2000 sub-cohort. Hypertension (HR 4.64, 95%CI 1.33-16.19), lupus anticoagulant (HR 3.85, 95%CI 1.1-13.41) and the number of months on hydroxychloroquine (HR 0.97, 95%CI 0.95-0.99) were independent predictors of vascular damage in the combined analysis of all aPL-positive patients. CONCLUSION The effects of aPL on damage accrual in SLE patients have been reduced over the last years. The widespread use of hydroxychloroquine and a better thromboprophylaxis are likely causing this change.
Collapse
Affiliation(s)
- Amaia Ugarte
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
| | | | - Ioana Ruiz-Arruza
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain.,University of The Basque Country, Bizkaia, The Basque Country, Spain
| | - Adriana Soto-Peleteiro
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
| | - Daniel Martin-Iglesias
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
| | - Cristina Gonzalez-Echavarri
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
| | - Guillermo Ruiz-Irastorza
- Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain.,University of The Basque Country, Bizkaia, The Basque Country, Spain
| |
Collapse
|
|
46
|
Appleton BD, Major AS. The latest in systemic lupus erythematosus-accelerated atherosclerosis: related mechanisms inform assessment and therapy. Curr Opin Rheumatol 2021; 33:211-218. [PMID: 33394753 PMCID: PMC8049098 DOI: 10.1097/bor.0000000000000773] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Accelerated atherosclerosis is a significant comorbidity and the leading cause of death for patients with systemic lupus erythematosus (SLE). It is now apparent that SLE-accelerated atherosclerosis is not driven solely by traditional cardiovascular risk factors, adding complexity to disease characterization and mechanistic understanding. In this review, we will summarize new insights into SLE-accelerated atherosclerosis evaluation, treatment, and mechanism. RECENT FINDINGS Recent work highlights the need to incorporate inflammatory biomarkers into cardiovascular disease (CVD) risk assessments. This is especially true for SLE patients, in which mechanisms of immune dysfunction likely drive CVD progression. There is new evidence that commonly prescribed SLE therapeutics hinder atherosclerosis development. This effect is achieved both by reducing SLE-associated inflammation and by directly improving measures of atherosclerosis, emphasizing the interconnected mechanisms of the two conditions. SUMMARY SLE-accelerated atherosclerosis is most likely the consequence of chronic autoimmune inflammation. Therefore, diligent management of atherosclerosis requires assessment of SLE disease activity as well as traditional cardiovascular risk factors. This supports why many of the therapeutics classically used to control SLE also modulate atherosclerosis development. Greater understanding of the mechanisms underlying this condition will allow for the development of more targeted therapeutics and improved outcomes for SLE patients.
Collapse
Affiliation(s)
- Brenna D. Appleton
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, 37232, USA
| | - Amy S. Major
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt Medical Center, Nashville, TN, 37232, USA
- Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN, 37212, USA
| |
Collapse
|
|
47
|
Ichikawa K, Kirino Y, Kunishita Y, Kishimoto D, Takase-Minegishi K, Yoshimi R, Nakajima H. Initial hydroxychloroquine monotherapy in systemic lupus erythematosus: report of three cases. Mod Rheumatol Case Rep 2021; 5:259-264. [PMID: 33533686 DOI: 10.1080/24725625.2021.1881215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Glucocorticoids (GCs) use is associated with increased organ damage in systemic lupus erythematosus (SLE), and the treatment goal is to stop their use. Treatment with hydroxychloroquine (HCQ) without daily GCs may benefit patients by minimising the cumulative dose of GCs, but clinical experience with HCQ monotherapy is limited. To accumulate evidence for initial HCQ monotherapy in SLE, we retrospectively analysed three new SLE patients who visited Yokohama City University Hospital in 2015. The patients were all Japanese females with a mean age of 26.0 ± 5.3 years, high anti-dsDNA antibody titres, no major organ damage, and a mean pre-treatment Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 9.3 ± 3.1. During the mean observation period of 3.8 ± 0.8 years, none of them received daily GCs or immunosuppressants, but one of the three patients were treated with short-term oral GCs and NSAIDs for a skin rash or arthralgia flairs. SLEDAI-2K was reduced to 3.3 ± 1.2. No other new SLE symptoms emerged, and the Systemic Lupus International Collaborating Clinics Damage Index (SDI) of them were maintained at 0. None of the patients developed HCQ-related retinal toxicity. Current experience with initial HCQ monotherapy suggests that such a therapeutic strategy may be useful in managing disease activity and preserving cumulative GCs in SLE patients without organ involvements.
