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Volkova A, Sokolov V, Tettamanti F, Verma M, Ugolkov Y, Peskov K, Tang W, Kimko H. An Integrative Mechanistic Model of Type 1 IFN-Mediated Inflammation in Systemic Lupus Erythematosus. CPT Pharmacometrics Syst Pharmacol 2025. [PMID: 40364448 DOI: 10.1002/psp4.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/09/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Type I interferon (IFN1) pathway-targeting therapies represent a highly promising class of remedies for the treatment of systemic lupus erythematosus. However, the overall clinical benefit of these compounds is afflicted by marked variability. In this study, we developed a quantitative systems pharmacology model of type I IFN-mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient-level data from Phase IIb anifrolumab clinical trial. Within-target and within-pathway validation was performed using study-level pharmacokinetics, IFNα, and/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (< 2.75) and high (≥ 2.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100-150 mg every 4 weeks). In contrast, IFNGS response under 150 mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFNα biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFNα, and IFNα fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (ΔIFNGS~25%), which was further enhanced in patients with high baseline IFNGS or IFNα (ΔIFNGS~50%-60%).
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Affiliation(s)
- Alina Volkova
- Modeling and Simulation Decisions FZ - LLC, Dubai, UAE
- Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences, Moscow, Russia
| | - Victor Sokolov
- Modeling and Simulation Decisions FZ - LLC, Dubai, UAE
- Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences, Moscow, Russia
| | - Florencia Tettamanti
- Systems Medicine, Clinical Pharmacology and Quantitative Pharmacology, R&D BioPharmaceuticals, AstraZeneca, Cambridge, UK
| | - Meghna Verma
- Systems Medicine, Clinical Pharmacology and Quantitative Pharmacology, R&D BioPharmaceuticals, AstraZeneca, Gaithersburg, Maryland, USA
| | - Yaroslav Ugolkov
- Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences, Moscow, Russia
- Research Center of Model-Informed Drug Development, Sechenov First Moscow State Medical University, Moscow, Russia
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Kirill Peskov
- Modeling and Simulation Decisions FZ - LLC, Dubai, UAE
- Marchuk Institute of Numerical Mathematics of the Russian Academy of Sciences, Moscow, Russia
- Research Center of Model-Informed Drug Development, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Weifeng Tang
- Systems Medicine, Clinical Pharmacology and Quantitative Pharmacology, R&D BioPharmaceuticals, AstraZeneca, Gaithersburg, Maryland, USA
| | - Holly Kimko
- Systems Medicine, Clinical Pharmacology and Quantitative Pharmacology, R&D BioPharmaceuticals, AstraZeneca, Gaithersburg, Maryland, USA
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Murat de Montai Q, Masseran C, Perray L, Mathian A, Dorgham K, Gorochov G, Teboul A, Francès C, Arnaud L, Barbaud A, Amoura Z, Charre C, Chasset F. Interferon-α biological activity is associated with disease activity and risk of flare in cutaneous lupus erythematosus: A monocentric study of 184 patients. J Am Acad Dermatol 2025; 92:1039-1048. [PMID: 39855347 DOI: 10.1016/j.jaad.2024.12.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/01/2024] [Accepted: 12/01/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Cutaneous lupus erythematosus (CLE) is associated with unpredictable flares and may induce permanent damage. There is currently no biomarker routinely available in CLE. OBJECTIVE To evaluate the performance of interferon-α (IFN-α) biological activity as biomarker of CLE activity and risk of flare. METHODS Cohort study including consecutive CLE patients with or without associated systemic lupus erythematosus. Serum IFN-α biological activity (IU/mL) was determined by assessing the antiviral protection afforded by patients' serum. RESULTS At first sampling, among 184 included patients, the prevalence of positive IFN-α activity (≥2 IU/mL) was 38%. Positive IFN-α activity was associated with active CLE (odds ratio = 3.11 [95% CI: 1.61-6.01], P = .006), moderate-to-severe CLE activity (odds ratio = 4.43 [95% CI: 1.99-9.86], P = .001) and associated systemic lupus erythematosus (odds ratio = 2.17 [95% CI: 1.19-4.00], P = .01). Among 65 patients with inactive CLE, the risk of CLE flare at 6 months was significantly higher among patients with positive vs undetectable IFN-α activity (hazard ratio 4.95 [95% CI: 1.12-21.78], P = .03). No association was found with anti-double-stranded DNA antibodies and low complement levels. LIMITATIONS IFN-α activity is not universally available. CONCLUSION IFN-α activity is associated with cutaneous activity and prognosis in CLE and can be used to predict CLE flares in clinical practice.
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Affiliation(s)
- Quitterie Murat de Montai
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Clémence Masseran
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Laura Perray
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France; Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (Cimi-Paris), INSERM U1135, Paris, France
| | - Alexis Mathian
- Sorbonne Université, Faculté de médecine, AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Centre national de référence du lupus systémique, du syndrome des antiphospholipides et autres maladies auto-immunes, Service de Médecine Interne 2, Institut E3M, INSERM U1135, Paris, France
| | - Karim Dorgham
- Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (Cimi-Paris), INSERM U1135, Paris, France; Sorbonne Université, Faculté de médecine, AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Centre national de référence du lupus systémique, du syndrome des antiphospholipides et autres maladies auto-immunes, Service de Médecine Interne 2, Institut E3M, INSERM U1135, Paris, France
| | - Guy Gorochov
- Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (Cimi-Paris), INSERM U1135, Paris, France; Sorbonne Université, Faculté de médecine, AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Centre national de référence du lupus systémique, du syndrome des antiphospholipides et autres maladies auto-immunes, Service de Médecine Interne 2, Institut E3M, INSERM U1135, Paris, France; Sorbonne Université, AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France
| | - Alexandre Teboul
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Camille Francès
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Laurent Arnaud
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Centre National de Références des Maladies Systémiques et Auto-immunes Rares Est Sud-Ouest (RESO), Université de Strasbourg, Strasbourg, France
| | - Annick Barbaud
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France
| | - Zahir Amoura
- Sorbonne Université, Faculté de médecine, AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Centre national de référence du lupus systémique, du syndrome des antiphospholipides et autres maladies auto-immunes, Service de Médecine Interne 2, Institut E3M, INSERM U1135, Paris, France
| | - Caroline Charre
- Department of Virology, Hospital Cochin, AP-HP, Paris, France; INSERM U1016, CNRS UMR8104, Université Paris Cité, Institut Cochin, Paris, France
| | - François Chasset
- Sorbonne Université, Faculté de médecine, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, Paris, France; Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (Cimi-Paris), INSERM U1135, Paris, France.
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Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther 2025; 10:102. [PMID: 40097390 PMCID: PMC11914703 DOI: 10.1038/s41392-025-02168-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/26/2024] [Accepted: 01/26/2025] [Indexed: 03/19/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.
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Affiliation(s)
- Xiaofeng Dai
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P. R. China.
| | - Yuting Fan
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China
- Department of Gastroenterology, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, P. R. China
| | - Xing Zhao
- Tissue Engineering and Stem Cell Experiment Center, Tumor Immunotherapy Technology Engineering Research Center, Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, P. R. China.
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Bhatt A, Gupta P, Furie R, Vashistha H. A focused report on IFN-1 targeted therapies for lupus erythematosus. Expert Opin Investig Drugs 2025; 34:121-129. [PMID: 40047795 DOI: 10.1080/13543784.2025.2473060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/24/2025] [Indexed: 03/21/2025]
Abstract
INTRODUCTION Patients with Systemic Lupus Erythematosus (SLE) experience varied manifestations and unpredictable flares, complicating treatment and drug development. Despite these challenges, anifrolumab, voclosporin, and belimumab were approved by FDA. These treatments complement, but don't replace, traditional therapies like NSAIDs, corticosteroids, antimalarials, and immunosuppressives. Therefore, there remains an unmet need for more effective medications targeting excessive proinflammatory cytokines in SLE patients. AREAS COVERED This review summarizes the clinical trial outcomes of four upcoming medications targeting cytokine activity: Litifilimab showed a 7-point reduction in CLASI-A in its phase II trial. Daxdilimab was unsuccessful in its phase II trial. Anifrolumab reduced SLE activity in both phase II and III trials. Deucravacitinib decreased disease activity by multiple measures in its phase II trial. EXPERT OPINION High levels of IFN-I (type 1 interferon) are present in most SLE patients, making this pathway an attractive target for drug development. Litifilimab downregulates IFN-I by targeting BDCA2, while dexadilimab targets ILT7 to recruit effector cells, reducing IFN-I production by killing PDCs. Anifrolumab binds to the IFN-I receptor, blocking the activity of all IFN-Is, and deucravacitinib reduces IFN-I by inhibiting TYK2, thereby interfering with downstream signaling. Therapies that target IFN-I represents a promising class of medications for SLE patients.
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Affiliation(s)
- Anushka Bhatt
- Division of Rheumatology, Department of Medicine, Northwell Health, Great Neck, NY, USA
| | - Pramiti Gupta
- McCombs school, University of Texas, Austin, TX, USA
| | - Richard Furie
- Division of Rheumatology, Department of Medicine, Northwell Health, Great Neck, NY, USA
| | - Himanshu Vashistha
- Division of Rheumatology, Department of Medicine, Northwell Health, Great Neck, NY, USA
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Huang X, Hong X, Yang S, Ye L, Yang X, Cui C, Wu Q, Wang W, Huang J, Yang G. Tolerability, safety, and pharmacokinetics of GR1603 injection in healthy subjects: a randomized, double-blind, placebo-controlled single-dose escalation clinical trial. Expert Opin Investig Drugs 2025; 34:89-95. [PMID: 39681526 DOI: 10.1080/13543784.2024.2443756] [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: 09/02/2024] [Revised: 12/02/2024] [Accepted: 12/14/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND GR1603 is a monoclonal antibody targeting the type I interferon receptor. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and pharmacodynamics of GR1603 in healthy volunteers. METHODS Healthy adults (≥18 years old) were enrolled in a placebo control, dose-escalation Phase I clinical trial receiving a single injectable dose of GR1603. Follow-up was 12 weeks. Adverse event (AE) profiles, vital signs, and blood samples were collected for assessment of safety, PK, and expression of type I interferon inducible genes. RESULTS Of the 46 subjects, 44 completed treatment. In the experimental group of 34 subjects (mean age 26.6 years), 30 experienced treatment-emergent adverse events (TEAEs), with a total of 102 occurrences, resulting in an incidence rate of 88.2%. The most commonly reported drug-related AEs were upper respiratory tract infection (17.6%), all of which were ≤ grade 2. GR1603 exhibits non-linear PK in the dose range of 0.1 mg/kg to 9 mg/kg. All samples were negative for anti-drug antibodies before and after dosing. The degrees of IFN gene signature were significantly inhibited in the higher dose groups. CONCLUSION The safety/tolerability, PK and exploratory metrics observed in this study support further clinical development of GR1603. CLINICAL TRIAL REGISTRATION www.chictr.org.cn/searchproj.html identifier is ChiCTR2100045628.
