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Stockfelt M, Teng YKO, Vital EM. Opportunities and limitations of B cell depletion approaches in SLE. Nat Rev Rheumatol 2025; 21:111-126. [PMID: 39815102 DOI: 10.1038/s41584-024-01210-9] [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: 12/05/2024] [Indexed: 01/18/2025]
Abstract
B cell depletion with rituximab, a chimeric monoclonal antibody that selectively targets B cells by binding CD20, has been used off label in severe and resistant systemic lupus erythematosus (SLE) for over two decades. Several biological mechanisms limit the efficacy of rituximab, including immunological reactions towards the chimeric molecule, increased numbers of residual B cells, including plasmablasts and plasma cells, and a post-treatment surge in B cell-activating factor (BAFF) levels. Consequently, rituximab induces remission in only a proportion of patients, and safety issues limit its use. However, the use of rituximab has established the value of B cell depletion strategies in SLE and has guided the development of several improved B cell depletion therapies for SLE. These include enhanced monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway. In this Review, we consider evidence gathered from over two decades of using rituximab in SLE and examine how B cell depletion therapies could be further optimized to achieve immunological and clinical efficacy. In addition, we discuss the prospects of B cell depletion strategies for personalized treatment in SLE based on genetic research and studies in pre-symptomatic individuals.
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Affiliation(s)
- Marit Stockfelt
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Y K Onno Teng
- Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - Edward M Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
- NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
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Roveta A, Parodi EL, Brezzi B, Tunesi F, Zanetti V, Merlotti G, Francese A, Maconi AG, Quaglia M. Lupus Nephritis from Pathogenesis to New Therapies: An Update. Int J Mol Sci 2024; 25:8981. [PMID: 39201667 PMCID: PMC11354900 DOI: 10.3390/ijms25168981] [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: 07/11/2024] [Revised: 08/03/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
Lupus Nephritis (LN) still represents one of the most severe complications of Systemic Lupus Erythematosus (SLE) and a major risk factor for morbidity and mortality. However, over the last few years, several studies have paved the way for a deeper understanding of its pathogenetic mechanisms and more targeted treatments. This review aims to provide a comprehensive update on progress on several key aspects in this setting: pathogenetic mechanisms of LN, including new insight into the role of autoantibodies, complement, vitamin D deficiency, and interaction between infiltrating immune cells and kidney resident ones; the evolving role of renal biopsy and biomarkers, which may integrate information from renal histology; newly approved drugs such as voclosporin (VOC) and belimumab (BEL), allowing a more articulate strategy for induction therapy, and other promising phase III-immunosuppressive (IS) agents in the pipeline. Several adjunctive treatments aimed at reducing cardiovascular risk and progression of chronic renal damage, such as antiproteinuric agents, represent an important complement to IS therapy. Furthermore, non-pharmacological measures concerning general lifestyle and diet should also be adopted when managing LN. Integrating these therapeutic areas requires an effort towards a holistic and multidisciplinary approach. At the same time, the availability of an increasingly wider armamentarium may translate into improvements in patient's renal outcomes over the next decades.
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Affiliation(s)
- Annalisa Roveta
- Research and Innovation Department (DAIRI), “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (A.R.); (A.F.); (A.G.M.)
| | - Emanuele Luigi Parodi
- Nephrology and Dialysis Unit, “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (E.L.P.); (B.B.)
| | - Brigida Brezzi
- Nephrology and Dialysis Unit, “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (E.L.P.); (B.B.)
| | - Francesca Tunesi
- Nephrology and Dialysis Unit, IRCCS “San Raffaele” Scientific Institute, 20132 Milan, Italy;
| | - Valentina Zanetti
- Department of Internal Medicine, University of Genova, 16126 Genoa, Italy;
| | - Guido Merlotti
- Department of Primary Care, Azienda Socio Sanitaria Territoriale (ASST) of Pavia, 27100 Pavia, Italy;
| | - Alessia Francese
- Research and Innovation Department (DAIRI), “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (A.R.); (A.F.); (A.G.M.)
| | - Antonio G. Maconi
- Research and Innovation Department (DAIRI), “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (A.R.); (A.F.); (A.G.M.)
| | - Marco Quaglia
- Nephrology and Dialysis Unit, “SS Antonio e Biagio e Cesare Arrigo” University Hospital, 15121 Alessandria, Italy; (E.L.P.); (B.B.)
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
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Zisa D, Zhang-Sun J, Christos PJ, Kirou KA. Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares. Lupus 2024; 33:938-947. [PMID: 38860319 PMCID: PMC11326872 DOI: 10.1177/09612033241260283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2024]
Abstract
OBJECTIVE To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). METHODS We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. RESULTS There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. CONCLUSION Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.
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Affiliation(s)
- Diane Zisa
- Columbia University Irving Medical Center, New York, NY, USA
| | | | | | - Kyriakos A Kirou
- Hospital for Special Surgery, New York, NY, USA
- Weill Cornell Medicine, New York, NY, USA
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Alee I, Chantawichitwong P, Leelahavanichkul A, Paludan SR, Pisitkun T, Pisitkun P. The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice. Sci Rep 2024; 14:11020. [PMID: 38745067 PMCID: PMC11094069 DOI: 10.1038/s41598-024-61597-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 05/07/2024] [Indexed: 05/16/2024] Open
Abstract
The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1β and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.
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Affiliation(s)
- Isara Alee
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Papasara Chantawichitwong
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Graduated Program in Molecular Medicine, Faculty of Science, Mahidol University, Salaya, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Søren R Paludan
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Trairak Pisitkun
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Prapaporn Pisitkun
- Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
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Liu M, Xu X, Fan S, Ren H, Zhao Y, Guan H. Mycophenolate mofetil reduces the risk of relapse in anti-leucine-rich glioma-inactivated protein 1 encephalitis: a prospective observational cohort study. Neurol Sci 2024; 45:253-260. [PMID: 37580515 DOI: 10.1007/s10072-023-06968-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/18/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Mycophenolate mofetil (MMF) is frequently used in the treatment of neurological autoimmune disorders. However, its effect on the relapse risk in anti-leucine-rich glioma-inactivated protein 1 (anti-LGI1) encephalitis is not well studied. METHODS In this prospective observational cohort study, anti-LGI1 encephalitis patients were grouped according to MMF treatment status (MMF and non-MMF groups). The primary outcome was relapse after disease onset. RESULTS A total of 83 patients were included, with a median onset age of 60 years. Fifty-four patients were men (65.1%). The MMF group comprised 28 patients and the non-MMF group comprised 55. Median follow-up from symptom onset was 26 months. Relapse occurred in 43 patients (51.8%). Median modified Rankin scale (mRS) score at enrollment was significantly higher in the MMF group than the non-MMF group (3 vs. 2; p = 0.001). Median mRS score at last follow-up was comparable between groups (1 vs. zero; p = 0.184). Both MMF treatment (HR 0.463; 95% CI, 0.231-0.929; p = 0.030) and cognitive impairment at enrollment (HR 3.391; 95% CI, 1.041-11.044; p = 0.043) were independent predictors of relapse. Starting immunotherapy before development of cognitive impairment trended towards reducing relapse risk. Outcome at last follow-up was good (mRS score 0-2) in all patients except for one in the non-MMF group. Adverse events associated with MMF treatment were mild and transient. CONCLUSION Although the outcome of anti-LGI1 encephalitis patients is generally favorable, relapse is common, especially in those with cognitive impairment. MMF treatment is well-tolerated and can significantly reduce the risk of relapse.
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Affiliation(s)
- Mange Liu
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaolu Xu
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Siyuan Fan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Ren
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanhuan Zhao
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongzhi Guan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Xipell M, Lledó GM, Egan AC, Tamirou F, Del Castillo CS, Rovira J, Gómez-Puerta JA, García-Herrera A, Cervera R, Kronbichler A, Jayne DRW, Anders HJ, Houssiau F, Espinosa G, Quintana LF. From systemic lupus erythematosus to lupus nephritis: The evolving road to targeted therapies. Autoimmun Rev 2023; 22:103404. [PMID: 37543287 DOI: 10.1016/j.autrev.2023.103404] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.
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Affiliation(s)
- Marc Xipell
- Department of Nephrology and Renal Transplantation, Clinic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Gema M Lledó
- Department of Autoimmune Diseases, Clínic Barcelona, Spain; Reference Center for Systemic Autoimmune Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Allyson C Egan
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, United Kingdom
| | - Farah Tamirou
- Rheumatology Department, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Belgium
| | | | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José A Gómez-Puerta
- Department of Rheumatology, Clínic Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain
| | - Adriana García-Herrera
- Department of Pathology, Clínic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ricard Cervera
- Department of Autoimmune Diseases, Clínic Barcelona, Spain
| | - Andreas Kronbichler
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - David R W Jayne
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Frédéric Houssiau
- Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, United Kingdom
| | - Gerard Espinosa
- Department of Autoimmune Diseases, Clínic Barcelona, Spain; Reference Center for Systemic Autoimmune Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
| | - Luis F Quintana
- Department of Nephrology and Renal Transplantation, Clinic Barcelona, Spain; Reference Center for Complex Glomerular Diseases of the Spanish Health System (CSUR), Department of Medicine, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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Parodis I, Long X, Karlsson MCI, Huang X. B Cell Tolerance and Targeted Therapies in SLE. J Clin Med 2023; 12:6268. [PMID: 37834911 PMCID: PMC10573616 DOI: 10.3390/jcm12196268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/02/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease of high clinical and molecular heterogeneity, and a relapsing-remitting pattern. The disease is currently without cure and more prevalent in women. B cell tolerance and production of autoantibodies are critical mechanisms that drive SLE pathophysiology. However, how the balance of the immune system is broken and how the innate and adaptive immune systems are interacting during lupus-specific autoimmune responses are still largely unknown. Here, we review the latest knowledge on B cell development, maturation, and central versus peripheral tolerance in connection to SLE and treatment options. We also discuss the regulation of B cells by conventional T cells, granulocytes, and unconventional T cells, and how effector B cells exert their functions in SLE. We also discuss mechanisms of action of B cell-targeted therapies, as well as possible future directions based on current knowledge of B cell biology.
