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Price EJ, Benjamin S, Bombardieri M, Bowman S, Carty S, Ciurtin C, Crampton B, Dawson A, Fisher BA, Giles I, Glennon P, Gupta M, Hackett KL, Larkin G, Ng WF, Ramanan AV, Rassam S, Rauz S, Smith G, Sutcliffe N, Tappuni A, Walsh SB. British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease. Rheumatology (Oxford) 2025; 64:409-439. [PMID: 38621708 PMCID: PMC12013823 DOI: 10.1093/rheumatology/keae152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 03/02/2024] [Indexed: 04/17/2024] Open
Abstract
Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.
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Affiliation(s)
- Elizabeth J Price
- Department of Rheumatology, Great Western Hospital NHS Foundation Trust, Swindon, UK
| | - Stuart Benjamin
- The Academy Library and Information Service, Great Western Hospital NHS Foundation Trust, Swindon, UK
| | - Michele Bombardieri
- Department of Rheumatology, Barts and The London School of Medicine and Dentistry, Barts Health NHS Trust, London, UK
- Centre for Experimental Medicine and Rheumatology, The William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Simon Bowman
- Department of Rheumatology, Milton Keynes University Hospital, Milton Keynes, UK
- Department of Rheumatology, University Hospitals Birmingham NHSFT, Birmingham, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Sara Carty
- Department of Rheumatology, Great Western Hospital NHS Foundation Trust, Swindon, UK
| | - Coziana Ciurtin
- Centre for Rheumatology, Division of Medicine, University College London, London, UK
| | - Bridget Crampton
- Patient Representative, Sjogren’s UK Helpline Lead, Sjogren’s UK (British Sjögren’s Syndrome Association), Birmingham, UK
| | - Annabel Dawson
- Patient Representative, Sjogren’s UK (British Sjögren’s Syndrome Association), Birmingham, UK
| | - Benjamin A Fisher
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ian Giles
- Centre for Rheumatology, Division of Medicine, University College London, London, UK
| | - Peter Glennon
- General Practice, NHS Staffordshire & Stoke on Trent ICB, Stafford, UK
| | - Monica Gupta
- Department of Rheumatology, Gartnavel General Hospital, Glasgow, UK
| | - Katie L Hackett
- Department of Social Work, Education and Community Wellbeing, Northumbria University, Newcastle upon Tyne, UK
| | | | - Wan-Fai Ng
- Translational and Clinical Research Institute & Newcastle NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
- Department of Rheumatology, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Athimalaipet V Ramanan
- Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK
- Translational Health Sciences, University of Bristol, Bristol, UK
| | - Saad Rassam
- Haematology and Haemato-Oncology, KIMS Hospital, Maidstone, Kent, UK
| | - Saaeha Rauz
- Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- Birmingham and Midland Eye Centre, Sandwell and West Birmingham NHS Trust, Birmingham, UK
| | - Guy Smith
- Department of Ophthalmology, Great Western Hospital NHS Foundation Trust, Swindon, UK
| | | | - Anwar Tappuni
- Institute of Dentistry, Queen Mary University of London, London, UK
| | - Stephen B Walsh
- London Tubular Centre, University College London, London, UK
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Zhao T, Zhang R, Li Z, Qin D, Wang X. Novel and potential future therapeutic options in Sjögren's syndrome. Heliyon 2024; 10:e38803. [PMID: 39430463 PMCID: PMC11490770 DOI: 10.1016/j.heliyon.2024.e38803] [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: 05/16/2024] [Revised: 09/28/2024] [Accepted: 09/30/2024] [Indexed: 10/22/2024] Open
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands and can lead to various systemic symptoms impacting multiple organs. Despite its common occurrence, treatment options for SS have been largely limited, primarily focusing on alleviating symptoms rather than addressing the underlying autoimmune causes. A shift towards personalized medicine leads to the development of new therapeutic strategies aimed at targeting specific molecular pathways implicated in SS. Innovations in biologics are paving the way for inhibiting particular cytokines or cell surface molecules directly involved in the autoimmune mechanism. Furthermore, advancements in regenerative medicine, including the promising field of stem cell therapy, offer the potential for restoring or replacing the impaired salivary and lacrimal glands, providing hope for a more permanent resolution to this condition. This review encompasses cutting-edge treatment strategies for SS, spanning clinical and preclinical drugs to the latest treatment technology. Such advancements promise to drive targeted therapy development and inspire innovative ideas for treatment paradigms in SS.