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MESH Headings
- Humans
- Double-Blind Method
- Adult
- Male
- Female
- Young Adult
- Healthy Volunteers
- Dose-Response Relationship, Drug
- Middle Aged
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Follow-Up Studies
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/pharmacokinetics
- Interferon Type I
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Affiliation(s)
- Xin Huang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Hong
- Center for Experimental Medicine, Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuang Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Ye
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoyan Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chang Cui
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Wu
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Wang
- BioPharmaceuticals R&D, Chongqing Genrix Biopharmaceutical Co. Ltd, Chongqing, China
| | - Jie Huang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guoping Yang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- XiangYa School of Pharmaceutical Sciences, Central South University, Changsha, China
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Tumlin J, Rovin B, Anders HJ, Mysler EF, Jayne DR, Takeuchi T, Lindholm C, Weiss G, Sorrentino A, Woollard K, Ferrari N. Targeting the Type I Interferon Pathway in Glomerular Kidney Disease: Rationale and Therapeutic Opportunities. Kidney Int Rep 2025; 10:29-39. [PMID: 39810777 PMCID: PMC11725820 DOI: 10.1016/j.ekir.2024.10.013] [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: 06/27/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 01/16/2025] Open
Abstract
Type I interferons (IFNs) are immunostimulatory molecules that can activate the innate and adaptive immune systems. In cases of immune dysfunction, prolonged activation of the type I IFN pathway has been correlated with kidney tissue damage in a wide range of kidney disorders, such as lupus nephritis (LN) and focal segmental glomerulosclerosis (FSGS). Genetic mutations, such as APOL1 risk variants in conjunction with elevated type I IFN expression, are also associated with higher rates of chronic kidney disease in patients with LN and collapsing FSGS. Long-term activation of the type I IFN pathway can result in chronic inflammation, leading to kidney tissue damage, cell death, and decline in organ function. Thus, therapeutic strategies targeting type I IFN could provide clinical benefits to patients with immune dysregulation who are at risk of developing impaired kidney function. Here, we present a critical review of type I IFN signaling, the consequences of chronically elevated type I IFN expression, and therapeutic strategies targeting type I IFN signaling in the context of kidney disease.
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Affiliation(s)
- James Tumlin
- NephroNet Clinical Trials Consortium, Buford, Georgia, USA
| | - Brad Rovin
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | | | - Tsutomu Takeuchi
- Department of Rheumatology and Applied Immunology, Saitama Medical University and Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan
| | | | - Gudrun Weiss
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Alessandro Sorrentino
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Kevin Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Nicola Ferrari
- Translational Science and Experimental Medicine, Early R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Lai B, Luo SF, Lai JH. Therapeutically targeting proinflammatory type I interferons in systemic lupus erythematosus: efficacy and insufficiency with a specific focus on lupus nephritis. Front Immunol 2024; 15:1489205. [PMID: 39478861 PMCID: PMC11521836 DOI: 10.3389/fimmu.2024.1489205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Type I interferons (IFN-Is) are important players in the immunopathogenesis of systemic lupus erythematosus (SLE). Pathogenic events in patients with SLE are potent triggers of IFN-I induction, yet IFN-I may induce or initiate the immunopathogenesis leading to these events. Because blocking IFN-I is effective in some clinical manifestations of SLE patients, concerns about the efficacy of anti-IFN-I therapy in patients with lupus nephritis remain. Tissues from kidney biopsies of patients with lupus nephritis revealed infiltration of various immune cells and activation of inflammatory signals; however, their correlation with renal damage is not clear, which raises serious concerns about how critical the role of IFN-I is among the potential contributors to the pathogenesis of lupus nephritis. This review addresses several issues related to the roles of IFN-I in SLE, especially in lupus nephritis, including (1) the contribution of IFN-I to the development and immunopathogenesis of SLE; (2) evidence supporting the association of IFN-I with lupus nephritis; (3) therapies targeting IFN-I and IFN-I downstream signaling molecules in SLE and lupus nephritis; (4) findings challenging the therapeutic benefits of anti-IFN-I in lupus nephritis; and (5) a perspective associated with anti-IFN-I biologics for lupus nephritis treatment. In addition to providing clear pictures of the roles of IFN-I in SLE, especially in lupus nephritis, this review addresses the lately published observations and clinical trials on this topic.
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Affiliation(s)
- Benjamin Lai
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shue-Fen Luo
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Jenn-Haung Lai
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
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Chen M, Zhang Y, Shi W, Song X, Yang Y, Hou G, Ding H, Chen S, Yang W, Shen N, Cui Y, Zuo X, Tang Y. SPATS2L is a positive feedback regulator of the type I interferon signaling pathway and plays a vital role in lupus. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1659-1672. [PMID: 39099414 PMCID: PMC11693870 DOI: 10.3724/abbs.2024132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 04/03/2024] [Indexed: 08/06/2024] Open
Abstract
Through genome-wide association studies (GWAS) and integrated expression quantitative trait locus (eQTL) analyses, numerous susceptibility genes ("eGenes", whose expressions are significantly associated with common variants) associated with systemic lupus erythematosus (SLE) have been identified. Notably, a subset of these eGenes is correlated with disease activity. However, the precise mechanisms through which these genes contribute to the initiation and progression of the disease remain to be fully elucidated. In this investigation, we initially identify SPATS2L as an SLE eGene correlated with disease activity. eSignaling and transcriptomic analyses suggest its involvement in the type I interferon (IFN) pathway. We observe a significant increase in SPATS2L expression following type I IFN stimulation, and the expression levels are dependent on both the concentration and duration of stimulation. Furthermore, through dual-luciferase reporter assays, western blot analysis, and imaging flow cytometry, we confirm that SPATS2L positively modulates the type I IFN pathway, acting as a positive feedback regulator. Notably, siRNA-mediated intervention targeting SPATS2L, an interferon-inducible gene, in peripheral blood mononuclear cells (PBMCs) from patients with SLE reverses the activation of the interferon pathway. In conclusion, our research highlights the pivotal role of SPATS2L as a positive-feedback regulatory molecule within the type I IFN pathway. Our findings suggest that SPATS2L plays a critical role in the onset and progression of SLE and may serve as a promising target for disease activity assessment and intervention strategies.
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Affiliation(s)
- Mengke Chen
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Yutong Zhang
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Weiwen Shi
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Xuejiao Song
- Department of DermatologyChina-Japan Friendship HospitalBeijing100029China
| | - Yue Yang
- Department of DermatologyChina-Japan Friendship HospitalBeijing100029China
- Department of PharmacyChina-Japan Friendship HospitalBeijing100029China
| | - Guojun Hou
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Huihua Ding
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Sheng Chen
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
| | - Wanling Yang
- of Paediatrics and Adolescent MedicineThe University of Hong KongHong Kong 999077China
| | - Nan Shen
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200032China
- Center for Autoimmune Genomics and EtiologyCincinnati Children’s Hospital Medical CenterCincinnati OH 45229USA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnati OH 45229USA
| | - Yong Cui
- Department of DermatologyChina-Japan Friendship HospitalBeijing100029China
| | - Xianbo Zuo
- Department of DermatologyChina-Japan Friendship HospitalBeijing100029China
- Department of PharmacyChina-Japan Friendship HospitalBeijing100029China
| | - Yuanjia Tang
- Shanghai Institute of RheumatologyRenji HospitalShanghai Jiao Tong University School of Medicine (SJTUSM)Shanghai200001China
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9
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Cruciani C, Gatto M, Iaccarino L, Doria A, Zen M. Monoclonal antibodies targeting interleukins for systemic lupus erythematosus: updates in early clinical drug development. Expert Opin Investig Drugs 2024; 33:801-814. [PMID: 38958085 DOI: 10.1080/13543784.2024.2376566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 07/02/2024] [Indexed: 07/04/2024]
Abstract
INTRODUCTION The advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In systemic lupus erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs. AREAS COVERED In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis. EXPERT OPINION An unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.
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Affiliation(s)
- Claudio Cruciani
- Rheumatology Unit, Department of Medicine, University of Padua, Padova, Italy
| | - Mariele Gatto
- Rheumatology Unit, Department of Clinical and Biological Sciences, University of Turin and Turin Mauriziano Hospital, Turin, Italy
| | - Luca Iaccarino
- Rheumatology Unit, Department of Medicine, University of Padua, Padova, Italy
| | - Andrea Doria
- Rheumatology Unit, Department of Medicine, University of Padua, Padova, Italy
| | - Margherita Zen
- Rheumatology Unit, Department of Medicine, University of Padua, Padova, Italy
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10
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Liu M, Wang S, Liang Y, Fan Y, Wang W. Genetic polymorphisms in genes involved in the type I interferon system (STAT4 and IRF5): association with Asian SLE patients. Clin Rheumatol 2024; 43:2403-2416. [PMID: 38963465 DOI: 10.1007/s10067-024-07046-8] [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: 05/21/2024] [Revised: 05/21/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
Systemic lupus erythematosus (SLE) is a common autoimmune disease with a polymorphic clinical presentation involving multisystem damages with significant differences in prevalence and disease severity among different ethnic groups. Although genetic, hormonal, and environmental factors have been demonstrated to contribute a lot to SLE, the pathogenesis of SLE is still unknown. Numerous evidence revealed that gene variants within the type I interferons (IFN) signaling pathway performed the great genetic associations with autoimmune diseases including SLE. To date, through genome-wide association studies (GWAS), genetic association studies showed that more than 100 susceptibility genes have been linked to the pathogenesis of SLE, among which TYK2, STAT1, STAT4, and IRF5 are important molecules directly connected to the type I interferon signaling system. The review summarized the genetic associations and the detailed risk loci of STAT4 and IRF5 with Asian SLE patients, explored the genotype distributions associated with the main clinical manifestations of SLE, and sorted out the potential reasons for the differences in susceptibility in Asia and Europe. Moreover, the therapies targeting STAT4 and IRF5 were also evaluated in order to propose more personalized and targeted treatment plans in SLE.