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Affiliation(s)
- Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, 17177 Stockholm, Sweden;
- Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, 17176 Stockholm, Sweden
- Department of Rheumatology, Faculty of Medicine and Health, Örebro University, 70281 Örebro, Sweden
| | - Xuan Long
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha 410011, China;
| | - Mikael C. I. Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
| | - Xin Huang
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha 410011, China;
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Athanassiou P, Athanassiou L. Current Treatment Approach, Emerging Therapies and New Horizons in Systemic Lupus Erythematosus. Life (Basel) 2023; 13:1496. [PMID: 37511872 PMCID: PMC10381582 DOI: 10.3390/life13071496] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/18/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine should be administered to every lupus patient irrespective of organ involvement. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporine and tacrolimus. However, despite conventional immunosuppressive treatment, flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression and increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent, has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor-targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.
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Affiliation(s)
| | - Lambros Athanassiou
- Department of Rheumatology, Asclepeion Hospital, Voula, GR16673 Athens, Greece
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9
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Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study. Eur J Pediatr 2022; 181:3439-3448. [PMID: 35834043 DOI: 10.1007/s00431-022-04560-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/03/2022]
Abstract
UNLABELLED Mycophenolate mofetil (MMF) is an immunosuppressive drug used for the treatment of autoimmune rheumatological diseases. To test the risk of hypothetical drug-induced hypogammaglobulinemia, the aim of this study was to report the trend of the immunoglobulin (Ig) values and of the infectious diseases in children treated with MMF. This study retrospectively evaluated demographic, clinical, and laboratory data of a cohort of patients affected by a chronic rheumatic disease receiving MMF, followed at the Rheumatology Unit of Meyer Children Hospital, Florence. A total of 29 pediatric patients were enrolled. In patients with normal values of immunoglobulins at the baseline, treatment with MMF resulted in a statistically significant reduction of the IgG levels (p = 0.0058) and in a decrease of IgM levels not reaching statistical significance. The levels of IgA were not affected. During the follow-up, seven patients developed an humoral immune defect. The univariate analysis did not identify any risk factors related to the iatrogenic hypogammaglobulinemia. The infection rate during MMF therapy was significantly higher than the 12-month period before therapy (p = 0.006), while the severe infections did not significantly increase (p = 0.1818), even considering only the patients with hypogammaglobulinemia. CONCLUSION In pediatric patients with chronic rheumatic diseases, immunological first level tests and serological analyses to screen the protection against the common childhood pathogens are suggested before starting an immunosuppressive drug. These patients should also complete the vaccination schedule. In patients treated with MMF a strict monitoring of Ig is required during treatment and after discontinuation of the drug. WHAT IS KNOWN • MMF is an immunosuppressive drug initially used for the treatment of the graft-versus-host disease. • Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase, expressed in lymphocytes; therefore, MMF could impair the immune system function. WHAT IS NEW • MMF resulted in a reduction of IgG and an increase of not severe infection rate. • Immunological first level tests, including Ig, lymphocyte subpopulations, and antibody response to vaccines, are suggested in pediatric patients before starting MMF; a strict monitoring of Ig is important before, during, and after MMF treatment.
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10
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Abraham R, Durkee MS, Ai J, Veselits M, Casella G, Asano Y, Chang A, Ko K, Oshinsky C, Peninger E, Giger ML, Clark MR. Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis. J Clin Invest 2022; 132:e155350. [PMID: 35608910 PMCID: PMC9246394 DOI: 10.1172/jci155350] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 05/19/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUNDIn human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts.METHODSData were acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep-learning models and other computer vision techniques.RESULTSHigh B cell densities were associated with protection from ESRD. In contrast, high densities of CD8+, γδ, and other CD4-CD8- T cells were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with Tfh cells, while CD4- T cells formed small neighborhoods in the tubulointerstitium, with frequency that predicted progression to ESRD.CONCLUSIONThese data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease.FUNDINGThis study was funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083), Alliance for Lupus Research, and NIH awards (S10-OD025081, S10-RR021039, and P30-CA14599).
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Affiliation(s)
- Rebecca Abraham
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | - Madeleine S. Durkee
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
- Department of Radiology, and
| | - Junting Ai
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | - Margaret Veselits
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | - Gabriel Casella
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
- Department of Radiology, and
| | - Yuta Asano
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Kichul Ko
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | - Charles Oshinsky
- Division of Rheumatology, University of Washington, Seattle, Washington, USA
| | - Emily Peninger
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
| | | | - Marcus R. Clark
- Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research
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11
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Assassi S, Volkmann ER, Zheng WJ, Wang X, Wilhalme H, Lyons MA, Roth MD, Tashkin DP. Peripheral blood gene expression profiling shows predictive significance for response to mycophenolate in systemic sclerosis-related interstitial lung disease. Ann Rheum Dis 2022; 81:854-860. [PMID: 35190386 PMCID: PMC9117450 DOI: 10.1136/annrheumdis-2021-221313] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 02/01/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To characterise the peripheral blood cell (PBC) gene expression changes ensuing from mycophenolate mofetil (MMF) or cyclophosphamide (CYC) treatment and to determine the predictive significance of baseline PBC transcript scores for response to immunosuppression in systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS PBC RNA samples from baseline and 12-month visits, corresponding to the active treatment period of both arms in Scleroderma Lung Study II, were investigated by global RNA sequencing. Joint models were created to examine the predictive significance of baseline composite modular scores for the course of forced vital capacity (FVC) per cent predicted measurements from 3 to 12 months. RESULTS 134 patients with SSc-ILD (CYC=69 and MMF=65) were investigated. CYC led to an upregulation of erythropoiesis, inflammation and myeloid lineage-related modules and a downregulation of lymphoid lineage-related modules. The modular changes resulting from MMF treatment were more modest and included a downregulation of plasmablast module. In the longitudinal analysis, none of the baseline transcript module scores showed predictive significance for FVC% course in the CYC arm. In contrast, in the MMF arm, higher baseline lymphoid lineage modules predicted better subsequent FVC% course, while higher baseline myeloid lineage and inflammation modules predicted worse subsequent FVC% course. CONCLUSION Consistent with the primary mechanism of action of MMF on lymphocytes, patients with SSc-ILD with higher baseline lymphoid module scores had better FVC% course, while those with higher myeloid cell lineage activation score had poorer FVC% course on MMF.
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Affiliation(s)
- Shervin Assassi
- Rheumatology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | | | - W Jim Zheng
- School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Xuan Wang
- Baylor Institute for Immunology Research, Dallas, Texas, USA
| | - Holly Wilhalme
- Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Marka A Lyons
- Rheumatology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Michael D Roth
- Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Donald P Tashkin
- Medicine, University of California Los Angeles, Los Angeles, California, USA
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12
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Revisited Cyclophosphamide in the Treatment of Lupus Nephritis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8345737. [PMID: 35707391 PMCID: PMC9192236 DOI: 10.1155/2022/8345737] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/09/2022] [Indexed: 11/18/2022]
Abstract
Lupus nephritis (LN) is the most common serious complication of systemic lupus erythematosus (SLE). The pathogenesis of LN is complex, and the majority causes of LN are the renal deposition of circulating or/and in situ-formed immune complexes. These immune complexes trigger glomerular and tubulointerstitial inflammation, which finally leads to proteinuria and loss of renal function. Despite the emergence of new biological agents, cyclophosphamide (CY), an alkylating agent, is still the first-line drug widely used to treat patients with severe LN. In this review, we outline the application history, molecular structure, and pharmacokinetics of CY in the treatment of LN. We also detail its latest known immunopharmacological mechanisms, with a focus on supplemental regulation and inhibition of CD4 and CD8 positive T cells, differences in the use of various guidelines, and the combination with other drugs. The side effects of CY are also mentioned in this review.