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Affiliation(s)
- Ting Zhao
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, 650500, China
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Runrun Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Zhaofu Li
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Dongdong Qin
- Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan University of Chinese Medicine, Kunming, 650500, China
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Xinchang Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
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Baldini C, Fulvio G, La Rocca G, Ferro F. Update on the pathophysiology and treatment of primary Sjögren syndrome. Nat Rev Rheumatol 2024; 20:473-491. [PMID: 38982205 DOI: 10.1038/s41584-024-01135-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/11/2024]
Abstract
Sjögren syndrome or Sjögren disease is a chronic form of autoimmune epithelitis characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, leading to progressive glandular dysfunction and subsequent xerostomia and xerophthalmia. Other common manifestations include pain and fatigue, various systemic manifestations and non-Hodgkin's lymphoma. Sjögren syndrome is therefore a complex and disabling disease associated with a reduced quality of life and with considerable long-term damage. Most of the available treatments are merely symptomatic with limited efficacy in both preventing glandular damage and suppressing systemic disease activity. In the past 10 years, great progress has been made in understanding the pathophysiology of Sjögren syndrome, opening new avenues towards a more targeted and individualized therapeutic approach to the disease. Indeed, several randomized controlled trials have just been completed or are poised to commence evaluating the effectiveness of novel drugs targeting both innate and adaptive immune pathways, including pro-inflammatory cytokines, the type I interferon system, B cell activation, B cell and T cell co-stimulation pathway, and ectopic germinal centre formation. Novel clinical trials are also ongoing exploring various targeted approaches (that is, IgG recycling inhibition, nuclease therapy and CAR-T cell therapy) for Sjögren syndrome.
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Affiliation(s)
- Chiara Baldini
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Giovanni Fulvio
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gaetano La Rocca
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Ferro
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Hou J, Feng Y, Yang Z, Ding Y, Cheng D, Shi Z, Li R, Xue L. Primary Sjögren's syndrome: new perspectives on salivary gland epithelial cells. Eur J Med Res 2024; 29:371. [PMID: 39014509 PMCID: PMC11253495 DOI: 10.1186/s40001-024-01967-5] [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: 08/13/2023] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease primarily affecting exocrine glands such as the salivary glands, leading to impaired secretion and sicca symptoms. As the mainstay of salivation, salivary gland epithelial cells (SGECs) have an important role in the pathology of pSS. Emerging evidence suggests that the interplay between immunological factors and SGECs may not be the initial trigger or the sole mechanism responsible for xerostomia in pSS, challenging conventional perceptions. To deepen our understanding, current research regarding SGECs in pSS was reviewed. Among the extensive aberrations in cellular architecture and function, this review highlighted certain alterations of SGECs that were identified to occur independently of or in absence of lymphocytic infiltration. In particular, some of these alterations may serve as upstream factors of immuno-inflammatory responses. These findings underscore the significance of introspecting the pathogenesis of pSS and developing interventions targeting SGECs in the early stages of the disease.
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Affiliation(s)
- Jiaqi Hou
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Yiyi Feng
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Zhixia Yang
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Yimei Ding
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Dandan Cheng
- Shanghai Skin Diseases Hospital, 200 Wuyi Road, Changning District, Shanghai, 200050, China
| | - Zhonghao Shi
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Rouxin Li
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China
| | - Luan Xue
- Rheumatology Department, Yueyang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, China.
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Belbézier A, Nguyen TTT, Arnaud M, Ducotterd B, Vangout M, Deroux A, Mansard C, Sarrot-Reynauld F, Bouillet L. Treatment of non-systemic Sjögren's syndrome: Potential prevention of systematization with immunosuppressant agent/biotherapy. J Transl Autoimmun 2024; 8:100238. [PMID: 38496268 PMCID: PMC10940795 DOI: 10.1016/j.jtauto.2024.100238] [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: 01/19/2024] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/19/2024] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune pathology manifested mainly by a dry syndrome, intense asthenia and arthromyalgia. Systemic manifestations may also occur. Since 2019, immunosuppressant agents (IS) or biotherapies are recommended only for patients with systemic involvement. However, before 2019, in some cases, paucisymptomatic patients had been treated with IS/biotherapies, often off-label. Objective: We propose to evaluate the benefit and safety of using IS/biotherapy in patients with SS without systemic involvement. Methods: We retrospectively collected the clinical records of all patients with SS diagnosed according to ACR/EULAR diagnostic criteria followed up between January 1980 and October 2023 at Grenoble University Hospital (France). Results: Eighty-three patients were included: 64 with an initially non-systemic form. Of these patients with an initially non-systemic form, 24 were treated with IS/biotherapy. None of them developed secondary systematization, whereas 11 out of 40 patients in the untreated group did (p < 0.05). On the other hand, IS/biotherapy did not appear to improve dry syndrome. There were no serious adverse events. Conclusion: Early introduction of an IS/biotherapy treatment appears to provide a benefit for the patient without side effects.