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Affiliation(s)
- Mengyao Liu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Shenglong Wang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yujiao Liang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yongsheng Fan
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China
| | - Weijie Wang
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China.
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11
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Yasmeen F, Pirzada RH, Ahmad B, Choi B, Choi S. Understanding Autoimmunity: Mechanisms, Predisposing Factors, and Cytokine Therapies. Int J Mol Sci 2024; 25:7666. [PMID: 39062908 PMCID: PMC11277571 DOI: 10.3390/ijms25147666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
Autoimmunity refers to an organism's immune response against its own healthy cells, tissues, or components, potentially leading to irreversible damage to vital organs. Central and peripheral tolerance mechanisms play crucial roles in preventing autoimmunity by eliminating self-reactive T and B cells. The disruption of immunological tolerance, characterized by the failure of these mechanisms, results in the aberrant activation of autoreactive lymphocytes that target self-tissues, culminating in the pathogenesis of autoimmune disorders. Genetic predispositions, environmental exposures, and immunoregulatory disturbances synergistically contribute to the susceptibility and initiation of autoimmune pathologies. Within the realm of immune therapies for autoimmune diseases, cytokine therapies have emerged as a specialized strategy, targeting cytokine-mediated regulatory pathways to rectify immunological imbalances. Proinflammatory cytokines are key players in inducing and propagating autoimmune inflammation, highlighting the potential of cytokine therapies in managing autoimmune conditions. This review discusses the etiology of autoimmune diseases, current therapeutic approaches, and prospects for future drug design.
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Affiliation(s)
- Farzana Yasmeen
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Rameez Hassan Pirzada
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bilal Ahmad
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bogeum Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
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12
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Feng W, Qiao J, Tan Y, Liu Q, Wang Q, Yang B, Yang S, Cui L. Interaction of antiphospholipid antibodies with endothelial cells in antiphospholipid syndrome. Front Immunol 2024; 15:1361519. [PMID: 39044818 PMCID: PMC11263079 DOI: 10.3389/fimmu.2024.1361519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 06/19/2024] [Indexed: 07/25/2024] Open
Abstract
Antiphospholipid syndrome (APS) is an autoimmune disease with arteriovenous thrombosis and recurrent miscarriages as the main clinical manifestations. Due to the complexity of its mechanisms and the diversity of its manifestations, its diagnosis and treatment remain challenging issues. Antiphospholipid antibodies (aPL) not only serve as crucial "biomarkers" in diagnosing APS but also act as the "culprits" of the disease. Endothelial cells (ECs), as one of the core target cells of aPL, bridge the gap between the molecular level of these antibodies and the tissue and organ level of pathological changes. A more in-depth exploration of the relationship between ECs and the pathogenesis of APS holds the potential for significant advancements in the precise diagnosis, classification, and therapy of APS. Many researchers have highlighted the vital involvement of ECs in APS and the underlying mechanisms governing their functionality. Through extensive in vitro and in vivo experiments, they have identified multiple aPL receptors on the EC membrane and various intracellular pathways. This article furnishes a comprehensive overview and summary of these receptors and signaling pathways, offering prospective targets for APS therapy.
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Affiliation(s)
- Weimin Feng
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Health Science Centre, Peking University, Beijing, China
| | - Jiao Qiao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Health Science Centre, Peking University, Beijing, China
| | - Yuan Tan
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Health Science Centre, Peking University, Beijing, China
| | - Qi Liu
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Health Science Centre, Peking University, Beijing, China
| | - Qingchen Wang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Boxin Yang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Shuo Yang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Liyan Cui
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- Institute of Medical Technology, Health Science Centre, Peking University, Beijing, China
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13
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Vendel AC, Jaroszewski L, Linnik MD, Godzik A. B- and T-Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis. Clin Pharmacol Ther 2024; 116:247-256. [PMID: 38676311 DOI: 10.1002/cpt.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024]
Abstract
B- and T-lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression in the pathogenesis of systemic lupus erythematosus (SLE), a multisystem autoimmune disease. Peripheral blood mononuclear cells from healthy volunteers (N = 7) were evaluated by mass cytometry by time-of-flight to establish baseline expression of BTLA and HVEM on human lymphocytes compared with patients with SLE during a self-reported flare (N = 5). High levels of BTLA protein were observed on B cells, CD4+, and CD8+ T cells, and plasmacytoid dendritic cells in healthy participants. HVEM protein levels were lower in patients with SLE compared with healthy participants, while BTLA levels were similar between SLE and healthy groups. Correlations of BTLA-HVEM hub genes' expression with patient and disease characteristics were also analyzed using whole blood gene expression data from patients with SLE (N = 1,760) and compared with healthy participants (N = 60). HVEM, being one of the SLE-associated genes, showed an exceptionally strong negative association with disease activity. Several other genes in the BTLA-HVEM signaling network were strongly (negative or positive) correlated, while BTLA had a low association with disease activity. Collectively, these data provide a clinical rationale for targeting BTLA with an agonist in SLE patients with low HVEM expression.
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Affiliation(s)
| | - Lukasz Jaroszewski
- University of California Riverside School of Medicine, Riverside, California, USA
| | | | - Adam Godzik
- University of California Riverside School of Medicine, Riverside, California, USA
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Jones SA, Morand EF. Targeting Interferon Signalling in Systemic Lupus Erythematosus: Lessons Learned. Drugs 2024; 84:625-635. [PMID: 38807010 PMCID: PMC11196297 DOI: 10.1007/s40265-024-02043-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2024] [Indexed: 05/30/2024]
Abstract
The development of new medicines for systemic lupus erythematosus (SLE) has not addressed unmet clinical need, with only three drugs receiving regulatory approval for SLE in the last 60 years, one of which was specifically licensed for lupus nephritis. In the last 20 years it has become clear that activation of type 1 interferons (IFN) is reproducibly detected in the majority of SLE patients, and the actions of IFN in the immune system and on target tissues is consistent with a pathogenic role in SLE. These findings led to considerable drug discovery activity, first with agents directly targeting IFN family cytokines, with results that were encouraging but underwhelming. In contrast, targeting the type I IFN receptor with the monoclonal antibody anifrolumab, thereby blocking all IFN family members, was effective in a phase II clinical trial. This led to a pair of phase III trials, one of which was negative and the other positive, reflecting the difficulty of obtaining outcomes from trials in this complex disease. Nonetheless, the balance of evidence resulted in approval of anifrolumab in multiple jurisdictions from 2021 onwards. Multiple approaches to targeting the type 1 IFN pathway have subsequently had positive phase II clinical trials, including antibodies targeting cells that produce IFN, and small molecules targeting the receptor kinase TYK2, required for IFN signalling. Despite multiple hurdles, it is clear that IFN targeting in SLE is here to stay. The story of IFN-targeting therapy in SLE has lessons for drug development overall in this disease.
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Affiliation(s)
- Sarah A Jones
- Centre for Inflammatory Disease, Monash University, Clayton, Australia
| | - Eric F Morand
- Centre for Inflammatory Disease, Monash University, Clayton, Australia.
- Department of Rheumatology, Monash Health, Melbourne, Australia.
- Monash Medical Centre, 246 Clayton Rd, Clayton, VIC, 3168, Australia.
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15
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Papachristodoulou E, Kyttaris VC. New and emerging therapies for systemic lupus erythematosus. Clin Immunol 2024; 263:110200. [PMID: 38582250 DOI: 10.1016/j.clim.2024.110200] [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: 02/10/2024] [Revised: 03/23/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Systemic Lupus Erythematosus (SLE) and lupus nephritis treatment is still based on non-specific immune suppression despite the first biological therapy for the disease having been approved more than a decade ago. Intense basic and translational research has uncovered a multitude of pathways that are actively being evaluated as treatment targets in SLE and lupus nephritis, with two new medications receiving FDA approval in the last 3 years. Herein we provide an overview of targeted therapies for SLE including medications targeting the B lymphocyte compartment, intracellular signaling, co-stimulation, and finally the interferons and other cytokines.
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Affiliation(s)
- Eleni Papachristodoulou
- Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Vasileios C Kyttaris
- Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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16
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Li XX, Maitiyaer M, Tan Q, Huang WH, Liu Y, Liu ZP, Wen YQ, Zheng Y, Chen X, Chen RL, Tao Y, Yu SL. Emerging biologic frontiers for Sjogren's syndrome: Unveiling novel approaches with emphasis on extra glandular pathology. Front Pharmacol 2024; 15:1377055. [PMID: 38828450 PMCID: PMC11140030 DOI: 10.3389/fphar.2024.1377055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/29/2024] [Indexed: 06/05/2024] Open
Abstract
Primary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by exocrine gland dysfunction, leading to dry eyes and mouth. Despite growing interest in biologic therapies for pSS, FDA approval has proven challenging due to trial complications. This review addresses the absence of a molecular-target-based approach to biologic therapy development and highlights novel research on drug targets and clinical trials. A literature search identified potential pSS treatment targets and recent advances in molecular understanding. Overlooking extraglandular symptoms like fatigue and depression is a notable gap in trials. Emerging biologic agents targeting cytokines, signal pathways, and immune responses have proven efficacy. These novel therapies could complement existing methods for symptom alleviation. Improved grading systems accounting for extraglandular symptoms are needed. The future of pSS treatment may involve gene, stem-cell, and tissue-engineering therapies. This narrative review offers insights into advancing pSS management through innovative biologic interventions.