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13
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Saharia KK, Husson JS, Niederhaus SV, Iraguha T, Avila SV, Yoo YJ, Hardy NM, Fan X, Omili D, Crane A, Carrier A, Xie WY, Vander Mause E, Hankey K, Bauman S, Lesho P, Mannuel HD, Ahuja A, Mathew M, Avruch J, Baddley J, Goloubeva O, Shetty K, Dahiya S, Rapoport AP, Luetkens T, Atanackovic D. Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine. Clin Transl Immunology 2022; 11:e1391. [PMID: 35505864 PMCID: PMC9052011 DOI: 10.1002/cti2.1391] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives Solid organ transplant recipients (SOTR) receiving post‐transplant immunosuppression show increased COVID‐19‐related mortality. It is unclear whether an additional dose of COVID‐19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants. Methods We analysed humoral immune responses against SARS‐CoV‐2 and its variants in 53 SOTR receiving SARS‐CoV‐2 vaccination. Results Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine‐induced IgG/IgA antibody titres against SARS‐CoV‐2 and its delta variants and fewer linear B‐cell epitopes, indicating reduced B‐cell diversity. Importantly, a third vaccine dose led to an increase in anti‐SARS‐CoV‐2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti‐SARS‐CoV‐2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS‐CoV‐2 and the improvement in neutralising activity was much less pronounced than for all the other variants. Conclusion Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS‐CoV‐2 variants except omicron where antibody responses and neutralising activity remained suboptimal.
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Affiliation(s)
- Kapil K Saharia
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD USA.,Divison of Infectious Diseases University of Maryland School of Medicine Baltimore MD USA
| | - Jennifer S Husson
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD USA.,Divison of Infectious Diseases University of Maryland School of Medicine Baltimore MD USA
| | - Silke V Niederhaus
- Department of Surgery University of Maryland School of Medicine Baltimore MD USA
| | - Thierry Iraguha
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Stephanie V Avila
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Youngchae J Yoo
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD USA
| | - Nancy M Hardy
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Xiaoxuan Fan
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA
| | - Destiny Omili
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Alice Crane
- Department of Surgery University of Maryland School of Medicine Baltimore MD USA
| | - Amber Carrier
- Department of Surgery University of Maryland School of Medicine Baltimore MD USA
| | - Wen Y Xie
- University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA.,Department of Surgery University of Florida College of Medicine Gainesville FL USA
| | - Erica Vander Mause
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Kim Hankey
- Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Sherri Bauman
- Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Patricia Lesho
- Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Heather D Mannuel
- University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA.,Baltimore Veterans Affairs Medical Center Baltimore MD USA
| | - Ashish Ahuja
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA
| | - Minu Mathew
- Divison of Infectious Diseases University of Maryland School of Medicine Baltimore MD USA
| | - James Avruch
- Department of Surgery University of Maryland School of Medicine Baltimore MD USA
| | - John Baddley
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD USA.,Divison of Infectious Diseases University of Maryland School of Medicine Baltimore MD USA.,University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Olga Goloubeva
- Department of Epidemiology and Public Health University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Kirti Shetty
- Division of Hepatology/Liver Transplantation University of Maryland School of Medicine Baltimore MD USA
| | - Saurabh Dahiya
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Aaron P Rapoport
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA
| | - Tim Luetkens
- Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA.,Department of Microbiology and Immunology University of Maryland Baltimore MD USA
| | - Djordje Atanackovic
- Department of Medicine University of Maryland School of Medicine Baltimore MD USA.,Transplant and Cellular Therapy Program University of Maryland Greenebaum Comprehensive Cancer Center Baltimore MD USA.,Department of Microbiology and Immunology University of Maryland Baltimore MD USA
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14
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Novel treatment strategies for acetylcholine receptor antibody-positive myasthenia gravis and related disorders. Autoimmun Rev 2022; 21:103104. [PMID: 35452851 DOI: 10.1016/j.autrev.2022.103104] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/18/2022] [Indexed: 11/21/2022]
Abstract
The presence of autoantibodies directed against the muscle nicotinic acetylcholine receptor (AChR) is the most common cause of myasthenia gravis (MG). These antibodies damage the postsynaptic membrane of the neuromuscular junction and cause muscle weakness by depleting AChRs and thus impairing synaptic transmission. As one of the best-characterized antibody-mediated autoimmune diseases, AChR-MG has often served as a reference model for other autoimmune disorders. Classical pharmacological treatments, including broad-spectrum immunosuppressive drugs, are effective in many patients. However, complete remission cannot be achieved in all patients, and 10% of patients do not respond to currently used therapies. This may be attributed to production of autoantibodies by long-lived plasma cells which are resistant to conventional immunosuppressive drugs. Hence, novel therapies specifically targeting plasma cells might be a suitable therapeutic approach for selected patients. Additionally, in order to reduce side effects of broad-spectrum immunosuppression, targeted immunotherapies and symptomatic treatments will be required. This review presents established therapies as well as novel therapeutic approaches for MG and related conditions, with a focus on AChR-MG.
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15
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Hussenbocus YAAM, Jin Z, Pan W, Liu L, Wu M, Hu H, Ding X, Wei H, Zou Y, Qian X, Wang M, Wu J, Tao J, Tan J, Da Z, Zhang M, Li J, Feng X, Sun L. Low dosage use of cyclophosphamide improves the survival of patients with systemic lupus erythematosus. Clin Rheumatol 2022; 41:2043-2052. [PMID: 35230560 DOI: 10.1007/s10067-022-06117-y] [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: 08/12/2021] [Revised: 12/28/2021] [Accepted: 02/22/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the effect of cyclophosphamide (CYC) on organ involvement and SLE patients' overall and cause-specific mortality. METHODS Information about CYC prescription was taken from the Jiangsu Lupus database, which was set up to collect medical records from SLE patients since their first admission during 1999-2009 in Jiangsu province, China. Follow-up studies were carried out in 2010 and 2015 to check the survival status of the patients. Cox regression models were used to estimate the hazard ratio (HR) and 95% CI. Kaplan-Meier model was used to assess the effect of CYC on mortality between organ involvement and non-involvement. RESULTS There were 221 deaths observed out of 2446 SLE patients. CYC users decreased overall mortality of SLE (8.4%) with adjusted HR (95% CI) of 0.74 (0.56-0.97), as compared to non-users. A decrease in overall mortality of SLE was found in the low dosage (< 600 mg) of CYC users, with adjusted HR (95% CI) of 0.54 (0.36-0.81). The protection of CYC on mortality of SLE was further observed in subgroups, such as female; SLEDAI score ≥ 15 group; and those with neuropsychiatric, renal, and hematological involvements, and low serum C3. In addition, CYC could eliminate the differences in mortality between organ involvement and non-involvement, including renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological involvement, but not for mucocutaneous and musculoskeletal involvement. CONCLUSION Low dosage use of CYC decreased the risk of overall mortality of SLE. CYC might improve the survival of SLE patients with renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological involvements. Key Points • Cyclophosphamide decreases overall mortality of SLE patients. • Decreased mortality is mainly observed from low dosage use of cyclophosphamide. • Cyclophosphamide improves the survival of SLE patients when major systems such as renal, neuropsychiatric, cardiopulmonary, gastrointestinal, and hematological are involved.
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Affiliation(s)
| | - Ziyi Jin
- Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
| | - Wenyou Pan
- Department of Rheumatology, Huai'an First People's Hospital, Huai'an, China
| | - Lin Liu
- Department of Rheumatology, Xuzhou Central Hospital, Xuzhou, China
| | - Min Wu
- Department of Rheumatology, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Huaixia Hu
- Department of Rheumatology, Lianyungang Second People's Hospital, Lianyungang, China
| | - Xiang Ding
- Department of Rheumatology, Lianyungang First People's Hospital, Lianyungang, China
| | - Hua Wei
- Department of Rheumatology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Yaohong Zou
- Department of Rheumatology, Wuxi People's Hospital, Wuxi, China
| | - Xian Qian
- Department of Rheumatology, Jiangsu Province Hospital of TCM, Nanjing, China
| | - Meimei Wang
- Department of Rheumatology, Southeast University Zhongda Hospital, Nanjing, China
| | - Jian Wu
- Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Juan Tao
- Department of Rheumatology, Wuxi TCM Hospital, Wuxi, China
| | - Jun Tan
- Department of Rheumatology, Zhenjiang First People's Hospital, Zhenjiang, China
| | - Zhanyun Da
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Miaojia Zhang
- Department of Rheumatology, Jiangsu Province Hospital, Nanjing, China
| | - Jing Li
- Department of Rheumatology, Affiliated Hospital of Jiangsu University, Jiangsu, China
| | - Xuebing Feng
- Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Lingyun Sun
- Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China. .,Department of Rheumatology and Immunology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
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16
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Schuller M, Pfeifer V, Kirsch AH, Klötzer KA, Mooslechner AA, Rosenkranz AR, Stiegler P, Schemmer P, Sourij H, Eller P, Prietl B, Eller K. B Cell Composition Is Altered After Kidney Transplantation and Transitional B Cells Correlate With SARS-CoV-2 Vaccination Response. Front Med (Lausanne) 2022; 9:818882. [PMID: 35187002 PMCID: PMC8847739 DOI: 10.3389/fmed.2022.818882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The COVID-19 pandemic has major implications on kidney transplant recipients (KTRs) since they show increased mortality due to impaired immune responses to SARS-CoV-2 infection and a reduced efficacy of SARS-CoV-2 vaccination. Surprisingly, dialysis patients have shown superior seroconversion rates after vaccination compared to KTRs. Therefore, we investigated peripheral blood B cell (BC) composition before and after kidney transplantation (KT) and aimed to screen the BC compartment to explain impaired antibody generation. METHODS A total of 105 patients were recruited, and multicolor flow cytometric phenotyping of peripheral venous blood BC subpopulations was performed before and 1 year after KT. Complete follow-up was available for 71 individuals. Anti-SARS-CoV-2 antibodies were collected retrospectively and were available for 40 subjects, who had received two doses of an mRNA-based vaccine (BNT162b2 or mRNA-1273). RESULTS Overall, relative BC frequencies within lymphocytes decreased, and their absolute counts trended in the same direction 1 year after KT as compared to CKD G5 patients. Frequencies and absolute numbers of naïve BCs remained stable. Frequencies of double negative BCs, a heterogeneous subpopulation of antigen experienced BCs lacking CD27 expression, were increased after KT, yet their absolute counts were similar at both time points. Transitional BCs (TrBCs) and plasmablasts were significantly reduced after KT in absolute and relative terms. Memory BCs were affected differently since class-switched and IgM-only subsets decreased after KT, but unswitched and IgD-only memory BCs remained unchanged. CD86+ and CD5+ expression on BCs was downregulated after KT. Correlational analysis revealed that TrBCs were the only subset to correlate with titer levels after SARS-CoV-2 vaccination. Responders showed higher TrBCs, both absolute and relative, than non-responders. CONCLUSION Together, after 1 year, KTRs showed persistent and profound compositional changes within the BC compartment. Low TrBCs, 1 year after KT, may account for the low serological response to SARS-CoV-2 vaccination in KTRs compared to dialysis patients. Our findings need confirmation in further studies as they may guide vaccination strategies.