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Affiliation(s)
- Aude Belbézier
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Thi Thu Thuy Nguyen
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Mélanie Arnaud
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Bruna Ducotterd
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Marie Vangout
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Alban Deroux
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Catherine Mansard
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Françoise Sarrot-Reynauld
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
| | - Laurence Bouillet
- Clinique Universitaire de Médecine Interne, Department of Internal Medicine, Grenoble University Hospital, F-38000, Grenoble, France
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Byrne L, McCarthy C, Fabre A, Gupta N. Pulmonary Manifestations of Sjögren's Disease. Semin Respir Crit Care Med 2024; 45:397-410. [PMID: 38621712 DOI: 10.1055/s-0044-1785675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Sjögren's disease (SjD) is a chronic, progressive autoimmune condition of exocrine and extraglandular tissues. It can present with isolated disease characterized by lymphocytic infiltration of salivary or lacrimal glands, but in approximately one-third of the patients, lymphocytic infiltration extends beyond exocrine glands to involve extraglandular organs such as the lungs. Pulmonary complications have been reported to occur between 9 and 27% of patients with SjD across studies. Respiratory manifestations occur on a spectrum of severity and include airways disease, interstitial lung disease, cystic lung disease, and lymphoma. Lung involvement can greatly affect patients' quality of life, has a major impact on the overall prognosis, and frequently leads to alteration in the treatment plans, highlighting the importance of maintaining a high index of clinical suspicion and taking appropriate steps to facilitate early recognition and intervention.
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Affiliation(s)
- Louise Byrne
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland
| | - Cormac McCarthy
- Department of Respiratory Medicine, St. Vincent's University Hospital, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Aurelie Fabre
- School of Medicine, University College Dublin, Dublin, Ireland
- Department of Histopathology, St. Vincent's University Hospital, Dublin, Ireland
| | - Nishant Gupta
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio
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Liao J, Yu X, Huang Z, He Q, Yang J, Zhang Y, Chen J, Song W, Luo J, Tao Q. Chemokines and lymphocyte homing in Sjögren's syndrome. Front Immunol 2024; 15:1345381. [PMID: 38736890 PMCID: PMC11082322 DOI: 10.3389/fimmu.2024.1345381] [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: 11/27/2023] [Accepted: 04/15/2024] [Indexed: 05/14/2024] Open
Abstract
Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.
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Affiliation(s)
- Jiahe Liao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Xinbo Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Ziwei Huang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Qian He
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Jianying Yang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Yan Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Jiaqi Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Weijiang Song
- Traditional Chinese Medicine Department, Peking University Third Hospital, Beijing, China
| | - Jing Luo
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
- Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship Hospital, Beijing, China
| | - Qingwen Tao
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
- Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship Hospital, Beijing, China
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Nguyen Y, Beydon M, Foulquier N, Gordon R, Bouillot C, Hammitt KM, Bowman SJ, Mariette X, McCoy SS, Cornec D, Seror R. Identification of outcome domains in primary Sjögren's disease: A scoping review by the OMERACT Sjögren disease working group. Semin Arthritis Rheum 2024; 65:152385. [PMID: 38340608 DOI: 10.1016/j.semarthrit.2024.152385] [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: 08/09/2023] [Revised: 12/29/2023] [Accepted: 01/03/2024] [Indexed: 02/12/2024]
Abstract
OBJECTIVES Sjögren's disease (SjD) is a heterogenous disease with a wide range of manifestations, ranging from symptoms of dryness, fatigue, and pain, to systemic involvement. Considerable advances have been made to evaluate systemic activity or patient-reported outcomes, but most of the instruments were not able to assess all domains of this multifaceted disease. The aim of this scoping review was to generate domains that have been assessed in randomized controlled trials, as the first phase of the Outcome Measures in Rheumatology (OMERACT) process of core domain set development. METHODS We systematically searched Medline (Pubmed) and EMBASE between 2002 and March 2023 to identify all randomized controlled trials assessing relevant domains, using both a manual approach and an artificial intelligence software (BIBOT) that applies natural language processing to automatically identify relevant abstracts. Domains were mapped to core areas, as suggested by the OMERACT 2.1 Filter. RESULTS Among the 5,420 references, we included 60 randomized controlled trials, focusing either on overall disease manifestations (53%) or on a single organ/symptom: dry eyes (17%), xerostomia (15%), fatigue (12%), or pulmonary function (3%). The most frequently assessed domains were perceived dryness (52% for overall dryness), fatigue (57%), pain (52%), systemic disease activity (45%), lacrimal gland function (47%) and salivary function (55%), B-cell activation (60%), and health-related quality of life (40%). CONCLUSION Our scoping review highlighted the heterogeneity of SjD, in the study designs and domains. This will inform the OMERACT SjD working group to select the most appropriate core domains to be used in SjD clinical trials and to guide the future agenda for outcome measure research in SjD.
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Affiliation(s)
- Yann Nguyen
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Center for Immunology of Viral Infections and Auto-immune Diseases (IMVA), Institut pour la Santé et la Recherche Médicale (INSERM), UMR1184, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France
| | - Maxime Beydon
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | | | - Rachael Gordon
- Department of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | | | - Simon J Bowman
- Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Xavier Mariette
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Center for Immunology of Viral Infections and Auto-immune Diseases (IMVA), Institut pour la Santé et la Recherche Médicale (INSERM), UMR1184, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France
| | - Sara S McCoy
- Division of Rheumatology, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, USA
| | - Divi Cornec
- LBAI, UMR1227, Univ Brest, Inserm, Brest, France; INSERM, UMR1227, Lymphocytes B, Autoimmunité et Immunothérapies, Université de Bretagne Occidentale, Service de Rhumatologie, CHU de Brest, Brest, France
| | - Raphaèle Seror
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Center for Immunology of Viral Infections and Auto-immune Diseases (IMVA), Institut pour la Santé et la Recherche Médicale (INSERM), UMR1184, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France.