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Affiliation(s)
- Xiao Xiao Li
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Maierhaba Maitiyaer
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Qing Tan
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Wen Hui Huang
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yu Liu
- Department of Clinical Medicine, The First Clinical Medical School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Zhi Ping Liu
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yue Qiang Wen
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yu Zheng
- Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Xing Chen
- Department of Geriatrics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Rui Lin Chen
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yi Tao
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Shui Lian Yu
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
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Ruiz-Irastorza G, Tektonidou MG, Khamashta M. Anticoagulant and non-anticoagulant therapy in thrombotic antiphospholipid syndrome: old drugs and new treatment targets. Rheumatology (Oxford) 2024; 63:SI96-SI106. [PMID: 38320592 DOI: 10.1093/rheumatology/kead538] [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: 07/05/2023] [Accepted: 09/21/2023] [Indexed: 02/08/2024] Open
Abstract
In this review, we discuss the current evidence on classic and newer oral anticoagulant therapy, older drugs such as HCQ and statins, and new potential treatment targets in APS. Vitamin K antagonists (VKAs) remain the cornerstone treatment for thrombotic events in APS. In patients fulfilling criteria for definite APS presenting with a first venous thrombosis, treatment with VKAs with a target international normalized ratio (INR) 2.0-3.0 is recommended. In patients with arterial thrombosis, treatment with VKA with target INR 2.0-3.0 or 3.0-4.0 is recommended by recent guidelines, considering the individual's bleeding and thrombosis recurrence risk. A combination of VKAs and low-dose aspirin (75-100 mg/daily) may also be considered. According to available evidence direct oral anticoagulants should be avoided in patients with arterial thrombosis and/or those with triple aPL positivity. Adjunctive treatment with HCQ and/or statins can be considered, especially in anticoagulation treatment-refractory APS. Potential targeted treatments in APS include B-cell targeting, complement inhibition, mammalian target of rapamycin inhibition, IFN targeting, adenosine receptors agonists, CD38 targeting or chimeric antigen receptor T-cell therapy. The safety and efficacy of these treatment targets needs to be examined in well-designed randomized controlled trials.
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Affiliation(s)
- Guillermo Ruiz-Irastorza
- Autoimmune Diseases Research Unit, Biocruces Bizkaia Health Research Institute, The Basque Country, Bizkaia, Spain
- University of The Basque Country, The Basque Country, Bizkaia, Spain
| | - Maria G Tektonidou
- First Department of Propaedeutic Internal Medicine, Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Munther Khamashta
- Department of Women & Children's Health, King's College London, London, UK
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Jia X, Lu Y, Zheng X, Tang R, Chen W. Targeted therapies for lupus nephritis: Current perspectives and future directions. Chin Med J (Engl) 2024; 137:34-43. [PMID: 38057972 PMCID: PMC10766263 DOI: 10.1097/cm9.0000000000002959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Indexed: 12/08/2023] Open
Abstract
ABSTRACT Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, poses a substantial risk of progression to end-stage renal disease, with increased mortality. Conventional therapy for LN relies on broad-spectrum immunosuppressants such as glucocorticoids, mycophenolate mofetil, and calcineurin inhibitors. Although therapeutic regimens have evolved over the years, they have inherent limitations, including non-specific targeting, substantial adverse effects, high relapse rates, and prolonged maintenance and remission courses. These drawbacks underscore the need for targeted therapeutic strategies for LN. Recent advancements in our understanding of LN pathogenesis have led to the identification of novel therapeutic targets and the emergence of biological agents and small-molecule inhibitors with improved specificity and reduced toxicity. This review provides an overview of the current evidence on targeted therapies for LN, elucidates the biological mechanisms of responses and failure, highlights the challenges ahead, and outlines strategies for subsequent clinical trials and integrated immunomodulatory approaches.
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Affiliation(s)
- Xiuzhi Jia
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, Guangdong 510080, China
| | - Yuewen Lu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, Guangdong 510080, China
| | - Xunhua Zheng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, Guangdong 510080, China
| | - Ruihan Tang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, Guangdong 510080, China
| | - Wei Chen
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, Guangdong 510080, China
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Gensous N, Lazaro E, Blanco P, Richez C. Anifrolumab: first biologic approved in the EU not restricted to patients with a high degree of disease activity for the treatment of moderate to severe systemic lupus erythematosus. Expert Rev Clin Immunol 2024; 20:21-30. [PMID: 37800604 DOI: 10.1080/1744666x.2023.2268284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/04/2023] [Indexed: 10/07/2023]
Abstract
INTRODUCTION Type 1 interferons (IFNs) play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) and various type I IFNs targeting therapeutic approaches have been developed. Anifrolumab, a monoclonal antibody that binds to the subunit 1 of the type I IFN receptor, has acquired considerable interest and has entered different clinical human trials willing to evaluate its efficacy and safety. AREAS COVERED This review summarizes the data obtained in phases 1, 2, and 3 clinical trials of anifrolumab for SLE patients. A focus is made on data of clinical efficacy and safety obtained in MUSE, TULIP-1 and TULIP-2 trials. EXPERT OPINION/COMMENTARY Anifrolumab is a promising therapeutic option for patients with SLE, currently authorized for moderate-to-severe SLE. Extensive real-world use is now going to generate data required to gain experience on the type of patients who benefit the most from the drug, and the exact positioning of anifrolumab in the therapeutic plan.
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Affiliation(s)
- Noémie Gensous
- Department of Internal Medicine and Clinical Immunology, CHU Bordeaux, Hôpital Saint-André, Bordeaux, France
- UMR/CNRS 5164, ImmunoConcEpT, CNRS, University of Bordeaux, Bordeaux, France
| | - Estibaliz Lazaro
- UMR/CNRS 5164, ImmunoConcEpT, CNRS, University of Bordeaux, Bordeaux, France
- Department of Internal Medicine and Infectious Diseases, Centre National de Référence des Maladies Auto-immunes Systémiques Rares RESO, CHU Bordeaux, Hôpital Haut Leveque, Pessac, France
| | - Patrick Blanco
- UMR/CNRS 5164, ImmunoConcEpT, CNRS, University of Bordeaux, Bordeaux, France
- Department of Immunology and Immunogenetics, CHU Bordeaux, Hôpital Pellegrin, Bordeaux, France
| | - Christophe Richez
- UMR/CNRS 5164, ImmunoConcEpT, CNRS, University of Bordeaux, Bordeaux, France
- Department of Rheumatology, Centre National de Référence des Maladies Auto-immunes Systémiques Rares RESO, CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France
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Lim D, Kleitsch J, Werth VP. Emerging immunotherapeutic strategies for cutaneous lupus erythematosus: an overview of recent phase 2 and 3 clinical trials. Expert Opin Emerg Drugs 2023; 28:257-273. [PMID: 37860982 DOI: 10.1080/14728214.2023.2273536] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/17/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION Cutaneous lupus erythematosus (CLE) is an autoimmune disease that is clinically heterogenous and may occur with or without the presence of systemic lupus erythematosus (SLE). While existing on a spectrum, CLE and SLE present differences in their underlying pathogenesis and therapeutic responses. No new therapies have been approved in recent decades by the U.S. Food and Drug Administration for CLE, although frequently refractory to conventional therapies. There is an unmet need to develop effective drugs for CLE as it significantly impacts patients' quality of life and may leave irreversible disfiguring damage. AREAS COVERED This review provides an update on the latest phase 2 and 3 clinical trials performed in CLE or SLE using skin-specific outcome measures. Emergent therapies are presented alongside their mechanism of action as recent translational studies have permitted identification of critical targets among immune cells and/or pathways involved in CLE. EXPERT OPINION While the recent literature has few trials for CLE, drugs targeting type I interferon, its downstream signaling and plasmacytoid dendritic cells have shown promising results. Further research is required to develop long-awaited effective therapies, and this review highlights the importance of implementing trials dedicated to CLE to fill the current gap in CLE therapeutics.
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Affiliation(s)
- Darosa Lim
- Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA
- Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Julianne Kleitsch
- Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA
- Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Victoria P Werth
- Department of Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, PA, USA
- Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
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Abstract
Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that can cause injury in almost every body system. While considered a classic example of autoimmunity, it is still relatively poorly understood. Treatment with immunosuppressive agents is challenging, as many agents are relatively non-specific, and the underlying disease is characterized by unpredictable flares and remissions. This State of The Art Review provides a comprehensive current summary of systemic lupus erythematosus based on recent literature. In basic and translational science, this summary includes the current state of genetics, epigenetics, differences by ancestry, and updates about the molecular and immunological pathogenesis of systemic lupus erythematosus. In clinical science, the summary includes updates in diagnosis and classification, clinical features and subphenotypes, and current guidelines and strategies for treatment. The paper also provides a comprehensive review of the large number of recent clinical trials in systemic lupus erythematosus. Current knowns and unknowns are presented, and potential directions for the future are suggested. Improved knowledge of immunological pathogenesis and the molecular differences that exist between patients should help to personalize treatment, minimize side effects, and achieve better outcomes in this difficult disease.
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Affiliation(s)
- Eric F Morand
- School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
- Department of Rheumatology, Monash Health, Melbourne, VIC, Australia
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22
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Chan J, Walters GD, Puri P, Jiang SH. Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE). BMC Rheumatol 2023; 7:37. [PMID: 37807057 PMCID: PMC10561476 DOI: 10.1186/s41927-023-00358-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 09/15/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND To determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults. METHODS Systematic review and meta-analysis following PRISMA guidelines. DATA SOURCES MEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021. STUDY CRITERIA Phase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. DATA EXTRACTION Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias. RESULTS Forty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR). Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes. CONCLUSION Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.
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Affiliation(s)
- Justin Chan
- John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
- Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
| | - Giles D Walters
- John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
- Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Prianka Puri
- Department of Nephrology, Royal Brisbane and Woman's Hospital Health Service District, Herston, QLD, Australia
| | - Simon H Jiang
- John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia
- Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia
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23
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Santos GDM, Saldanha A, Orsi FA. Should we be targeting type 1 interferons in antiphospholipid syndrome? Clin Immunol 2023; 255:109754. [PMID: 37678720 DOI: 10.1016/j.clim.2023.109754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023]
Abstract
Systemic autoimmune diseases are characterized by increased production of type I interferon (IFN-1) and upregulation of IFN-1-inducible genes, suggesting an important role of the IFN-1 pathway in their pathogenesis. Recent studies have demonstrated increased IFN-1 expression in both primary and secondary antiphospholipid syndrome (APS), along with increased toll-like receptor type 9 activity and plasmacytoid dendritic cell function. The increasing knowledge of the association between IFN-1 and APS pathology may provide a rationale for conducting clinical trials to assess the efficacy of IFN-1-targeting drugs in reducing APS-related complications. In this narrative review, we summarize the current knowledge on the role of IFN-1 in APS pathogenesis, explore its clinical implications, and examine the existing evidence regarding therapeutic options that have been investigated to date.