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Affiliation(s)
- Max Schuller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Verena Pfeifer
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander H. Kirsch
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Konstantin A. Klötzer
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Agnes A. Mooslechner
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander R. Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Philipp Stiegler
- General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Philipp Eller
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Barbara Prietl
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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17
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Macher S, Bsteh G, Berger T, Höftberger R. Diagnostic approach and treatment regimens in adult patients suffering from antibody-mediated or paraneoplastic encephalitis. Curr Pharm Des 2022; 28:454-467. [PMID: 35100954 DOI: 10.2174/1381612828666220131093259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 12/17/2021] [Indexed: 11/22/2022]
Abstract
Identification of patients with antibody-mediated encephalitis poses a diagnostic challenge and any delay in that respect will increase the interval until initiation of immunotherapy and may negatively affect the patient´s clinical outcome. Within this review we focus on therapeutic strategies in antibody-mediated encephalitis and propose how to proceed with patients, who are suspected to have encephalitis of unknown origin. We further briefly outline differences in treatment of paraneoplastic and antibody-mediated encephalitis according to its pathomechanisms.
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Affiliation(s)
- Stefan Macher
- Department of Neurology, Medical University of Vienna, Vienna, Austria; 2 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Gabriel Bsteh
- Department of Neurology, Medical University of Vienna, Vienna, Austria; 2 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Thomas Berger
- Department of Neurology, Medical University of Vienna, Vienna, Austria; 2 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
| | - Romana Höftberger
- Department of Neurology, Medical University of Vienna, Vienna, Austria; 2 Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria
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18
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Alamilla-Sanchez ME, Alcala-Salgado MA, Alonso-Bello CD, Fonseca-Gonzalez GT. Mechanism of Action and Efficacy of Immunosupressors in Lupus Nephritis. Int J Nephrol Renovasc Dis 2021; 14:441-458. [PMID: 34924767 PMCID: PMC8675090 DOI: 10.2147/ijnrd.s335371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Approximately 70% of the patients with systemic lupus erythematosus will have clinical evidence of kidney damage during their evolution. Patients with impaired renal function at onset and those with recurrent flares have a poor prognosis. Understanding the mechanism of action of immunosuppressants is essential for proper prescription. Steroids inhibit the DNA sequence that promotes the release of inflammatory cytokines. Phosphoramide mustard, metabolite of cyclophosphamide, cross-link with the DNA, causing the aggregation of an alkyl group, causing cell death. Mycophenolate inhibits inosine monophosphate dehydrogenase, prevents de novo synthesis of guanine, inducing cell arrest in S phase. Azathioprine blocks the synthesis of purines and induces apoptosis. Calcineurin inhibitors prevent the dephosphorylation of NFAT and reduce the production of interleukin 2. Antimalarials alter the enzymatic release of lysosomes by increasing intravesicular pH. The mechanism of action of rituximab is related to complement-dependent cytotoxicity and the elimination of anti-CD20-labeled B cells. Progress in the knowledge and management of low doses of steroids may change the current paradigm and reduce the frequency of related adverse events. Mycophenolate seems to be a better choice than cyclophosphamide for induction, it is also preferred over azathioprine as a maintenance immunosuppressive agent, although azathioprine is preferred in women with a desire for conception, those pregnant, or with low resources. For treatment-resistant cases, tacrolimus, rituximab or belimumab may be effective. Ongoing clinical trials with new drugs offer promising results.
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Affiliation(s)
| | | | - Cesar D Alonso-Bello
- Department of Immunology, Centro Medico Nacional “20 de Noviembre”, Mexico City, Mexico
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19
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Chan SCW, Lau CS. Systemic Lupus Erythematosus and Immunodeficiency. RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2021; 2:131-138. [PMID: 36465072 PMCID: PMC9524792 DOI: 10.2478/rir-2021-0019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 06/17/2023]
Abstract
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease caused by a combination of genetic, epigenetic, and environmental factors. Recent advances in genetic analysis coupled with better understanding of different immune regulatory and signaling pathways have revealed the complex relationship between autoimmunity, including SLE, and immunodeficiency. Furthermore, the expanding therapeutic armamentarium has led to the increasing awareness of secondary immunodeficiency in these patients. This article serves to update the current understanding of SLE and immunodeficiency by discussing the shared genetic factors and immunobiology. We also summarize the effects of immunosuppressive therapies with a focus on secondary antibody deficiency (SAD) after B-cell targeted therapies.
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Affiliation(s)
- Shirley Chiu Wai Chan
- Department of Medicine, Division of Rheumatology and Clinical Immunology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Chak Sing Lau
- Department of Medicine, Division of Rheumatology and Clinical Immunology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
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20
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Atisha-Fregoso Y, Toz B, Diamond B. Meant to B: B cells as a therapeutic target in systemic lupus erythematosus. J Clin Invest 2021; 131:149095. [PMID: 34128474 PMCID: PMC8203443 DOI: 10.1172/jci149095] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell-activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted.
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Affiliation(s)
- Yemil Atisha-Fregoso
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, New York, USA
| | - Bahtiyar Toz
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, New York, USA
| | - Betty Diamond
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
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21
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Differential efficacy of mycophenolate mofetil in adults with relapsing myelin oligodendrocyte glycoprotein antibody-associated disorders. Mult Scler Relat Disord 2021; 53:103035. [PMID: 34077831 DOI: 10.1016/j.msard.2021.103035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/08/2021] [Accepted: 05/12/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Myelin oligodendrocyte glycoprotein-immunoglobulin (MOG-IgG) associated disorder (MOGAD) has been recognized as a distinct disease entity with recurrent attacks. But the standard therapeutic approach to reduce relapses is unknown. Different doses of mycophenolate mofetil (MMF) are frequently used in MOGAD. We aimed to investigate the response to stratified doses of MMF in adult patients with MOGAD. METHODS We determined the frequency of relapses in patients receiving various doses of MMF treatment for MOGAD. Patients were reviewed for relapses before and during long-term treatment. Cox proportional hazards models were used to analyze the correlation between the MMF dosage and the annualized relapse rate (ARR) as well as clinical features. RESULTS 22 patients receiving low-dose MMF (< 1000 mg/day), 19 patients receiving moderate-dose MMF (1000 mg/day ≤ MMF dose < 2000 mg/day) and 21 patients receiving high-dose MMF (≥ 2000 mg/day) were collected in our cohort. Cox regression analysis showed that high-dose MMF treatment significantly reduced the risk of relapses (HR 0.501 [95% CI 0.268-0.934], p = 0.030) compared with low-dose and moderate-dose of MMF treatment, after adjusted by age, gender, disease duration and prednisone therapy. Patients (13/62) concomitant with autoimmune diseases, had a higher proportion of relapses (76.92%) compared with those without autoimmune diseases (18.37%) (HR = 5.96, 95% CI 1.73-20.48, p < 0.001). The overall median ARR reduced from 1.13 to 0.32 under high-dose MMF treatment (p = 0.004). However, there was no significant reduction in ARR either in patients with low-dose or those with moderate-dose of MMF. CONCLUSION This study suggests that high-dose of MMF treatment may reduce recurrent demyelinating attacks, with the lowest ARR. Randomized controlled studies are required to validate the effective therapeutic regimen.
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van Dam LS, Osmani Z, Kamerling SWA, Kraaij T, Bakker JA, Scherer HU, Rabelink TJ, Voll RE, Alexander T, Isenberg DA, van Kooten C, Teng YKO. A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE. Rheumatology (Oxford) 2021; 59:2734-2745. [PMID: 31951278 PMCID: PMC7516125 DOI: 10.1093/rheumatology/kez623] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/21/2019] [Indexed: 02/06/2023] Open
Abstract
Objectives SLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell–targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation. Methods Autoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation. Results Reductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ. Conclusion This study demonstrated the impact of different B cell–targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.