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9
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Maleki-Fischbach M, Kastsianok L, Koslow M, Chan ED. Manifestations and management of Sjögren's disease. Arthritis Res Ther 2024; 26:43. [PMID: 38331820 PMCID: PMC10851604 DOI: 10.1186/s13075-024-03262-4] [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: 08/23/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024] Open
Abstract
Sjögren's disease is a heterogeneous autoimmune disorder that may be associated with systemic manifestations such as pulmonary or articular involvement. Systemic complications have prognostic implications and need to be identified and managed in a timely manner. Treatment should be tailored to the type and severity of organ involvement, ideally based on multidisciplinary evaluation.
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Affiliation(s)
- Mehrnaz Maleki-Fischbach
- Division of Rheumatology and Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
| | - Liudmila Kastsianok
- Division of Rheumatology and Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA
| | - Matthew Koslow
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA
| | - Edward D Chan
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA
- Pulmonary Section, Rocky Mountain Regional Veterans Affairs Medical Center Aurora, Aurora, CO, USA
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10
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Zhou X, Xu D, Li M, Zeng X. New investigational drugs to treat Sjogren's syndrome: lessons learnt from immunology. Expert Opin Investig Drugs 2024; 33:105-114. [PMID: 38293750 DOI: 10.1080/13543784.2024.2312216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 01/26/2024] [Indexed: 02/01/2024]
Abstract
INTRODUCTION Sjögren's syndrome is a heterogeneous autoimmune condition that impairs quality of life because of dryness, fatigue, pain, and systemic involvements. Current treatment largely depends on empirical evidence, with no effective therapy approved. Clinical trials on targeted drugs often fail to report efficacy due to common factors. AREAS COVERED This review summarizes the pathogenesis and what caused the failure of new investigational drugs in clinical trials, highlighting solutions for more effective investigations, with greater consistency between research outcomes, clinical use, and patient needs. EXPERT OPINION Unlinked pathobiology with symptoms resulted in misidentified targets and disappointing trials. Useful stratification tools are necessary for the heterogeneous SS patients. Composite endpoints or improvements in ESSDAI scores are needed, considering the high placebo response, and the unbalance between symptom burden and disease activity. Compared to classic biologics, targeted cell therapy will be a more promising field of investigation in the coming years.
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Affiliation(s)
- Xingyu Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Dong Xu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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Balint G, Watson Buchanan W, Kean CA, Kean W, Rainsford KD. Sjögren's syndrome. Inflammopharmacology 2024; 32:37-43. [PMID: 37195497 DOI: 10.1007/s10787-023-01222-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 03/27/2023] [Indexed: 05/18/2023]
Abstract
Sjögren's syndrome (SS) is characterised as keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth) commonly associated with salivary gland enlargement, and is referred to as Primary Sjögren's syndrome. It is known as Secondary Sjögren's syndrome when it occurs in patients, with connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, polymyositis, and systemic sclerosis. SS has also been associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation, human immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), chronic biliary cirrhosis, neoplastic and myeloplastic syndromes, fibromyalgia, and chronic fatigue syndrome.
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Affiliation(s)
- Geza Balint
- 3rd Department of Rheumatology, National Institute of Rheumatology and Physiotherapy, Frankel Leó út 27-29, Budapest, 1023, Hungary
| | - W Watson Buchanan
- Department of Medicine, McMaster University, Hamilton, ON, L8P 1H6, Canada
| | - Colin A Kean
- Haldimand War Memorial Hospital, 400 Broad Street, Dunnville, ON, N1A 2P7, Canada
| | - Walter Kean
- Department of Medicine, McMaster University, Hamilton, ON, L8P 1H6, Canada.
- Haldimand War Memorial Hospital, 400 Broad Street, Dunnville, ON, N1A 2P7, Canada.
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Zervou MI, Tarlatzis BC, Grimbizis GF, Spandidos DA, Niewold TB, Goulielmos GN. Association of endometriosis with Sjögren's syndrome: Genetic insights (Review). Int J Mol Med 2024; 53:20. [PMID: 38186322 PMCID: PMC10781419 DOI: 10.3892/ijmm.2024.5344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 12/20/2023] [Indexed: 01/09/2024] Open
Abstract
Patients with a history of endometriosis have an increased risk of developing various autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and celiac disease. There is a potential association between endometriosis and an increased susceptibility for Sjögren's syndrome (SS). SS is a common chronic, inflammatory, systemic, autoimmune, multifactorial disease of complex pathology, with genetic, epigenetic and environmental factors contributing to the development of this condition. It occurs in 0.5‑1% of the population, is characterized by the presence of ocular dryness, lymphocytic infiltrations and contributes to neurological, gastrointestinal, vascular and dermatological manifestations. Endometriosis is an inflammatory, estrogen‑dependent, multifactorial, heterogeneous gynecological disease, affecting ≤10% of reproductive‑age women. It is characterized by the occurrence of endometrial tissue outside the uterine cavity, mainly in the pelvic cavity, and is associated with pelvic pain, dysmenorrhea, deep dyspareunia and either subfertility or infertility. It is still unclear whether SS appears as a secondary response to endometriosis, or it is developed due to any potential shared mechanisms of these conditions. The aim of the present review was to explore further the biological basis only of the co‑occurrence of these disorders but not their association at clinical basis, focusing on the analysis of the partially shared genetic background between endometriosis and SS, and the clarification of the possible similarities in the underlying pathogenetic mechanisms and the relevant molecular pathways.