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Affiliation(s)
- Gabrielle de Mello Santos
- Hospital das Clinicas of University of São Paulo Medical School (HCFMUSP), Brazil; HEMORIO - State Institute of Hematology "Arthur de Siqueira Cavalcanti", Brazil
| | - Artur Saldanha
- Hospital das Clinicas of University of São Paulo Medical School (HCFMUSP), Brazil; HEMOAL - Hematology and Hemotherapy Center of Alagoas, Brazil
| | - Fernanda Andrade Orsi
- Hospital das Clinicas of University of São Paulo Medical School (HCFMUSP), Brazil; Department of Pathology, Faculty of Medical Sciences of the University of Campinas (UNICAMP), Brazil.
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Juha M, Molnár A, Jakus Z, Ledó N. NETosis: an emerging therapeutic target in renal diseases. Front Immunol 2023; 14:1253667. [PMID: 37744367 PMCID: PMC10514582 DOI: 10.3389/fimmu.2023.1253667] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/15/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Neutrophil extracellular traps (NETs) are web-like structures composed of nuclear and granular components. The primary role of NETS is to prevent the dissemination of microbes and facilitate their elimination. However, this process is accompanied by collateral proinflammatory adverse effects when the NET release becomes uncontrollable, or clearance is impaired. Although NET-induced organ damage is conducted primarily and indirectly via immune complexes and the subsequent release of cytokines, their direct effects on cells are also remarkable. NETosis plays a critical pathogenic role in several renal disorders, such as the early phase of acute tubular necrosis, anti-neutrophil cytoplasmic antibody-mediated renal vasculitis, lupus nephritis, thrombotic microangiopathies, anti-glomerular basement membrane disease, and diabetic nephropathy. Their substantial contribution in the course of these disorders makes them a desirable target in the therapeutic armamentarium. This article gives an in-depth review of the heterogeneous pathogenesis and physiological regulations of NETosis and its pivotal role in renal diseases. Based on the pathogenesis, the article also outlines the current therapeutic options and possible molecular targets in the treatment of NET-related renal disorders. Methods We carried out thorough literature research published in PubMed and Google Scholar, including a comprehensive review and analysis of the classification, pathomechanisms, and a broad spectrum of NET-related kidney disorders. Conclusions NETosis plays a pivotal role in certain renal diseases. It initiates and maintains inflammatory and autoimmune disorders, thus making it a desirable target for improving patient and renal outcomes. Better understanding and clinical translation of the pathogenesis are crucial aspects to treatment, for improving patient, and renal outcomes.
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Affiliation(s)
- Márk Juha
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Adél Molnár
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Zoltán Jakus
- Department of Physiology, Semmelweis University, Budapest, Hungary
| | - Nóra Ledó
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
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25
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Londe AC, Fernandez-Ruiz R, Julio PR, Appenzeller S, Niewold TB. Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response. J Rheumatol 2023; 50:1103-1113. [PMID: 37399470 DOI: 10.3899/jrheum.2022-0827] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2023] [Indexed: 07/05/2023]
Abstract
Type I interferon (IFN-I) is thought to play a role in many systemic autoimmune diseases. IFN-I pathway activation is associated with pathogenic features, including the presence of autoantibodies and clinical phenotypes such as more severe disease with increased disease activity and damage. We will review the role and potential drivers of IFN-I dysregulation in 5 prototypic autoimmune diseases: systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, primary Sjögren syndrome, and systemic sclerosis. We will also discuss current therapeutic strategies that directly or indirectly target the IFN-I system.
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Affiliation(s)
- Ana Carolina Londe
- A.C. Londe, MSc, Autoimmunity Lab, and Graduate Program in Physiopathology, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Ruth Fernandez-Ruiz
- R. Fernandez-Ruiz, MD, Department of Medicine, Hospital for Special Surgery, New York, New York, USA
| | - Paulo Rogério Julio
- P. Rogério Julio, MSc, Autoimmunity Lab, and Graduate Program of Child and Adolescent Health, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Simone Appenzeller
- S. Appenzeller, MD, PhD, Autoimmunity Lab, and Rheumatology Unit, Department of Medicine, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Timothy B Niewold
- T.B. Niewold, MD, Department of Medicine, Hospital for Special Surgery, New York, New York, USA.
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26
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Tanaka Y, Kusuda M, Yamaguchi Y. Interferons and systemic lupus erythematosus: Pathogenesis, clinical features, and treatments in interferon-driven disease. Mod Rheumatol 2023; 33:857-867. [PMID: 36440704 DOI: 10.1093/mr/roac140] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/24/2022] [Accepted: 11/09/2022] [Indexed: 08/27/2023]
Abstract
Type I interferons (IFNs) have recently received a lot of attention with the elucidation of the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs are associated with many SLE symptoms and play a role in the pathogenesis of autoimmune diseases that may occur concurrently with SLE, such as Sjögren's syndrome, antiphospholipid syndrome, myositis, scleroderma, and interferonopathy. Type I IFNs could be the link between these diseases. However, direct measurement of type I IFN levels and the IFN gene signature is currently unavailable in clinical practice. This review discusses type I IFN signalling in SLE, investigates the role of type I IFN in the clinical manifestations and symptoms associated with SLE and other IFN-related diseases, and discusses the clinical tests that can be used to diagnose SLE and measure disease activity. In addition, the role of type I IFN-blocking therapies as potential treatments for SLE is discussed.
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
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27
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Rodríguez-Carrio J, Burska A, Conaghan PG, Dik WA, Biesen R, Eloranta ML, Cavalli G, Visser M, Boumpas DT, Bertsias G, Wahren-Herlenius M, Rehwinkel J, Frémond ML, Crow MK, Rönnblom L, Versnel MA, Vital EM. 2022 EULAR points to consider for the measurement, reporting and application of IFN-I pathway activation assays in clinical research and practice. Ann Rheum Dis 2023; 82:754-762. [PMID: 36858821 DOI: 10.1136/ard-2022-223628] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 02/04/2023] [Indexed: 03/03/2023]
Abstract
BACKGROUND Type I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings. OBJECTIVE To develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility. METHODS EULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined. RESULTS Two overarching principles and 11 PtC were defined. The first set (PtC 1-4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5-11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda. CONCLUSIONS IFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology.
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Affiliation(s)
- Javier Rodríguez-Carrio
- Department of Functional Biology, University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain
| | - Agata Burska
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Philip G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Willem A Dik
- Erasmus MC, University Medical Center Rotterdam, Laboratory Medical Immunology, Department of Immunology, Rotterdam, The Netherlands
| | - Robert Biesen
- Charité University Medicine Berlin, Department of Rheumatology, Berlin, Germany
| | - Maija-Leena Eloranta
- Uppsala University, Department of Medical Sciences, Rheumatology, Uppsala, Sweden
| | - Giulio Cavalli
- Vita-Salute San Raffaele University, Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Milan, Italy
| | - Marianne Visser
- EULAR PARE Patient Research Partner, Amsterdam, The Netherlands
| | - Dimitrios T Boumpas
- Medicine, University of Crete, Medical School, Department of Internal Medicine, Heraklion, Greece
| | - George Bertsias
- University of Crete, Medical School, Department of Rheumatology-Clinical Immunology, Heraklion, Greece
| | - Marie Wahren-Herlenius
- Karolinska Institutet, Division of Rheumatology, Stockholm, Sweden
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Marie-Louise Frémond
- Université de Paris Cité, Hôpital Necker-Enfants Malades, Immuno-Hématologie et Rhumatologie pédiatriques, Paris, France
| | - Mary K Crow
- Hospital for Special Surgery, Weill Cornell Medical College, Mary Kirkland Center for Lupus Research, New York, New York, USA
| | - Lars Rönnblom
- Uppsala University, Department of Medical Sciences, Rheumatology, Uppsala, Sweden
| | - Marjan A Versnel
- Erasmus MC, University Medical Center Rotterdam, Department of Immunology, Rotterdam, The Netherlands
| | - Edward M Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
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28
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Wang Y, Lin S, Wu J, Jiang M, Lin J, Zhang Y, Ding H, Zhou H, Shen N, Di W. Control of lupus activity during pregnancy via the engagement of IgG sialylation: novel crosstalk between IgG sialylation and pDC functions. Front Med 2023; 17:549-561. [PMID: 37010728 DOI: 10.1007/s11684-022-0965-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 09/06/2022] [Indexed: 04/04/2023]
Abstract
Immunoglobulin (IgG) glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases, including systemic lupus erythematosus (SLE), thus underlining the pathogenic role of glycosylation aberration in autoimmunity. This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy. Relative to that in serum samples from the control cohort, IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages (from preconception to the third trimester of pregnancy) and was significantly associated with lupus activity and fetal loss during lupus pregnancy. The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation. The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells (pDCs). RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase (SYK) signaling pathway significantly differed between IgG- and deSia-IgG-treated pDCs. This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG. Finally, the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG. Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.
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Affiliation(s)
- You Wang
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Sihan Lin
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jiayue Wu
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Meng Jiang
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianhua Lin
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Yu Zhang
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Huihua Ding
- Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China
| | - Haibo Zhou
- Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.
| | - Nan Shen
- Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA.
| | - Wen Di
- Department of Obstetrics and Gynaecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
- Shanghai Key Laboratory of Gynaecologic Oncology, Shanghai, 200127, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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Mohan C, Zhang T, Putterman C. Pathogenic cellular and molecular mediators in lupus nephritis. Nat Rev Nephrol 2023:10.1038/s41581-023-00722-z. [PMID: 37225921 DOI: 10.1038/s41581-023-00722-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2023] [Indexed: 05/26/2023]
Abstract
Kidney involvement in patients with systemic lupus erythematosus - lupus nephritis (LN) - is one of the most important and common clinical manifestations of this disease and occurs in 40-60% of patients. Current treatment regimens achieve a complete kidney response in only a minority of affected individuals, and 10-15% of patients with LN develop kidney failure, with its attendant morbidity and considerable prognostic implications. Moreover, the medications most often used to treat LN - corticosteroids in combination with immunosuppressive or cytotoxic drugs - are associated with substantial side effects. Advances in proteomics, flow cytometry and RNA sequencing have led to important new insights into immune cells, molecules and mechanistic pathways that are instrumental in the pathogenesis of LN. These insights, together with a renewed focus on the study of human LN kidney tissue, suggest new therapeutic targets that are already being tested in lupus animal models and early-phase clinical trials and, as such, are hoped to eventually lead to meaningful improvements in the care of patients with systemic lupus erythematosus-associated kidney disease.