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Affiliation(s)
| | | | | | | | - Jaap A Bakker
- Department of Clinical Chemistry and Laboratory Medicine
| | - Hans U Scherer
- Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands
| | | | - Reinhard E Voll
- Department of Rheumatology and Clinical Immunology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany
| | - David A Isenberg
- Centre for Rheumatology, Division of Medicine, University College London, London, UK
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B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders. Pharmaceuticals (Basel) 2021; 14:ph14010037. [PMID: 33419217 PMCID: PMC7825598 DOI: 10.3390/ph14010037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/02/2021] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.
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A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome. Pediatr Nephrol 2021; 36:1175-1182. [PMID: 33118048 PMCID: PMC7594934 DOI: 10.1007/s00467-020-04811-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 09/18/2020] [Accepted: 10/02/2020] [Indexed: 11/15/2022]
Abstract
BACKGROUND Steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80% experiencing at least one relapse after first flare. B cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B cell recovery, possibly due to development of autoreactive long-lived plasma cells. We investigated sequential combination of antiCD20 antibody targeting all B cell subsets, and antiCD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of one or several attempts at B cell depletion. METHODS Fourteen patients with median disease duration 7.8 years received 1000 mg/1.73 m2 obinutuzumab followed by 1000 mg/1.73 m2 daratumumab 2 weeks later. Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B cell recovery. RESULTS Median age at treatment was 11.0 [IQR 10.4-14.4] years. B cell depletion was achieved in all patients, and B cell reconstitution occurred in all at median 9.5 months after obinutuzumab injection. After median follow-up 20.3 months (IQR 11.5-22.6), 5/14 patients relapsed including 4 within 100 days following B cell repletion. Relapse-free survival was 60% at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500-1000/mm3) occurred in 2/14 patients. Intravenous immunoglobulins were given to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. CONCLUSION Global antiB cell strategy combining obinutuzumab and daratumumab induces prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS.
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Xiong ZH, Cao XS, Guan HL, Zheng HL. Immunotherapies application in active stage of systemic lupus erythematosus in pregnancy: A case report and review of literature. World J Clin Cases 2020; 8:6396-6407. [PMID: 33392323 PMCID: PMC7760451 DOI: 10.12998/wjcc.v8.i24.6396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/27/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Pregnancy in the setting of systemic lupus erythematosus can worsen the condition from the stable to active stage, with quality of life and fertility desire being particular concerns. Pregnancy in the active stage of systemic lupus erythematosus (ASLE), although rare and complicated to manage, can be treated favorably with immunotherapies ifs used properly. Here we report such a success case.
CASE SUMMARY A 31-year-old primigravida patient, diagnosed with SLE seven years ago, was induced ASLE after a cold at 21 + weeks. The patient’s vital signs on presentation were normal. Her laboratory exam was remarkable for significant proteinuria, liver and renal dysfunction, and low C3 and C4 levels. Infectious work-up was negative. The patient was diagnosed with ASLE. She was given immunosuppressive agents (methylprednisolone, gamma globulin and azathioprine etc.) and plasma adsorption therapy, monitoring blood pressure every 8 h, fetal heart rate twice a day, and liver and renal function at least twice a week. Successful maternal and fetal outcomes are presented here.
CONCLUSION Child-bearing in ASLE has become more promising, even for this difficult case of ASLE with multiple organ damage. Thorough antepartum counseling, cautious maternal-fetal monitoring, and multi-organ function monitoring by multidisciplinary specialties are keys to favorable pregnancy outcomes.
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Affiliation(s)
- Zhi-Hui Xiong
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Xiao-Song Cao
- Department of Medical Clinic, Lanxi No. 5 Middle School, Lanxi 321100, Zhejiang Province, China
| | - Hai-Lian Guan
- Department of Obstetrics, Tongde Hospital of Zhejiang Province, Hangzhou 310012, Zhejiang Province, China
| | - Hui-Ling Zheng
- Department of Obstetrics, The Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou 310005, Zhejiang Province, China
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Skin-Associated B Cells in the Pathogenesis of Cutaneous Autoimmune Diseases-Implications for Therapeutic Approaches. Cells 2020; 9:cells9122627. [PMID: 33297481 PMCID: PMC7762338 DOI: 10.3390/cells9122627] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/01/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022] Open
Abstract
B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).
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Peter HH, Ochs HD, Cunningham-Rundles C, Vinh DC, Kiessling P, Greve B, Jolles S. Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations. J Allergy Clin Immunol 2020; 146:479-491.e5. [PMID: 32896308 PMCID: PMC7471860 DOI: 10.1016/j.jaci.2020.07.016] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 02/08/2023]
Abstract
The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.
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Affiliation(s)
- Hans-Hartmut Peter
- Freiburg University Hospital, Centre for Chronic Immunodeficiency, Freiburg, Germany
| | - Hans D Ochs
- Seattle Children's Research Institute, Seattle, Wash; Department of Pediatrics, University of Washington, Seattle, Wash
| | | | - Donald C Vinh
- Division of Infectious Diseases, Department of Medicine and Department of Medical Microbiology, McGill University Health Centre, Montreal, Quebec, Canada; Infectious Diseases & Immunity in Global Health Program, Research Institute-McGill University Health Centre, Montreal, Quebec, Canada
| | | | | | - Stephen Jolles
- Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.
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Differential Effects of MS Therapeutics on B Cells-Implications for Their Use and Failure in AQP4-Positive NMOSD Patients. Int J Mol Sci 2020; 21:ijms21145021. [PMID: 32708663 PMCID: PMC7404039 DOI: 10.3390/ijms21145021] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/11/2020] [Accepted: 07/13/2020] [Indexed: 12/25/2022] Open
Abstract
B cells are considered major contributors to multiple sclerosis (MS) pathophysiology. While lately approved disease-modifying drugs like ocrelizumab deplete B cells directly, most MS medications were not primarily designed to target B cells. Here, we review the current understanding how approved MS medications affect peripheral B lymphocytes in humans. These highly contrasting effects are of substantial importance when considering these drugs as therapy for neuromyelitis optica spectrum disorders (NMOSD), a frequent differential diagnosis to MS, which is considered being a primarily B cell- and antibody-driven diseases. Data indicates that MS medications, which deplete B cells or induce an anti-inflammatory phenotype of the remaining ones, were effective and safe in aquaporin-4 antibody positive NMOSD. In contrast, drugs such as natalizumab and interferon-β, which lead to activation and accumulation of B cells in the peripheral blood, lack efficacy or even induce catastrophic disease activity in NMOSD. Hence, we conclude that the differential effect of MS drugs on B cells is one potential parameter determining the therapeutic efficacy or failure in antibody-dependent diseases like seropositive NMOSD.
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JIANG Y, ZHANG Q, WANG H, TANG D, ZHANG Y, Yimo, ZHANG, YU L. Expressions of IFN-γ and IL-4 before and after Treatment of Lupus Nephritis with Traditional Chinese Medicine Combined with Cyclophosphamide and Their Values for Efficacy Prediction and Evaluation. IRANIAN JOURNAL OF PUBLIC HEALTH 2020; 49:886-895. [PMID: 32953676 PMCID: PMC7475630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
BACKGROUND To explore IFN-γ (interferon-γ) and IL-4 (interleukin-4) expressions before and after the treatment of LN (lupus nephritis) and their values for efficacy prediction and evaluation. METHODS Altogether 107 patients with LN treated in the First Hospital of Qiqihaer City, Qiqihar, China from March 2017 to September 2018 were enrolled. Sixty-two patients were treated with cyclophosphamide and prednisolone (control group), while another 45 patients were treated with Qing Shen Fang based on the control group (observation group). Their clinical efficacy and changes in immune indices after treatment were observed. RESULTS Compared with those in the control group, clinical efficacy, IFN-γ, IL-4, hemoglobin, complements C3 and C4, ESR (erythrocyte sedimentation rate), serum IgG, SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, and TCMSSS (Traditional Chinese Medicine Syndrome Score Scale) score were significantly improved after treatment in the study group. Based on the observation, IFN-γ and IL-4 could be used as potential indicators for evaluating clinical efficacy. CONCLUSION The combination of cyclophosphamide, prednisolone, and Qing Shen Fang improves conditions of patients with LN and significantly reduces their IFN-γ and IL-4 levels in serum. IFN-γ and IL-4 can be used as potential indicators for the efficacy prediction and evaluation of the disease.
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Affiliation(s)
- Yan JIANG
- Department of Traditional Chinese Medicine, The First Hospital of Qiqihar City, Qiqihar City 161000, China
| | - Qichang ZHANG
- Department of Traditional Chinese Medicine, The First Hospital of Qiqihar City, Qiqihar City 161000, China
| | - Haoyu WANG
- Department of Basic Science of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin City 150040, China
| | - Dabei TANG
- Department of Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin City 150040, China
| | - Yan ZHANG
- Department of Nephrology, The Second Affiliated Hospital of Qiqihar Medical College, Qiqihar City 161006, China
| | | | - ZHANG
- Department of Nephrology, Qiqihar Traditional Chinese Medicine Hospital, Qiqihar City 161006, China
| | - Li YU
- Department of Traditional Chinese Medicine, The First Hospital of Qiqihar City, Qiqihar City 161000, China,Corresponding Author:
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Antibody signatures in patients with histopathologically defined multiple sclerosis patterns. Acta Neuropathol 2020; 139:547-564. [PMID: 31950335 PMCID: PMC7035238 DOI: 10.1007/s00401-019-02120-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/20/2019] [Accepted: 12/22/2019] [Indexed: 12/15/2022]
Abstract
Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I–III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló’s concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló’s), healthy controls, patients with Sjögren’s syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló’s, AQP1 reactivity was also significantly higher compared to patients without Baló’s (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló’s patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló’s patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.