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Affiliation(s)
- Maria I. Zervou
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
| | - Basil C. Tarlatzis
- First Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Grigoris F. Grimbizis
- Unit for Human Reproduction, First Department of Obstetrics and Gynecology, 'Papageorgiou' General Hospital, Aristotle University Medical School, 56403 Thessaloniki, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71403 Heraklion, Greece
| | - Timothy B. Niewold
- Barbara Volcker Center for Women and Rheumatic Disease, New York, NY 10021, USA
- Hospital for Special Surgery, New York, NY 10021, USA
| | - George N. Goulielmos
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
- Department of Internal Medicine, University Hospital of Heraklion, 71500 Heraklion, Greece
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13
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Liu R, Zhang Y, Li K, Xu H, Cheng Z, Pang F, Wu H, Guo Z, He J, Tang X, Zhou X, Jiang Q. Effect of acupuncture on regulating IL-17, TNF-ɑ and AQPs in Sjögren's syndrome. Oral Dis 2024; 30:50-62. [PMID: 37518974 DOI: 10.1111/odi.14680] [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: 04/08/2023] [Revised: 06/19/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
AIM The aim of the study was to observe the effect of acupuncture on regulating interleukin (IL)-17, tumor necrosis factor (TNF)-ɑ, and aquaporins (AQPs) in Sjögren's syndrome (SS) on patients and on non-obese diabetic (NOD) models. METHODS Levels of anti-AQP 1, 5, 8, and 9 antibodies, IL-17, and TNF-ɑ in the serum of SS patients were compared prior and following 20 acupuncture treatment visits during 8 weeks. While in murine model, five groups were divided to receive interventions for 4 weeks, including control, model, acupuncture, isoflurane, and hydroxychloroquine. The submaxillofacial gland index, histology, immunohistochemistry of AQP1, 5, salivary flow, together with IL-17, and TNF-ɑ expression in peripheral blood were compared among the groups. RESULTS Acupuncture reduced IL-17, TNF-ɑ, and immunoglobin A levels, and numeric analog scale of dryness in 14 patients with SS (p < 0.05). The salivary flow was increased, and the water intake decreased in NOD mice receiving acupuncture treatments. IL-17 and TNF-ɑ levels in peripheral serum were down-regulated (p < 0.05) and AQP1, 5 expression in the submandibular glands up-regulated in mice. CONCLUSION The effect on relieving xerostomia with acupuncture may be achieved by up-regulating the expression of AQP1. AQP5, down-regulating levels of IL-17 and TNF-ɑ, and a decrease in inflammation of glands.
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Affiliation(s)
- Ruihua Liu
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kesong Li
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Haodong Xu
- Department of Rheumatology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Zengyu Cheng
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengtao Pang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hengbo Wu
- Department of Rheumatology, Xi'an Hospital of Traditional Chinese Medicine, Shanxi, China
| | - Zilin Guo
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiale He
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaopo Tang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinyao Zhou
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Quan Jiang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Fox RI, Fox CM, McCoy SS. Emerging treatment for Sjögren's disease: a review of recent phase II and III trials. Expert Opin Emerg Drugs 2023; 28:107-120. [PMID: 37127914 PMCID: PMC10330372 DOI: 10.1080/14728214.2023.2209720] [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: 01/20/2023] [Accepted: 04/28/2023] [Indexed: 05/03/2023]
Abstract
INTRODUCTION Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients' quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry. AREAS COVERED The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences. EXPERT OPINION This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.