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Affiliation(s)
- Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA.
| | - Ting Zhang
- Division of Rheumatology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chaim Putterman
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
- Division of Rheumatology and Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
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30
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Rodríguez-Carrio J, Burska A, Conaghan PG, Dik WA, Biesen R, Eloranta ML, Cavalli G, Visser M, Boumpas DT, Bertsias G, Wahren-Herlenius M, Rehwinkel J, Frémond ML, Crow MK, Ronnblom L, Vital E, Versnel M. Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider. RMD Open 2023; 9:e002864. [PMID: 36882218 PMCID: PMC10008483 DOI: 10.1136/rmdopen-2022-002864] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/13/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Type I interferons (IFN-I) contribute to a broad range of rheumatic and musculoskeletal diseases (RMDs). Compelling evidence suggests that the measurement of IFN-I pathway activation may have clinical value. Although several IFN-I pathway assays have been proposed, the exact clinical applications are unclear. We summarise the evidence on the potential clinical utility of assays measuring IFN-I pathway activation. METHODS A systematic literature review was conducted across three databases to evaluate the use of IFN-I assays in diagnosis and monitor disease activity, prognosis, response to treatment and responsiveness to change in several RMDs. RESULTS Of 366 screened, 276 studies were selected that reported the use of assays reflecting IFN-I pathway activation for disease diagnosis (n=188), assessment of disease activity (n=122), prognosis (n=20), response to treatment (n=23) and assay responsiveness (n=59). Immunoassays, quantitative PCR (qPCR) and microarrays were reported most frequently, while systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis, systemic sclerosis and primary Sjögren's syndrome were the most studied RMDs. The literature demonstrated significant heterogeneity in techniques, analytical conditions, risk of bias and application in diseases. Inadequate study designs and technical heterogeneity were the main limitations. IFN-I pathway activation was associated with disease activity and flare occurrence in SLE, but their incremental value was uncertain. IFN-I pathway activation may predict response to IFN-I targeting therapies and may predict response to different treatments. CONCLUSIONS Evidence indicates potential clinical value of assays measuring IFN-I pathway activation in several RMDs, but assay harmonisation and clinical validation are urged. This review informs the EULAR points to consider for the measurement and reporting of IFN-I pathway assays.
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Affiliation(s)
- Javier Rodríguez-Carrio
- Area of Immunology, University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain
| | - Agata Burska
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - P G Conaghan
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Willem A Dik
- Laboratory Medical Immunology, department of Immunology, Erasmus MC University Medical Center Rotterdam, The Netherlands
| | - Robert Biesen
- Department of Rheumatology, Charité University Medicine Berlin, Berlin, Germany
| | - Maija-Leena Eloranta
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Giulio Cavalli
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Vita-Salute San Raffaele University, Milan, Italy
| | - Marianne Visser
- EULAR, PARE Patient Research Partners, Amsterdam, The Netherlands
| | - Dimitrios T Boumpas
- Department of Internal Medicine, University of Crete, Medical School, Heraklion, Greece
| | - George Bertsias
- Department of Rheumatology-Clinical Immunology, University of Crete, Medical School, Heraklion, Greece
| | - Marie Wahren-Herlenius
- Karolinska Institutet, Division of Rheumatology, Stockholm, Sweden
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Norway
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, UK
| | - Marie-Louise Frémond
- Université de Paris Cité, Hôpital Necker-Enfants Malades, Immuno-Hématologie et Rhumatologie pédiatriques, Paris, France
| | - Mary K Crow
- Hospital for Special Surgery, Weill Cornell Medical College, Mary Kirkland Center for Lupus Research, New York, USA
| | - Lars Ronnblom
- Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden
| | - Ed Vital
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Biomedical Research Centre, Leeds, UK
| | - Marjan Versnel
- Department of Immunology, Erasmus MC University Medical Center Rotterdam, The Netherlands
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31
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Bruera S, Chavula T, Madan R, Agarwal SK. Targeting type I interferons in systemic lupus erythematous. Front Pharmacol 2023; 13:1046687. [PMID: 36726783 PMCID: PMC9885195 DOI: 10.3389/fphar.2022.1046687] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/05/2022] [Indexed: 01/18/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for the treatment of certain manifestations of SLE. In the current narrative review, we will discuss the role of type I IFN in SLE pathogenesis and the potential translation of these data into strategies using type I IFN as a biomarker and therapeutic target for patients with SLE.
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Affiliation(s)
- Sebastian Bruera
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Thandiwe Chavula
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Riya Madan
- Section of General Internal Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Sandeep K. Agarwal
- Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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32
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Skartsis N, Muller YD, Ferreira LMR. Regulatory T cell homeostasis: Requisite signals and implications for clinical development of biologics. Clin Immunol 2023; 246:109201. [PMID: 36470337 PMCID: PMC12066019 DOI: 10.1016/j.clim.2022.109201] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
Novel biologics are currently being tested in clinical trials for the treatment of autoimmune diseases and the prevention of transplant allograft rejection. Their premise is to deliver highly efficient immunosuppression while minimizing side-effects, as they specifically target inflammatory mediators involved in the dysregulation of the immune system. However, the pleiotropism of soluble mediators and cell-to-cell interactions with potential to exert both proinflammatory and regulatory influences on the outcome of the immune response can lead to unpredictable results. Predicting responses to biologic drugs requires mechanistic understanding of the cell type-specific effect of immune mediators. Elucidation of the central role of regulatory T cells (Treg), a small subset of T cells dedicated to immune homeostasis, in preventing the development of auto- and allo-immunity has provided a deeper understanding of the signaling pathways that govern immune tolerance. This review focuses on the requisite signals that promote Treg homeostasis and discusses the anticipated outcomes of biologics targeting these signals. Our goal is to inform and facilitate the design of cell-specific biologics that thwart T effector cells (Teff) while promoting Treg function for the treatment of autoimmune diseases and the prevention of transplant rejection.
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Affiliation(s)
- Nikolaos Skartsis
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Clinic William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.
| | - Yannick D Muller
- Division of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Leonardo M R Ferreira
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
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Infante B, Mercuri S, Dello Strologo A, Franzin R, Catalano V, Troise D, Cataldo E, Pontrelli P, Alfieri C, Binda V, Frontini G, Netti GS, Ranieri E, Gesualdo L, Castellano G, Stallone G. Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies. Int J Mol Sci 2022; 23:ijms232415998. [PMID: 36555640 PMCID: PMC9783870 DOI: 10.3390/ijms232415998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/05/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.
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Affiliation(s)
- Barbara Infante
- Unit of Nephology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Silvia Mercuri
- Unit of Nephology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Andrea Dello Strologo
- Unit of Nephology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Valeria Catalano
- Unit of Clinical Pathology, Center for Molecular Medicine, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy
| | - Dario Troise
- Unit of Nephology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Emanuela Cataldo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Carlo Alfieri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Valentina Binda
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy
| | - Giulia Frontini
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy
| | - Giuseppe Stefano Netti
- Unit of Clinical Pathology, Center for Molecular Medicine, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy
| | - Elena Ranieri
- Unit of Clinical Pathology, Center for Molecular Medicine, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Correspondence: ; Tel.: +39-0255034551; Fax: +39-0255034550
| | - Giovanni Stallone
- Unit of Nephology, Dialysis and Transplantation, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Lichtnekert J, Anders HJ, Lech M. Lupus Nephritis: Current Perspectives and Moving Forward. J Inflamm Res 2022; 15:6533-6552. [PMID: 36483271 PMCID: PMC9726217 DOI: 10.2147/jir.s363722] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/22/2022] [Indexed: 08/07/2023] Open
Abstract
Lupus nephritis is a severe organ manifestation of systemic lupus erythematosus, and its pathogenesis involves complex etiology and mechanisms. Despite significant knowledge gains and extensive efforts put into understanding the development and relapsing disease activity, lupus nephritis remains a substantial cause of morbidity and mortality in lupus patients. Current therapies retain a significant unmet medical need regarding rates of complete response, preventing relapse of lupus nephritis, progression of chronic kidney disease to kidney failure, drug toxicity, and pill burden-related drug non-adherence. Connected to progression of chronic kidney disease are the associated risks for disabling or even lethal cardiovascular events, as well as chronic kidney disease-related secondary immunodeficiency and serious infections. In this regard, biomarkers are needed that can predict treatment response to specific drugs to enable personalized precision medicine. A series of clinical trials with innovative immunomodulatory drugs are ongoing and raise expectations for improvements in the management of lupus nephritis. Here, we review how new developments in pathogenesis connect with current and future perspectives for the management of lupus nephritis.
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Affiliation(s)
- Julia Lichtnekert
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, München, Germany
| | - Hans-Joachim Anders
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, München, Germany
| | - Maciej Lech
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, München, Germany
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Wang L, Yang Z, Yu H, Lin W, Wu R, Yang H, Yang K. Predicting diagnostic gene expression profiles associated with immune infiltration in patients with lupus nephritis. Front Immunol 2022; 13:839197. [PMID: 36532018 PMCID: PMC9755505 DOI: 10.3389/fimmu.2022.839197] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 11/09/2022] [Indexed: 12/03/2022] Open
Abstract
Objective To identify potential diagnostic markers of lupus nephritis (LN) based on bioinformatics and machine learning and to explore the significance of immune cell infiltration in this pathology. Methods Seven LN gene expression datasets were downloaded from the GEO database, and the larger sample size was used as the training group to obtain differential genes (DEGs) between LN and healthy controls, and to perform gene function, disease ontology (DO), and gene set enrichment analyses (GSEA). Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), were applied to identify candidate biomarkers. The diagnostic value of LN diagnostic gene biomarkers was further evaluated in the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from LN patients and to analyze their correlation with diagnostic markers. Results Thirty and twenty-one DEGs were screened in kidney tissue and peripheral blood, respectively. Both of which covered macrophages and interferons. The disease enrichment analysis of DEGs in kidney tissues showed that they were mainly involved in immune and renal diseases, and in peripheral blood it was mainly enriched in cardiovascular system, bone marrow, and oral cavity. The machine learning algorithm combined with external dataset validation revealed that C1QA(AUC = 0.741), C1QB(AUC = 0.758), MX1(AUC = 0.865), RORC(AUC = 0.911), CD177(AUC = 0.855), DEFA4(AUC= 0.843)and HERC5(AUC = 0.880) had high diagnostic value and could be used as diagnostic biomarkers of LN. Compared to controls, pathways such as cell adhesion molecule cam, and systemic lupus erythematosus were activated in kidney tissues; cell cycle, cytoplasmic DNA sensing pathways, NOD-like receptor signaling pathways, proteasome, and RIG-1-like receptors were activated in peripheral blood. Immune cell infiltration analysis showed that diagnostic markers in kidney tissue were associated with T cells CD8 and Dendritic cells resting, and in blood were associated with T cells CD4 memory resting, suggesting that CD4 T cells, CD8 T cells and dendritic cells are closely related to the development and progression of LN. Conclusion C1QA, C1QB, MX1, RORC, CD177, DEFA4 and HERC5 could be used as new candidate molecular markers for LN. It may provide new insights into the diagnosis and molecular treatment of LN in the future.