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Laisuan W, Pisitkun P, Ngamjanyaporn P, Suangtamai T, Rotjanapan P. Prospective Pilot Study of Cyclophosphamide as an Adjunct Treatment in Patients With Adult-Onset Immunodeficiency Associated With Anti-interferon-γ Autoantibodies. Open Forum Infect Dis 2020; 7:ofaa035. [PMID: 32099846 PMCID: PMC7029682 DOI: 10.1093/ofid/ofaa035] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/27/2020] [Indexed: 11/12/2022] Open
Abstract
Background Adult-onset immunodeficiency associated with interferon-γ autoantibody (IGA) is an emerging disease. The majority of patients require both antimicrobial and immunosuppressive treatments. However, anti-CD20 therapy is not fully accessible in a resource-limited setting to date. Background The objectives of this work were to study the efficacy of cyclophosphamide treatment and the role of laboratory biomarkers for disease progression monitoring. Methods A prospective pilot cohort study was conducted among patients with anti-interferon-γ autoantibodies (IGA) who had recurrent infections and required long-term antimicrobial therapy between 2015 and 2018. The patients were categorized into 2 groups: receipt of intravenous cyclophosphamide (IVCY) and receipt of anti-CD20 therapy (RTX). Clinical and laboratory data were determined. Results A total of 17 IGA patients were enrolled. Prolonged fever was the most common manifestation, and the most common infection identified was nontuberculous mycobacterial infections. Both were found in 88.24% of all patients.After completion of IVCY, 9/11 patients achieved complete remission and tended to reach remission faster compared with individuals in the RTX group. The median duration from treatment initiation to remission (interquartile range) was 84 (42-154) days in the IVCY group and 99 (51-202) days in the RTX group. In remission patients, the biomarkers of interest had normalized after treatment, except interferon γ autoantibody titers. There were no differences in adverse events among the 2 groups. Conclusion IVCY may be considered as alternative therapy in this population, especially in resource-limited countries. A comparable clinical outcome to RTX may support its use on a larger scale. However, further study is encouraged.
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Affiliation(s)
- Wannada Laisuan
- Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Prapaporn Pisitkun
- Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pintip Ngamjanyaporn
- Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanitta Suangtamai
- Division of Allergy Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Porpon Rotjanapan
- Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis-Role in Pathogenesis and Effect of Immunosuppressive Treatments. Int J Mol Sci 2019; 20:ijms20246231. [PMID: 31835612 PMCID: PMC6940927 DOI: 10.3390/ijms20246231] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/19/2022] Open
Abstract
Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.
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Gabcova G, Horak P, Mikulkova Z, Skacelova M, Zehnalova S, Smrzova A, Petrackova A, Mrazek F, Kriegova E. Modulatory Effect of the Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen on Circulating Immune Cells in Systemic Lupus Erythematosus. Arch Immunol Ther Exp (Warsz) 2019; 67:415-425. [PMID: 31620814 DOI: 10.1007/s00005-019-00563-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 09/28/2019] [Indexed: 12/26/2022]
Abstract
A Euro-Lupus regimen of low-dose intravenous cyclophosphamide (CFA) is commonly used to treat severe organ manifestations of systemic lupus erythematosus (SLE), particularly lupus nephritis (LN). There are no data on the distributions and dynamics of immune cell populations in patients with various treatment outcomes. The circulating immune cells of 11 female SLE patients were assessed before and after Euro-Lupus regimen (cumulative dose of 3000 mg CFA) by flow cytometry together with those of 16 healthy women. A subanalysis was performed in LN patients who achieved complete remission (CR; n = 3), partial remission (PR; n = 4), and no response (NR; n = 2). In SLE, the Euro-Lupus regimen decreased the percentage and absolute count of B cells; increased the percentage of CD8+ T cells, T regulatory cells, neutrophils, and monocyte subsets; and activated T and NK cells compared to healthy controls (P < 0.050). Patients with LN achieving CR had significantly lower proportions of CD27+ B memory cells compared to poor responders (PR/NR, P = 0.035). The post-treatment percentages and absolute numbers of B cells, T cells, NK cells, monocytes, and neutrophils showed high inter-individual variability with no association with treatment outcome. Our pilot study revealed the dynamics of changes in immune cell populations in SLE patients during a Euro-Lupus regimen, mainly the lowering of B cells. In LN patients who achieved CR, a lower proportion of CD27+ B memory cells was evident compared to poor responders (PR/NR). Further studies on usefulness of monitoring immune cells for treatment response prediction on larger cohorts are needed.
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Affiliation(s)
- Gabriela Gabcova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Hnevotinska 3, 775 15, Olomouc, Czech Republic
| | - Pavel Horak
- Department of Internal Medicine III-Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic
| | - Zuzana Mikulkova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Hnevotinska 3, 775 15, Olomouc, Czech Republic
| | - Martina Skacelova
- Department of Internal Medicine III-Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic
| | - Sarka Zehnalova
- Department of Computer Science, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, Ostrava, Czech Republic
| | - Andrea Smrzova
- Department of Internal Medicine III-Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic
| | - Anna Petrackova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Hnevotinska 3, 775 15, Olomouc, Czech Republic
| | - Frantisek Mrazek
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Hnevotinska 3, 775 15, Olomouc, Czech Republic
| | - Eva Kriegova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacký University Olomouc, University Hospital Olomouc, Hnevotinska 3, 775 15, Olomouc, Czech Republic.
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Baker D, Jacobs BM, Gnanapavan S, Schmierer K, Giovannoni G. Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis. Mult Scler Relat Disord 2019; 35:19-25. [PMID: 31279232 DOI: 10.1016/j.msard.2019.06.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 06/10/2019] [Accepted: 06/25/2019] [Indexed: 12/15/2022]
Abstract
There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.
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Affiliation(s)
- David Baker
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom.
| | - Benjamin M Jacobs
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom
| | - Sharmilee Gnanapavan
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom; Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom
| | - Klaus Schmierer
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom; Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom
| | - Gavin Giovannoni
- BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom; Clinical Board:Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom
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35
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Cytometric Characterization of Main Immunocompetent Cells in Patients with Systemic Sclerosis: Relationship with Disease Activity and Type of Immunosuppressive Treatment. J Clin Med 2019; 8:jcm8050625. [PMID: 31071980 PMCID: PMC6571868 DOI: 10.3390/jcm8050625] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 05/05/2019] [Indexed: 12/17/2022] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disease that is characterized by widespread skin and internal organ fibrosis vasculopathy and immune response abnormalities, including T, B, natural killer (NK), and natural killer T (NKT) cell involvement. The aim of the study was to investigate the immune cell profile in patients with systemic sclerosis in relation to the disease activity, severity, and antibody presence and their relation to the type of immunosuppressive treatment. Cytometric examination identified following cell lines: B cells (Breg, B memory, B mature) and plasmablasts, T cell, T double positive—Tdp, T double negative—Tdn, NK, and NKT cell and monocytes. The disease severity and activity were assessed based on the Medsger and the EULAR Scleroderma Trials and Research Group (EUSTAR) 2017 scales respectively. In the study, SSc patients were characterized by higher total lymphocyte count parallel to increased frequency of Ts and Th cells. In SSc patients, increment of Tdp and reduction of Tdn as well as NK and NKT cells were observed. Additionally in SSc patients the reduction of B memory was noted. Head to head comparison between cyclophosphamide (CYC) and mycophenolate mofetil (MMF) treatment showed a reduction of CD19+ cells, but increment of plasmablasts in CYC treated patients.
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36
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Patel SY, Carbone J, Jolles S. The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management. Front Immunol 2019; 10:33. [PMID: 30800120 PMCID: PMC6376447 DOI: 10.3389/fimmu.2019.00033] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 01/08/2019] [Indexed: 12/11/2022] Open
Abstract
Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.
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Affiliation(s)
- Smita Y. Patel
- Clinical Immunology Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Javier Carbone
- Clinical Immunology Department, Hospital General Universitario Gregorio Marañon, Madrid, Spain
| | - Stephen Jolles
- Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
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Slight-Webb S, Guthridge JM, Chakravarty EF, Chen H, Lu R, Macwana S, Bean K, Maecker HT, Utz PJ, James JA. Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients. JCI Insight 2019; 4:124575. [PMID: 30674728 DOI: 10.1172/jci.insight.124575] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 12/11/2018] [Indexed: 11/17/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF-) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4+ Th17-type and CD4+ Treg-type cells, compared with MMF- patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.