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Affiliation(s)
- Robert I. Fox
- Scripps Memorial Hospital and Research Foundation, San Diego, California, United States
| | - Carla M. Fox
- Scripps Memorial Hospital and Research Foundation, San Diego, California, United States
| | - Sara S. McCoy
- University of Wisconsin-Madison Ringgold standard institution, Madison, United States
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Blinova VG, Vasilyev VI, Rodionova EB, Zhdanov DD. The Role of Regulatory T Cells in the Onset and Progression of Primary Sjögren's Syndrome. Cells 2023; 12:1359. [PMID: 37408193 DOI: 10.3390/cells12101359] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 07/07/2023] Open
Abstract
Regulatory T cells (Tregs) play a key role in maintaining immune balance and regulating the loss of self-tolerance mechanisms in various autoimmune diseases, including primary Sjögren's syndrome (pSS). With the development of pSS primarily in the exocrine glands, lymphocytic infiltration occurs in the early stages, mainly due to activated CD4+ T cells. Subsequently, in the absence of rational therapy, patients develop ectopic lymphoid structures and lymphomas. While the suppression of autoactivated CD4+ T cells is involved in the pathological process, the main role belongs to Tregs, making them a target for research and possible regenerative therapy. However, the available information about their role in the onset and progression of this disease seems unsystematized and, in certain aspects, controversial. In our review, we aimed to organize the data on the role of Tregs in the pathogenesis of pSS, as well as to discuss possible strategies of cell therapy for this disease. This review provides information on the differentiation, activation, and suppressive functions of Tregs and the role of the FoxP3 protein in these processes. It also highlights data on various subpopulations of Tregs in pSS, their proportion in the peripheral blood and minor salivary glands of patients as well as their role in the development of ectopic lymphoid structures. Our data emphasize the need for further research on Tregs and highlight their potential use as a cell-based therapy.
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Affiliation(s)
- Varvara G Blinova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| | - Vladimir I Vasilyev
- Joint and Heart Treatment Center, Nizhnyaya Krasnoselskaya St. 4, 107140 Moscow, Russia
| | | | - Dmitry D Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
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Tsuboi H, Toko H, Honda F, Abe S, Takahashi H, Yagishita M, Hagiwara S, Ohyama A, Kondo Y, Nakano K, Tanaka Y, Shimizu T, Nakamura H, Kawakami A, Fujieda Y, Atsumi T, Suzuki Y, Kawano M, Nishina N, Kaneko Y, Takeuchi T, Kobayashi H, Takei M, Ogasawara M, Tamura N, Takasaki Y, Yokota K, Akiyama Y, Mimura T, Murakami K, Mimori T, Ohshima S, Azuma N, Sano H, Nishiyama S, Matsumoto I, Sumida T. Abatacept ameliorates both glandular and extraglandular involvements in patients with Sjögren's syndrome associated with rheumatoid arthritis: Findings from an open-label, multicentre, 1-year, prospective study: The ROSE (Rheumatoid Arthritis with Orencia Trial Toward Sjögren's Syndrome Endocrinopathy) and ROSE II trials. Mod Rheumatol 2023; 33:160-168. [PMID: 35134994 DOI: 10.1093/mr/roac011] [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: 11/18/2021] [Revised: 01/11/2022] [Accepted: 01/16/2022] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). MATERIALS AND METHODS We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon's test, Schirmer's test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. RESULTS 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients. CONCLUSION Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in SS associated with RA.
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Affiliation(s)
- Hiroto Tsuboi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hirofumi Toko
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Fumika Honda
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Saori Abe
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroyuki Takahashi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Mizuki Yagishita
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Shinya Hagiwara
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Ayako Ohyama
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yuya Kondo
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kazuhisa Nakano
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Toshimasa Shimizu
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hideki Nakamura
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.,Department of Medicine, Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuichiro Fujieda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Yasunori Suzuki
- Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
| | - Mitsuhiro Kawano
- Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan
| | - Naoshi Nishina
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kaneko
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Tsutomu Takeuchi
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Hitomi Kobayashi
- Department of Medicine, Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Masami Takei
- Department of Medicine, Division of Hematology and Rheumatology, Nihon University School of Medicine, Tokyo, Japan
| | - Michihiro Ogasawara
- Department of Internal Medicine and Rheumatology, Juntendo University, School of Medicine, Tokyo, Japan
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University, School of Medicine, Tokyo, Japan
| | - Yoshinari Takasaki
- Department of Internal Medicine and Rheumatology, Juntendo University, School of Medicine, Tokyo, Japan
| | - Kazuhiro Yokota
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yuji Akiyama
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Toshihide Mimura
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Kosaku Murakami
- Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan
| | - Shiro Ohshima
- Department of Rheumatology and Allergology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan
| | - Naoto Azuma
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Hyogo, Japan
| | - Hajime Sano
- Department of Internal Medicine, Division of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Hyogo, Japan
| | - Susumu Nishiyama
- Rheumatic Disease Center, Kurashiki Medical Center, Okayama, Japan
| | - Isao Matsumoto
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Takayuki Sumida
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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Ritter J, Chen Y, Stefanski AL, Dörner T. Current and future treatment in primary Sjögren's syndrome - A still challenging development. Joint Bone Spine 2022; 89:105406. [PMID: 35537697 DOI: 10.1016/j.jbspin.2022.105406] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/14/2022] [Accepted: 04/20/2022] [Indexed: 11/17/2022]
Abstract
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by sicca symptoms, systemic manifestations and constitutional symptoms substantially diminishing patient's quality of life. In this review, we summarize recent recommendations for management of pSS patients and current clinical studies in pSS addressing unmet medical needs. Expanding knowledge about disease pathogenesis and the introduction of validated outcome measures, such as capturing disease activity (ESSDAI) and patient-reported outcomes (ESSPRI) have shaped recent developments. In contrast, lack of evidence for current treatment options remarkably limits the management of pSS patients as reflected by the 2019 updated EULAR recommendations for management of Sjögren's syndrome. In this context, symptomatic treatment is usually appropriate for sicca symptoms, whereas systemic treatment is reserved for moderate to severe organ manifestations including care by a multidisciplinary team in centers of expertise. Most promising targets for new treatment modalities are based on immunopathological insights and include direct B cell targeting strategies, targeting co-stimulation by CD40/CD40L blocking, inhibition of key cytokine activity (BLyS/BAFF, type I interferon) and intracellular signaling pathways.