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Affiliation(s)
- Lin Wang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhihua Yang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hangxing Yu
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wei Lin
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ruoxi Wu
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hongtao Yang
- Nephrology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Kang Yang
- Nephrology Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Henan, China
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37
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Crow MK. Advances in lupus therapeutics: Achieving sustained control of the type I interferon pathway. Curr Opin Pharmacol 2022; 67:102291. [PMID: 36183477 DOI: 10.1016/j.coph.2022.102291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 01/25/2023]
Abstract
Achieving sustained control of disease activity in patients with systemic lupus erythematosus has been impeded by the complexity of its immunopathogenesis as well its clinical heterogeneity. In spite of these challenges, gains in understanding disease mechanisms have identified immune targets that are currently under study in trials of candidate therapeutics. Defining the type I interferon (IFN-I) pathway and autoantibodies specific for nucleic acid binding proteins as core pathogenic mediators allows an analysis of approaches that could control production of those mediators and improve patient outcomes. This review describes therapeutic targets and agents that could achieve control of the IFN-I pathway. Toll-like receptor 7, involved in IFN-I production and differentiation of B cells, and long-lived plasma cells, the producers of autoantibodies specific for RNA-binding proteins, components of the immune complex drivers of IFN-I, are particularly attractive therapeutic targets.
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Affiliation(s)
- Mary K Crow
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Cornell Medicine, 535 East 70th Street, New York, NY 10021, USA.
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38
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Psarras A, Wittmann M, Vital EM. Emerging concepts of type I interferons in SLE pathogenesis and therapy. Nat Rev Rheumatol 2022; 18:575-590. [PMID: 36097207 DOI: 10.1038/s41584-022-00826-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2022] [Indexed: 11/09/2022]
Abstract
Type I interferons have been suspected for decades to have a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidence has now overturned several long-held assumptions about how type I interferons are regulated and cause pathological conditions, providing a new view of SLE pathogenesis that resolves longstanding clinical dilemmas. This evidence includes data on interferons in relation to genetic predisposition and epigenetic regulation. Importantly, data are now available on the role of interferons in the early phases of the disease and the importance of non-haematopoietic cellular sources of type I interferons, such as keratinocytes, renal tubular cells, glial cells and synovial stromal cells, as well as local responses to type I interferons within these tissues. These local effects are found not only in inflamed target organs in established SLE, but also in histologically normal skin during asymptomatic preclinical phases, suggesting a role in disease initiation. In terms of clinical application, evidence relating to biomarkers to characterize the type I interferon system is complex, and, notably, interferon-blocking therapies are now licensed for the treatment of SLE. Collectively, the available data enable us to propose a model of disease pathogenesis that invokes the unique value of interferon-targeted therapies. Accordingly, future approaches in SLE involving disease reclassification and preventative strategies in preclinical phases should be investigated.
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Affiliation(s)
- Antonios Psarras
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.,Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Miriam Wittmann
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.,Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - 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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Ahmed AA, Osman N, Furie R. An evaluation of anifrolumab for use in adults with systemic lupus erythematosus. Expert Rev Clin Immunol 2022; 18:1095-1106. [PMID: 36083692 DOI: 10.1080/1744666x.2022.2123793] [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] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Type 1 interferons play a key role in the pathogenesis of systemic lupus erythematosus (SLE). An important clinical question is whether inhibiting the type 1 interferon pathway reduce the disease activity in SLE patients. This review evaluates the safety and efficacy of the monoclonal antibody against the type 1 interferon alpha receptor, anifrolumab, in patients with SLE. AREAS COVERED Key terms (SLE, type 1 interferon, anifrolumab) were used to query the PubMed database for phase 1, 2 and 3 clinical trials of anifrolumab for SLE patients. Phase 1 studies showed anifrolumab has non-linear pharmacokinetics and the optimal safe dose is 300 mg given intravenously every four weeks. The MUSE (phase 2) and the TULIP-2 (phase 3) trials showed that anifrolumab when added to standard therapy significantly reduced disease activity in SLE patients. Common adverse events associated with anifrolumab were upper respiratory and urinary infections as well as shingles. EXPERT OPINION Anifrolumab is an exciting new therapeutic for SLE patients. Additional analyses of the combined TULIP-1 and TULIP-2 datasets as well as future studies with anifrolumab will generate yet more data in SLE. No doubt anifrolumab will be studied in other diseases where type I interferons play an important role.
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Affiliation(s)
- Abdullah Ali Ahmed
- Rheumatology, Stony Brook University The State University of New York101 Nicolls Road, Stony Brook, New York 11794-0701, United States
| | - Naureen Osman
- Rheumatology, Northwell Health865 Northern Boulevard, Great Neck, New York 11021, United States
| | - Richard Furie
- Rheumatology, Northwell Health865 Northern Boulevard, Great Neck, New York 11021, United States
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40
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Abstract
Systemic lupus erythematosus (SLE) is a typical autoimmune disease with a complex pathogenesis and genetic predisposition. With continued understanding of this disease, it was found that SLE is related to the interferon gene signature. Most studies have emphasized the important role of IFN-α in SLE, but our previous study suggested a nonnegligible role of IFN-γ in SLE. Some scholars previously found that IFN-γ is abnormally elevated as early as before the classification of SLE and before the emergence of autoantibodies and IFN-α. Due to the large overlap between IFN-α and IFN-γ, SLE is mostly characterized by expression of the IFN-α gene after onset. Therefore, the role of IFN-γ in SLE may be underestimated. This article mainly reviews the role of IFN-γ in SLE and focuses on the nonnegligible role of IFN-γ in SLE to gain a more comprehensive understanding of the disease.
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41
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Fetter T, Braegelmann C, de Vos L, Wenzel J. Current Concepts on Pathogenic Mechanisms and Histopathology in Cutaneous Lupus Erythematosus. Front Med (Lausanne) 2022; 9:915828. [PMID: 35712102 PMCID: PMC9196867 DOI: 10.3389/fmed.2022.915828] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/06/2022] [Indexed: 11/13/2022] Open
Abstract
Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune disease that may be limited to the skin or can be associated with systemic lupus erythematosus (SLE). CLE occurs in several morphologic subtypes ranging from isolated, disc-shaped plaques to disseminated skin lesions. The typical histopathologic pattern of skin lesions is named interface dermatitis and characterized by a lymphocytic infiltrate and necroptotic keratinocytes at the dermo-epidermal junction. Other histopathologic patterns primarily involve the dermis or subcutis, depending on the subtype. One critical mechanism in CLE is the chronic reactivation of innate and adaptive immune pathways. An important step in this process is the recognition of endogenous nucleic acids released from dying cells by various pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and other cytosolic receptors. Crucial cells in CLE pathogenesis comprise plasmacytoid dendritic cells (pDCs) as major producers of type I IFN, T cells exerting cytotoxic effects, and B cells, previously believed to contribute via secretion of autoantibodies. However, B cells are increasingly considered to have additional functions, supported by studies finding them to occur in highest numbers in chronic discoid lupus erythematosus (CDLE), a subtype in which autoantibodies are often absent. More precise knowledge of how CLE subtypes differ pathophysiologically may allow a tailored pharmacotherapy in the future, taking into account the specific molecular signature in relation to the morphologic subtype.
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Affiliation(s)
- Tanja Fetter
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
| | | | - Luka de Vos
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
| | - Joerg Wenzel
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
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42
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Plüß M, Piantoni S, Wincup C, Korsten P. Rapid Response of Refractory Systemic Lupus Erythematosus Skin Manifestations to Anifrolumab-A Case-Based Review of Clinical Trial Data Suggesting a Domain-Based Therapeutic Approach. J Clin Med 2022; 11:3449. [PMID: 35743519 PMCID: PMC9225134 DOI: 10.3390/jcm11123449] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/11/2022] [Accepted: 06/13/2022] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite combination treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab, which had been present for more than 12 months. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction in the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach.
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Affiliation(s)
- Marlene Plüß
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany;
| | - Silvia Piantoni
- Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, ASST Spedali Civili and University of Brescia, 25121 Brescia, Italy;
| | - Chris Wincup
- Department of Rheumatology, King’s College Hospital, London SE5 9RS, UK;
| | - Peter Korsten
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany;
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Liu J, Zhang H, Su Y, Zhang B. Application and prospect of targeting innate immune sensors in the treatment of autoimmune diseases. Cell Biosci 2022; 12:68. [PMID: 35619184 PMCID: PMC9134593 DOI: 10.1186/s13578-022-00810-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/09/2022] [Indexed: 12/22/2022] Open
Abstract
Dysregulation of auto-reactive T cells and autoantibody-producing B cells and excessive inflammation are responsible for the occurrence and development of autoimmune diseases. The suppression of autoreactive T cell activation and autoantibody production, as well as inhibition of inflammatory cytokine production have been utilized to ameliorate autoimmune disease symptoms. However, the existing treatment strategies are not sufficient to cure autoimmune diseases since patients can quickly suffer a relapse following the end of treatments. Pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-I like receptors (RLRs), C-type lectin receptors (CLRs) and various nucleic acid sensors, are expressed in both innate and adaptive immune cells and are involved in the development of autoimmune diseases. Here, we have summarized advances of PRRs signaling pathways, association between PRRs and autoimmune diseases, application of inhibitors targeting PRRs and the corresponding signaling molecules relevant to strategies targeting autoimmune diseases. This review emphasizes the roles of different PRRs in activating both innate and adaptive immunity, which can coordinate to trigger autoimmune responses. The review may also prompt the formulation of novel ideas for developing therapeutic strategies against autoimmune diseases by targeting PRRs-related signals.