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Affiliation(s)
- Samantha Slight-Webb
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Joel M Guthridge
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Eliza F Chakravarty
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Hua Chen
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Rufei Lu
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Susan Macwana
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Krista Bean
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | | | - Paul J Utz
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
| | - Judith A James
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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Nishimura H, Yamada Y, Hisano S, Mitsuke A, Tatarano S, Gotanda T, Hayami H, Nakagawa M, Enokida H. Long-term desensitization for ABO-incompatible living related kidney transplantation recipients with high refractory and rebound anti-blood type antibody: case report. BMC Nephrol 2018; 19:254. [PMID: 30290778 PMCID: PMC6173835 DOI: 10.1186/s12882-018-1053-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 09/20/2018] [Indexed: 12/28/2022] Open
Abstract
Background ABO-incompatible living related kidney transplantation (ABO-iLKT) has increased the possibilities for kidney transplantation in patients with end stage renal disease. Due to advancements in immunosuppressive agents and the identification of immunological conditions following ABO-iLKT, this transplantation technique has achieved the same success rate as ABO-compatible LKT. However, some patients continue to generate anti-blood type antibodies, despite conventional immunosuppressant treatment. Case presentation A 60-year-old man was referred to our hospital for kidney transplantation. The proposed transplant was ABO incompatible, from a donor with blood-type A to a recipient with blood-type O. The recipient’s anti-A blood-type IgG antibody titer was measured at 4096-fold dilution. Following desensitization therapy, including mycophenolate mofetil (MMF) 750 mg/day for 3 months, intravenous Rituximab 200 mg, and two sessions of double filtration plasmapheresis, the anti-A blood-type IgG antibody titer decreased to only 516-fold dilution and did not meet our target of less than 128-fold dilution. MMF was thus continued for an additional 4 months and four additional sessions of plasmapheresis were undertaken. Following these interventions, antibody titers decreased to 128-fold dilution and ABO-iLKT was performed. Following transplant, antibody-mediated rejection was not observed and renal function was preserved. However, a post-operative renal biopsy 1.5 months later showed evidence of T-cell-mediated rejection IB. The patient was treated with steroids, with no increase in serum creatinine. Conclusion Our findings suggest that the long-term single MMF desensitization therapy could be a suitable option for ABO-iLKT with high refractory and rebound anti-blood type antibody. Further studies are required to establish the optimal immunosuppression regimen to control B cell- mediated immunity in ABO-iLKT.
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Affiliation(s)
- Hiroaki Nishimura
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yasutoshi Yamada
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Satoshi Hisano
- Department of Pathology, Fukuoka University school of Medicine, Fukuoka, Japan
| | - Akihiko Mitsuke
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Syuichi Tatarano
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Takenari Gotanda
- Department of Urology, Kagoshima City Hospital, Kagoshima, Japan
| | - Hiroshi Hayami
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Masayuki Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Hideki Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
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Nawata T, Kubo M, Fujii S, Shiragami K, Ikegami T, Kobayashi S, Hisano S, Yano M. Treatment of Class IV Lupus Nephritis with Mycophenolate Mofetil Monotherapy. Intern Med 2018; 57:2067-2070. [PMID: 29491296 PMCID: PMC6096032 DOI: 10.2169/internalmedicine.0304-17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Lupus nephritis (LN) occurs in up to 60% of systemic lupus erythematosus patients. Combination therapy involving a corticosteroid and cyclophosphamide or mycophenolate mofetil (MMF) has been a standard therapy for LN. However, clinicians generally prefer to minimize steroid use in LN treatment. We herein report the case of a Japanese man with LN whose severe chronic heart failure prevented us from using steroid therapy. Instead, his LN was successfully treated with MMF monotherapy. Based on our experience with this case, we suggest that MMF monotherapy may represent a feasible LN treatment option in patients who cannot tolerate steroid therapy.
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Affiliation(s)
- Takashi Nawata
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Makoto Kubo
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Shohei Fujii
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Kosaku Shiragami
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Tadayoshi Ikegami
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Shigeki Kobayashi
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
| | - Satoshi Hisano
- Department of Pathology, Faculty of Medicine Fukuoka University, Japan
| | - Masafumi Yano
- Department of Medicine and Clinical Science, Division of Cardiology and Clinical Immunology, Yamaguchi University Graduate School of Medicine, Japan
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40
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Park HY, Oh MJ, Kim Y, Choi I. Immunomodulatory activities of Corchorus olitorius leaf extract: Beneficial effects in macrophage and NK cell activation immunosuppressed mice. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.05.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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41
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Piper CJM, Wilkinson MGL, Deakin CT, Otto GW, Dowle S, Duurland CL, Adams S, Marasco E, Rosser EC, Radziszewska A, Carsetti R, Ioannou Y, Beales PL, Kelberman D, Isenberg DA, Mauri C, Nistala K, Wedderburn LR. CD19 +CD24 hiCD38 hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α. Front Immunol 2018; 9:1372. [PMID: 29988398 PMCID: PMC6024011 DOI: 10.3389/fimmu.2018.01372] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 06/04/2018] [Indexed: 01/12/2023] Open
Abstract
Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40–CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.
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Affiliation(s)
| | - Meredyth G Ll Wilkinson
- Centre for Rheumatology, University College London, London, United Kingdom.,Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
| | - Claire T Deakin
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom.,Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom.,NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
| | - Georg W Otto
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.,Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Stefanie Dowle
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.,Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Chantal L Duurland
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Stuart Adams
- Haematology, Specialist Integrated Haematological Malignancy Diagnostic Service (SIHMDS), Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Emiliano Marasco
- B Cell Physiopathology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy
| | - Elizabeth C Rosser
- Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Anna Radziszewska
- Centre for Rheumatology, University College London, London, United Kingdom.,Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
| | - Rita Carsetti
- B Cell Physiopathology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy
| | - Yiannis Ioannou
- Centre for Rheumatology, University College London, London, United Kingdom.,Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
| | - Philip L Beales
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.,Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Daniel Kelberman
- NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.,Experimental and Personalised Medicine, Genetics and Genomic Medicine, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom
| | - David A Isenberg
- Centre for Rheumatology, University College London, London, United Kingdom.,Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom
| | - Claudia Mauri
- Centre for Rheumatology, University College London, London, United Kingdom
| | - Kiran Nistala
- Centre for Rheumatology, University College London, London, United Kingdom
| | - Lucy R Wedderburn
- Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom.,Infection, Inflammation and Rheumatology Section, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom.,NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom
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42
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Immunology of idiopathic nephrotic syndrome. Pediatr Nephrol 2018; 33:573-584. [PMID: 28451893 DOI: 10.1007/s00467-017-3677-5] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/05/2017] [Accepted: 04/07/2017] [Indexed: 12/18/2022]
Abstract
The pathogenesis of idiopathic nephrotic syndrome (INS) is as yet unknown, but several lines of evidence indicate that the immune system may play a crucial pathogenic role in non-genetic INS. The most important of these are, first, the effectiveness of therapy based on immunosuppression and, second, a vast body of data derived both from experimental models and from patient studies that implicate T cells and more recently B cells as major players in INS pathogenesis. However, recent findings also suggest a direct role of podocytes as drivers of the disease process, and the interplay between the glomerulus and the immune system is still being elucidated. In this review we provide an overview of current knowledge on the role of different components of the immune system in determining disease. Advances in our understanding of the pathogenesis of INS may help drive new, more tailored therapeutic approaches.
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Gheita TA, Abaza NM, Hammam N, Mohamed AAA, El-Gazzar II, Eissa AH. Anti-dsDNA titre in female systemic lupus erythematosus patients: relation to disease manifestations, damage and antiphospholipid antibodies. Lupus 2018; 27:1081-1087. [PMID: 29460701 DOI: 10.1177/0961203318760209] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Attempts are ongoing to unveil unresolved queries about anti-double-stranded deoxyribonucleic acid (anti-dsDNA), their precise pathogenic effects and to what extent blocking them would be a useful therapeutic goal. Objectives The aim of the present study was to determine the anti-dsDNA antibodies titre in systemic lupus erythematosus (SLE) patients and investigate their relation to the disease characteristics, activity, damage and antiphospholipid autoantibodies (aPL). Methods Seventy female SLE patients and 35 age- and sex-matched controls were included. The anti-dsDNA level and aPL were measured. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) were assessed. Results The mean age of the patients was 27.5 ± 5.1 years, disease duration 7.7 ± 5.4 years, and SLEDAI and SLICC/ACR-DI scores were 6.8 ± 8.04 and 1.2 ± 1.3, respectively. Anti-dsDNA was positive in 61.4% of the patients and the titre (133.2 ± 100.5 IU/ml) was significantly higher compared to controls (22.03 ± 17.2 IU/ml) ( p < 0.0001). The anti-dsDNA level was significantly increased in those with musculoskeletal manifestations ( p = 0.007) and positive anti-β2 glycoprotein (anti-β2GP) ( p = 0.037) and decreased in those with neuropsychiatric manifestations ( p = 0.004) and those receiving cyclophosphamide (CYC) ( p = 0.013). The anti-dsDNA level tended to be higher in active patients. The anti-dsDNA titre significantly correlated with the erythrocyte sedimentation rate ( p = 0.001), anticardiolipin IgG and IgA antibodies ( p = 0.008) and anti-β2GP IgG ( p = 0.03) and IgA ( p = 0.002) and inversely with the total leucocytic count ( p < 0.0001) and SLICC/ACR-DI ( p = 0.001). Conclusion Anti-dsDNA is remarkably increased in SLE patients especially those with musculoskeletal manifestations and aPL. A protective role seems likely in those with neuropsychiatric manifestations and those receiving CYC and may form a shield against disease tissue damage.