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Affiliation(s)
- Jacob Ritter
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany
| | - Yidan Chen
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Ana-Luisa Stefanski
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany
| | - Thomas Dörner
- Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Gesellschaft, Berlin, Germany.
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Sequí-Sabater JM, Beretta L. Defining the Role of Monocytes in Sjögren's Syndrome. Int J Mol Sci 2022; 23:ijms232112765. [PMID: 36361554 PMCID: PMC9654893 DOI: 10.3390/ijms232112765] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 01/24/2023] Open
Abstract
Sjögren's syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin's lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren's syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren's syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren's syndrome pathophysiology and redefine the involvement of monocytes in this disease.
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Affiliation(s)
- Jose Miguel Sequí-Sabater
- Rheumatology Department, Reina Sofía University Hospital, Menéndez Pidal Ave., 14005 Córdoba, Spain
- Maimonides Institute for Research in Biomedicine of Córdoba (IMIBIC), University of Córdoba, Menéndez Pidal Ave., 14005 Córdoba, Spain
| | - Lorenzo Beretta
- Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano, Francesco Sforza St. 35, 20122 Milan, Italy
- Correspondence:
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Sebastian A, Madej M, Gajdanowicz P, Sebastian M, Łuczak A, Zemelka-Wiącek M, Jutel M, Wiland P. Interferon Gamma Targeted Therapy: Is It Justified in Primary Sjögren's Syndrome? J Clin Med 2022; 11:jcm11185405. [PMID: 36143051 PMCID: PMC9504735 DOI: 10.3390/jcm11185405] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/01/2022] [Accepted: 09/13/2022] [Indexed: 11/21/2022] Open
Abstract
Background: The pathomechanism of primary Sjögren syndrome (pSS) is multifactorial. Many cytokines take part in this process, including interferon. The study aimed to quantify certain cytokines involved in the pathomechanism of primary Sjögren syndrome (IL2, IL5, IL6, IL10, IL13, TNFα, IFNγ) and determine their common clinical correlation. On this basis, we discuss the potential use of anti-cytokine drugs in pSS therapy. Methods: The study group consisted of adult patients with a confirmed diagnosis of pSS. Results: The most frequently detected cytokines were IFNγ (82% of patients), TNFα (70%), IL6 (50%), and IL2 (42.5%). In all patients, except for one patient, IFNγ was found in the presence of other specific cytokines. There was no difference in clinical symptoms, age, and laboratory test results between the group of patients with IL-6 + TNFα + IFNγ positive cytokine, and the group of patients in whom they were not detected. There was no correlation between the presence of IL5, IL13, IL2, IL6, IL10, TNFα and musculoskeletal symptoms, skin lesions, glandular domains, pulmonary neurological, lymphadenopathy, biological and hematological domains in ESSDAI (p > 0.05). Conclusions: IFNγ most likely plays a central role in the pathomechanism of the disease. We have not noticed a clinical correlation between the three most common cytokines (IL6, IFNγ and TNFα), preliminary research results open up the possibility of searching for new treatments for pSS. The lower percentage of patients with detectable levels of TNFα and IL6 may explain the ineffectiveness of drugs targeting cytokines in clinical trials to date.
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Affiliation(s)
- Agata Sebastian
- Department of Rheumatology and Internal Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
- Correspondence:
| | - Marta Madej
- Department of Rheumatology and Internal Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Paweł Gajdanowicz
- Department of Clinical Immunology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Maciej Sebastian
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Anna Łuczak
- Department of Rheumatology and Internal Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | | | - Marek Jutel
- Department of Clinical Immunology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Piotr Wiland
- Department of Rheumatology and Internal Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
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Ocular Manifestations in Patients with Inflammatory Bowel Disease in the Biologics Era. J Clin Med 2022; 11:jcm11154538. [PMID: 35956153 PMCID: PMC9369806 DOI: 10.3390/jcm11154538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 01/27/2023] Open
Abstract
Background: Extra-intestinal manifestations are frequent in inflammatory bowel disease (IBD). Ocular disorders are generally under diagnosed as they are challenging diagnosis. Aims: We assessed the prevalence of ophthalmological manifestations in patients with IBD, and investigated characteristics associated with ocular manifestations. Methods: We performed a retrospective study including patients followed for IBD and had an ophthalmologic visit from January 2013 to July 2020, among 1432 patients followed during this period. Two groups were considered: the first group included patients whose an ocular diagnosis was considered as “related to IBD”, and the second group including patients whose an ocular diagnosis was considered “not related to IBD”. Results: Among 1432 patients with IBD, eighty-seven (6.1%) patients had an ophthalmologic visit. Fifty-three patients (3.7%) were considered to have an ocular extra-intestinal manifestation or an iatrogenic effect of IBD treatment, and 34 diagnoses (2.4%) were considered not related to IBD. Inflammatory surface pathologies were the most frequent (33.2%), including 15 patients with dry eye (17.2%), 9 with blepharitis (10.3%), and 5 with chalazions (meibomian cyst) (5.7%). Uveitis was diagnosed in 13 patients (14.9%), episcleritis in 5 patients (5.7%), and scleritis in 2 patients (2.3%). Characteristics of patients with an ophthalmological diagnosis “related to IBD” versus “not related to IBD” were not statistically different. Conclusion: In our cohort, less than 5% of patients had ophthalmological extra-intestinal manifestation. The most frequent ocular diagnosis were dry eye and uveitis. No disease characteristics of IBD were found to be associated with ocular manifestations.