Collapse
Affiliation(s)
- Kento Ichikawa
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yohei Kirino
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yosuke Kunishita
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Daiga Kishimoto
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kaoru Takase-Minegishi
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryusuke Yoshimi
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideaki Nakajima
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| |
Collapse
|
|
48
|
Devaux CA, Camoin-Jau L, Mege JL, Raoult D. Can hydroxychloroquine be protective against COVID-19-associated thrombotic events ? JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2021; 54:37-45. [PMID: 33500211 PMCID: PMC7783458 DOI: 10.1016/j.jmii.2020.12.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/15/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023]
Abstract
Although SARS-CoV-2 is considered a lung-tropic virus, severe COVID-19 is not just a viral pulmonary infection, clinically it is a multi-organ pathology with major coagulation abnormalities and thromboembolism events. Recently, antiphospholipid (aPL) antibodies were found increased in a large number of COVID-19 patients. Elevated aPL have been well documented in antiphospholipid syndrome (APS), a systemic autoimmune disorder characterized by recurrent venous or arterial thrombosis and/or obstetrical morbidity. Among treatment regimen of APS, hydroxychloroquine (HCQ) is one of the molecules proposed in the primary prevention of thrombosis and obstetrical morbidity in those patients. Due to its antithrombotic properties documented in APS therapy, HCQ could be considered a good candidate for the prevention of thrombotic events in COVID-19 patients in association with anticoagulant and its repurposing deserves further evaluation.
Collapse
Affiliation(s)
- Christian A Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; CNRS, Marseille, France.
| | - Laurence Camoin-Jau
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; Laboratoire D'Hématologie, Hôpital de La Timone, APHM, Boulevard Jean- Moulin, 13005, Marseille, France
| | - Jean-Louis Mege
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| |
Collapse
|
|
49
|
Rosina S, Chighizola CB, Ravelli A, Cimaz R. Pediatric Antiphospholipid Syndrome: from Pathogenesis to Clinical Management. Curr Rheumatol Rep 2021; 23:10. [PMID: 33511497 PMCID: PMC7843475 DOI: 10.1007/s11926-020-00976-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW Elucidating the pathogenic mechanisms mediated by antiphospholipid antibodies (aPL) might exert important clinical implications in pediatric antiphospholipid syndrome (APS). RECENT FINDINGS aPL are traditionally regarded as the main pathogenic players in APS, inducing thrombosis via the interaction with fluid-phase and cellular components of coagulation. Recent APS research has focused on the role of β2 glycoprotein I, which bridges innate immunity and coagulation. In pediatric populations, aPL should be screened in appropriate clinical settings, such as thrombosis, multiple-organ dysfunction, or concomitant systemic autoimmune diseases. Children positive for aPL tests often present non-thrombotic non-criteria manifestations or asymptomatic aPL positivity. In utero aPL exposure has been suggested to result in developmental disabilities, warranting long-term follow-up. The knowledge of the multifaceted nature of pediatric APS should be implemented to reduce the risk of underdiagnosing/undertreating this condition. Hopefully, recent pathogenic insights will open new windows of opportunity in the management of pediatric APS.
Collapse
Affiliation(s)
- Silvia Rosina
- Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Cecilia Beatrice Chighizola
- Experimental Laboratory of Immunological and Rheumatologic Researches, Immunology and Rheumatology Unit, San Luca Hospital, IRCCS Istituto Auxologico Italiano, Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy.
| | - Angelo Ravelli
- Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy.,University of Genoa, Genoa, Italy.,Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Rolando Cimaz
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.,RECAP_RD, University of Milan, Milan, Italy.,Pediatric Rheumatology Unit, ASST G. Pini & CTO, Milan, Italy
| |
Collapse
|
|
50
|
Dima A, Jurcut C, Arnaud L. Hydroxychloroquine in systemic and autoimmune diseases: Where are we now? Joint Bone Spine 2021; 88:105143. [PMID: 33515791 DOI: 10.1016/j.jbspin.2021.105143] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/23/2020] [Indexed: 12/28/2022]
Abstract
Hydroxychloroquine (HCQ), one of the oldest drugs used in rheumatology, came recently into attention as one of the potential therapies tested for the severe acute respiratory syndrome coronavirus-2 disease treatment. Used initially as an antimalarial, then translated to rheumatic diseases, HCQ has been used in a wide range of pathologies, including infectious diseases, immune disorders, diabetes, dyslipidemia, or neoplasia. Regarding systemic diseases, HCQ is the mainstay treatment for systemic lupus erythematosus (SLE), where, according to last European guidelines, it is proposed to all SLE patients unless contraindicated or with side effects. HCQ proved positive impact in SLE on robust outcomes, such as accrual damage, disease activity and survival, but also pleiomorphic effects, including decrease in the need for glucocorticoids, reduction in the risk of neonatal lupus, lower fasting glucose and protection against diabetes, thrombotic risk, dyslipidemia, infections, etc. Moreover, HCQ can be used during pregnancy and breast-feeding. Besides SLE, the role for HCQ in the anti-phospholipid syndrome and Sjögren's disease is still under debate. On the contrary, recent advances showed only limited interest for rheumatoid arthritis, especially due the lack of structural damage prevention. There are still no strong data to sustain the HCQ use in other systemic diseases. In this review, we summarised the utility and efficacy of HCQ in different clinical conditions relevant for rheumatology practice.
Collapse
Affiliation(s)
- Alina Dima
- Department of rheumatology, Colentina clinical hospital, 020125 Bucharest, Romania
| | - Ciprian Jurcut
- Department of internal medicine, Dr. Carol Davila Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Laurent Arnaud
- National reference centre for rare auto-immune and systemic diseases Est Sud-Est (RESO), 67000 Strasbourg, France; Department of rheumatology, hôpitaux universitaires de Strasbourg, 67098 Strasbourg, France; Université de Strasbourg, Inserm UMR-S 1109, 67000 Strasbourg, France.
| |
Collapse
|