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Affiliation(s)
- T A Gheita
- 1 Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - N M Abaza
- 2 Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - N Hammam
- 3 Rheumatology and Rehabilitation Department, Faculty of Medicine, Assuit University, Assiut, Egypt.,4 Faculty of Rehabilitation, University of Alberta, Edmonton, Alberta, Canada
| | - A A A Mohamed
- 3 Rheumatology and Rehabilitation Department, Faculty of Medicine, Assuit University, Assiut, Egypt
| | - I I El-Gazzar
- 1 Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - A H Eissa
- 5 Clinical Pathology (Immunology) Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Schrezenmeier E, Jayne D, Dörner T. Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives. J Am Soc Nephrol 2018; 29:741-758. [PMID: 29326157 DOI: 10.1681/asn.2017040367] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The unique contributions of memory B cells and plasma cells in kidney diseases remain unclear. In this review, we evaluate the clinical experience with treatments directed at B cells, such as rituximab, and at plasma cells, such as proteasome inhibition, to shed light on the role of these two B lineage compartments in glomerular diseases. Specifically, analysis of these targeted interventions in diseases such as ANCA-associated vasculitis, SLE, and antibody-mediated transplant rejection permits insight into the pathogenetic effect of these cells. Notwithstanding the limitations of preclinical models and clinical studies (heterogeneous populations, among others), the data suggest that memory B and plasma cells represent two engines of autoimmunity, with variable involvement in these diseases. Whereas memory B cells and plasma cells appear to be key in ANCA-associated vasculitis and antibody-mediated transplant rejection, respectively, SLE seems likely to be driven by both autoimmune compartments. These conclusions have implications for the future development of targeted therapeutics in immune-mediated renal disease.
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Affiliation(s)
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Thomas Dörner
- Rheumatology and Clinical Immunology, Department of Medicine, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; and
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Huang C, Zhang L, Ling F, Wen S, Luo Y, Liu H, Liu J, Zheng W, Liang M, Sun J, Lin YK. Effect of immune tolerance induced by immature dendritic cells and CTLA4-Ig on systemic lupus erythematosus: An in vivo study. Exp Ther Med 2018; 15:2499-2506. [PMID: 29456655 DOI: 10.3892/etm.2018.5697] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 07/27/2017] [Indexed: 11/06/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease in which tissue damage is caused by autoantibodies. The induction of specific immune tolerance, including the utilization of immune regulatory cells, may enhance the therapeutic effects of organ transplantation in patients with SLE. Furthermore, inhibiting immune responses has been reported to be an effective treatment for SLE. However, few studies have explored the association between an increased immune tolerance and a decreased immune response in SLE treatment. Dendritic cells (DCs), which are highly efficient antigen-presenting cells, are able to induce specific tolerance, while cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) inhibits the immune response. In the present study, interleukin (IL)-10-treated DCs and CTLA4-Ig were administered to mice with SLE alone or in combination and the therapeutic effects were investigated. IL-10 was added into the culture medium of bone marrow-derived DCs to prevent them from differentiating into mature cells. Low levels of major histocompatibility complex II, cluster of differentiation (CD)40, CD80 and CD86 were detected, which indicated that the immature state of DCs was maintained. IL-10-treated DCs were subsequently injected into the caudal vein of B6.MRL-Faslpr/J lupus mice, which are an established animal model of SLE. To amplify the tolerance effect, mice were simultaneously injected with CTLA4-Ig. Compared with the IL-10-treated DC and CTLA4-Ig groups, combined treatment with IL-10-treated DCs and CTLA4-Ig strongly induced immune tolerance in mice with SLE, as indicated by the significantly reduced levels of urine protein, anti-nuclear antibody, double-stranded DNA and IL-17A. A significant decrease in the proportion of T helper cells and an increase in the proportion of CD4+ forkhead box protein P3+ Treg cells was also observed, further confirming the induction of immune tolerance. These results suggest that combined treatment with IL-10-DCs and CTLA4-Ig may be a promising novel therapeutic strategy for the treatment of SLE.
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Affiliation(s)
- Cuili Huang
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Lidan Zhang
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Fang Ling
- Department of Cell Biology and Genetics, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Sijian Wen
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yanyan Luo
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Hui Liu
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jingping Liu
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Wenjun Zheng
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Ming Liang
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jian Sun
- Department of Cell Biology and Genetics, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - You-Kun Lin
- Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Fang C, Luo T, Lin L. The correlational research among serum CXCL13 levels, circulating plasmablasts and memory B cells in patients with systemic lupus erythematosus: A STROBE-compliant article. Medicine (Baltimore) 2017; 96:e8675. [PMID: 29310341 PMCID: PMC5728742 DOI: 10.1097/md.0000000000008675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We investigated whether serum CXC ligand 13 protein (CXCL13) levels correlate with the circulating plasmablasts and memory B-cells alteration in systemic lupus erythematosus (SLE) patients. The diagnostic use of CXCL13 concentrations in active lupus was also analyzed.A total of 36 SLE patients and 18 healthy controls were included. Serum CXCL13 levels were examined by enzyme-linked immunosorbent assay. The frequency and absolute count of circulating plasmablasts and memory B cells were analyzed by flow cytometry. Receiver operating characteristic curves (ROC curves) were generated to analyze the utility of serum CXCL13 level and plasmablasts frequency as tools for the recognition of active SLE.Elevation of serum CXCL13 levels, higher plasmablasts frequency, and reduction of memory B-cells count were observed in SLE patients, compared with healthy controls. Interestingly, correlational analyses showed not only significantly positive association between CXCL13 levels and SLE Disease Activity Index (SLEDAI) or plasmablasts frequency, but an inverse correlation between CXCL13 concentration and memory B-cell count. ROC curves showed that serum CXCL13 level and plasmablasts frequency were practical in identifying active disease from overall SLE patients, with considerable accuracy.Serum CXCL13 levels correlate with the alteration of plasmablasts and memory B cells in SLE. CXCL13 may be used as a practical tool in judgment of active SLE.
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Affiliation(s)
| | - Tingting Luo
- Ultrasonic Cardiogram Department, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Davis LS, Reimold AM. Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus. Rheumatology (Oxford) 2017; 56:i100-i113. [PMID: 28375452 DOI: 10.1093/rheumatology/kew417] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Indexed: 12/21/2022] Open
Abstract
This review summarizes traditional and emerging therapies for SLE. Evidence suggests that the heterogeneity of SLE is a crucial aspect contributing to the failure of large clinical trials for new targeted therapies. A clearer understanding of the mechanisms driving disease pathogenesis combined with recent advances in medical science are predicted to enable accelerated progress towards improved SLE diagnosis and personalized approaches to treatment.
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Affiliation(s)
- Laurie S Davis
- Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center
| | - Andreas M Reimold
- Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center.,Dallas VA Medical Center, Dallas, TX, USA
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Taylor EB, Ryan MJ. Immunosuppression With Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Autoimmune Disease. J Am Heart Assoc 2017; 6:JAHA.116.005394. [PMID: 28242635 PMCID: PMC5524041 DOI: 10.1161/jaha.116.005394] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominantly affects women and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Immune system dysfunction is recognized as an important factor in the pathogenesis of hypertension. We recently showed that preventing autoimmunity prevents the development of hypertension in an experimental model of SLE (female NZBWF1 mice). The present study tests the hypothesis that mycophenolate mofetil (MMF), an immunosuppressive therapy used clinically to treat SLE by depleting proliferating B and T lymphocytes, can improve blood pressure control. Methods and Results Female SLE and control (NZW/LacJ) mice were treated daily for 8 weeks with 60 mg/kg MMF. Circulating CD45R+ B cells were lower in MMF‐treated SLE mice after 4 weeks of treatment, but neither CD4+ nor CD8+ T cells were reduced by MMF. Plasma anti–double‐stranded DNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared with controls and were lower in SLE mice after 8 weeks of MMF. Mean arterial pressure was elevated in SLE mice compared with controls and lower in SLE mice treated with MMF compared with vehicle‐treated SLE mice. MMF also reduced both renal injury (urinary albumin excretion and glomerulosclerosis) and the infiltration of CD45R+ B cells and CD3+CD4+ T cells in kidneys from mice with SLE. Conclusions These data suggest that MMF selectively depleted CD45R+ B cells and lowered subsequent autoantibody production, furthering the concept that autoantibodies mechanistically contribute to the pathogenesis of hypertension.
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Affiliation(s)
- Erin B Taylor
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS
| | - Michael J Ryan
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS
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Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder with complex genetic underpinnings. This review attempts to assemble the myriad of genomic findings to build a clearer picture of the pathobiology of SLE to serve as a guide for therapeutics. Over 100 genes are now known for SLE, and several more penetrant ones have led to the emergence of more defined lupus phenotypes. Also discussed here are the targeted therapies that have come up on the horizon and the specific biologic mechanisms of more traditional therapies which have only recently been explored. The diagnostic toolbox has been enhanced by the addition of new antibodies, gene expression signatures, and mutation panels. This provides an opportunity to piece together the lupus puzzle and even revisit the clinical classification of SLE.
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