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Affiliation(s)
- Jun Liu
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Hui Zhang
- NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. .,Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China. .,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. .,Basic and Translational Research Laboratory of Immune Related Diseases, Xi'an, 710061, Shaanxi, China.
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Connelly K, Vettivel J, Golder V, Kandane-Rathnayake R, Morand EF. Measurement of specific organ domains in lupus randomized controlled trials: a scoping review. Rheumatology (Oxford) 2022; 61:1341-1353. [PMID: 34664636 DOI: 10.1093/rheumatology/keab777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs. METHODS We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively. RESULTS Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies. CONCLUSION Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed.
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Affiliation(s)
- Kathryn Connelly
- School of Clinical Sciences, Monash University and
- Department of Rheumatology, Monash Health, Clayton, Vic., Australia
| | | | - Vera Golder
- School of Clinical Sciences, Monash University and
- Department of Rheumatology, Monash Health, Clayton, Vic., Australia
| | | | - Eric F Morand
- School of Clinical Sciences, Monash University and
- Department of Rheumatology, Monash Health, Clayton, Vic., Australia
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Merrill JT, Werth VP, Furie R, van Vollenhoven R, Dörner T, Petronijevic M, Velasco J, Majdan M, Irazoque-Palazuelos F, Weiswasser M, Korish S, Ye Y, Gaudy A, Schafer PH, Liu Z, Agafonova N, Delev N. Phase 2 Trial of Iberdomide in Systemic Lupus Erythematosus. N Engl J Med 2022; 386:1034-1045. [PMID: 35294813 DOI: 10.1056/nejmoa2106535] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Iberdomide, a cereblon modulator promoting degradation of the transcription factors Ikaros and Aiolos, which affect leukocyte development and autoimmunity, is being evaluated for the treatment of systemic lupus erythematosus (SLE). METHODS In this phase 2 trial, we randomly assigned patients in a 2:2:1:2 ratio to receive oral iberdomide (at a dose of 0.45, 0.30, or 0.15 mg) or placebo once daily for 24 weeks, in addition to standard medications. The primary end point at week 24 was a response on the SLE Responder Index (SRI-4), which was defined as a reduction of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 score (a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group 2004 index, and no increase of 0.3 points or more in the Physician's Global Assessment score (on a visual-analogue scale ranging from 0 [no disease activity] to 3 [maximal disease]). RESULTS A total of 288 patients received the assigned intervention: 81 received iberdomide at a dose of 0.45 mg, 82 received iberdomide at a dose of 0.30 mg, 42 received iberdomide at a dose of 0.15 mg, and 83 received placebo. At week 24, the percentages of patients with an SRI-4 response were 54% in the iberdomide 0.45-mg group, 40% in the iberdomide 0.30-mg group, 48% in the iberdomide 0.15-mg group, and 35% in the placebo group (adjusted difference between the iberdomide 0.45-mg group and the placebo group, 19.4 percentage points; 95% confidence interval, 4.1 to 33.4; P = 0.01), with no significant differences between the groups that received the lower doses of iberdomide and the group that received placebo. Iberdomide-associated adverse events included urinary tract and upper respiratory tract infections and neutropenia. CONCLUSIONS In this 24-week, phase 2 trial involving patients with SLE, iberdomide at a dose of 0.45 mg resulted in a higher percentage of patients with an SRI-4 response than did placebo. Data from larger, longer trials are needed to determine the efficacy and safety of iberdomide in SLE. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03161483; EudraCT number, 2016-004574-17.).
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Affiliation(s)
- Joan T Merrill
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Victoria P Werth
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Richard Furie
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Ronald van Vollenhoven
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Thomas Dörner
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Milan Petronijevic
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Jorge Velasco
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Maria Majdan
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Fedra Irazoque-Palazuelos
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Michael Weiswasser
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Shimon Korish
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Ying Ye
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Allison Gaudy
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Peter H Schafer
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Zhaohui Liu
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Nataliya Agafonova
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
| | - Nikolay Delev
- From the Oklahoma Medical Research Foundation, Oklahoma City (J.T.M.); the University of Pennsylvania and the Corporal Michael J. Crescenz VA Medical Center - both in Philadelphia (V.P.W.); Northwell Health, Great Neck, NY (R.F.); Amsterdam University Medical Centers, Amsterdam (R.V.); Charité-Universitätsmedizin, Berlin (T.D.); the Military Medical Academy, Belgrade, Serbia (M.P.); Instituto Centro de Enfermedades Reumáticas, Buenos Aires (J.V.); Independent Public Clinical Hospital Number 4, Medical University of Lublin, Lublin, Poland (M.M.); Centro de Investigación y Tratamiento Reumatológico, Mexico City, Mexico (F.I.-P.); and Bristol Myers Squibb, Princeton, NJ (M.W., S.K., Y.Y., A.G., P.H.S., Z.L., N.A., N.D.)
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Fernandez-Ruiz R, Niewold TB. Type I Interferons in Autoimmunity. J Invest Dermatol 2022; 142:793-803. [PMID: 35016780 PMCID: PMC8860872 DOI: 10.1016/j.jid.2021.11.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/30/2022]
Abstract
Dysregulated IFN-1 responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren's syndrome, and dermatomyositis demonstrate enhanced IFN-1 signaling. IFN-1 excess is associated with disease severity and autoantibodies and could potentially predict response to newer therapies targeting IFN-1 pathways. In this review, we provide an overview of the signaling pathway and immune functions of IFN-1s in health and disease. We also review the systemic autoimmune diseases classically associated with IFN-1 upregulation and current therapeutic strategies targeting the IFN-1 system.
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Affiliation(s)
- Ruth Fernandez-Ruiz
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, New York, USA
| | - Timothy B Niewold
- Judith & Stewart Colton Center for Autoimmunity, Department of Medicine Research, NYU Grossman School of Medicine, New York, New York, USA.
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Sim TM, Ong SJ, Mak A, Tay SH. Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside. Int J Mol Sci 2022; 23:2505. [PMID: 35269647 PMCID: PMC8910773 DOI: 10.3390/ijms23052505] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/21/2022] [Accepted: 02/21/2022] [Indexed: 01/15/2023] Open
Abstract
Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.
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Affiliation(s)
- Tao Ming Sim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; (T.M.S.); (A.M.)
| | - Siying Jane Ong
- Division of Rheumatology, Department of Medicine, National University Hospital, Singapore 119074, Singapore;
| | - Anselm Mak
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; (T.M.S.); (A.M.)
- Division of Rheumatology, Department of Medicine, National University Hospital, Singapore 119074, Singapore;
| | - Sen Hee Tay
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; (T.M.S.); (A.M.)
- Division of Rheumatology, Department of Medicine, National University Hospital, Singapore 119074, Singapore;
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Sternhagen E, Bettendorf B, Lenert A, Lenert PS. The Role of Clinical Features and Serum Biomarkers in Identifying Patients with Incomplete Lupus Erythematosus at Higher Risk of Transitioning to Systemic Lupus Erythematosus: Current Perspectives. J Inflamm Res 2022; 15:1133-1145. [PMID: 35210816 PMCID: PMC8863324 DOI: 10.2147/jir.s275043] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/02/2022] [Indexed: 12/16/2022] Open
Abstract
Discovery of antinuclear antibodies (ANA) enabled earlier diagnosis of systemic lupus erythematosus (SLE) and other ANA+ connective tissue diseases (CTD). Rheumatologists increasingly encounter high referral volume of ANA+ patients. It has been estimated that only a small percentage of these patients will eventually transition to either SLE or other specified CTD. Incomplete lupus erythematosus (ILE) has been defined as a subset of patients who have some SLE-specific clinical manifestations but do not meet currently accepted classification criteria for SLE. Several studies have been performed with the goal of identifying clinical features, serum and tissue biomarkers that can distinguish those patients with ILE at risk of transitioning to SLE from those who will not. Increased autoantibody diversity, presence of anti-double-stranded DNA (dsDNA) antibodies, high expression of type I and type II interferon (IFN)-gene products, increased serum levels of B-cell-activating factor of the TNF family (BAFF), and certain serum cytokines and complement products have been identified as markers with positive predictive value, particularly when combined together. Once this patient population is better characterized biochemically, clinical trials should be considered with the primary objective to completely halt or slow down the transition from ILE to SLE. Hydroxychloroquine (HCQ) appears to be a promising agent due to its good tolerability and low toxicity profile and open-label studies in ILE patients have already shown its ability to delay the onset of SLE. Other therapeutics, like those targeting abnormal type I and type II IFN-signatures, B-cell specific signaling pathways, complement activation pathways and high BAFF levels should also be evaluated, but the risk to benefit ratio must be carefully determined before they can be considered.
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Affiliation(s)
- Erin Sternhagen
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Brittany Bettendorf
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Aleksander Lenert
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
| | - Petar S Lenert
- Division of Immunology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, 52242, USA
- Correspondence: Petar S Lenert, Clinical Professor of Medicine, C428-2GH, 200 Hawkins Drive, Iowa City, Iowa City, 52242, USA, Email
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Abstract
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by remissions and flares. Twenty percent of SLE presents in childhood where the course of SLE is often more severe with significant morbidity and mortality. Several biologic agents have been developed recently for the treatment of lupus, and although some have proven to be safe and efficacious, many have failed to demonstrate significant benefit in clinical trials. There continues to be a desperate need for safe, effective medications that target specific pathway abnormalities seen in SLE. This is an area of intense research that is changing clinical practice in the treatment of childhood SLE. In this article, we discuss the use of B-cell inhibitors, including belimumab and rituximab, as well as the anti-complement drug eculizumab. Promising treatments on the horizon include the jak-stat inhibitors as well as anifrolumab, which targets interferon. [Pediatr Ann. 2022;51(2):e63-e71.].
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Jung SM, Kim WU. Targeted Immunotherapy for Autoimmune Disease. Immune Netw 2022; 22:e9. [PMID: 35291650 PMCID: PMC8901705 DOI: 10.4110/in.2022.22.e9] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/04/2022] Open
Abstract
In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.
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Affiliation(s)
- Seung Min Jung
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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