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Zhou X, Xu H, Chen J, Wu H, Zhang Y, Tian F, Tang X, Zhang H, Ge L, Li K, Jiang W, Liu Z, Jiang Q. Efficacy and Safety of Acupuncture on Symptomatic Improvement in Primary Sjögren's Syndrome: A Randomized Controlled Trial. Front Med (Lausanne) 2022; 9:878218. [PMID: 35602489 PMCID: PMC9121854 DOI: 10.3389/fmed.2022.878218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/17/2022] [Indexed: 01/24/2023] Open
Abstract
Aim We sought to evaluate the efficacy of acupuncture in treating the main symptoms of primary Sjögren's syndrome, specifically dryness, pain, and fatigue. Methods A total of 120 patients with primary Sjögren's syndrome were randomized in a parallel-group, controlled trial. Participants received acupuncture or sham acupuncture for the first 8 weeks, then were followed for 16 weeks thereafter. The primary outcome was the proportion of participants with a ≥ 30% reduction in ≥ 2 of 3 numeric analog scale scores for dryness, pain, and fatigue. The secondary outcomes included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-reported Index (ESSPRI); the EULAR Sjögren's Syndrome Disease Activity Index; the Schirmer test score; unstimulated saliva flow; serum immunoglobulin G, A, and M concentrations; the Medical Outcome Study Short Form 36 score; salivary gland ultrasound imaging; and the Hospital Anxiety and Depression Scale score. Results The proportions of patients meeting the primary endpoint were 28.33% (17/60) in the acupuncture group and 31.66% (19/60) in the sham group, without a statistically significant difference (P = 0.705). The IgG concentration at week 16 and the homogeneity in ultrasonography of the salivary glands at week 8 showed significant differences between the 2 groups (P = 0.0490 and P = 0.0334, respectively). No other differences were observed between the 2 groups. ESSPRI and unstimulated saliva flow were improved in both groups compared to baseline, albeit with a significant difference between them. Conclusion In patients with primary Sjögren's syndrome, acupuncture did not satisfactorily improve symptoms compared to placebo. However, interesting discoveries and possible underlying reasons were demonstrated and discussed, which may be useful to studies in the future. Clinical Trial Registration [www.ClinicalTrials.gov], identifier [NCT02691377].
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Affiliation(s)
- Xinyao Zhou
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Haodong Xu
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Postgraduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jinzhou Chen
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Intensive Care Unit, Meishan Hospital of Traditional Chinese Medicine, Meishan, China
| | - Hengbo Wu
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Postgraduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Zhang
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Feng Tian
- Beijing CreateMed Medicine Technology Co., Ltd., Beijing, China
| | - Xiaopo Tang
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huadong Zhang
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Ge
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kesong Li
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen Jiang
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhishun Liu
- Department of Acupuncture and Moxibustion, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Quan Jiang
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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22
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Atzeni F, Gozza F, Cafaro G, Perricone C, Bartoloni E. Cardiovascular Involvement in Sjögren’s Syndrome. Front Immunol 2022; 13:879516. [PMID: 35634284 PMCID: PMC9134348 DOI: 10.3389/fimmu.2022.879516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/22/2022] [Indexed: 12/26/2022] Open
Abstract
Sjögren Syndrome (SS) seems to be associated with a greater “overall risk” of cardiovascular (CV) and cerebrovascular events. Although not conventionally considered a feature of the disease, CV events represent a major burden in SS patients. CV risk is the consequence of a complex combination of multiple factors, including traditional risk factors and disease-related mechanisms. A complex relationships between disease-related features, endothelial dysfunction and traditional risk factor has been suggested. Several drugs are available for treating the systemic manifestations of SS, however they have shown positive effects on different outcomes of the disease, but until today the data on the role of these drugs on CV events are scarse. Given these data, the aim of this review was to evaluate the risk of CV risk in primary SS and the effect of the drugs on this manifestation.
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Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
- *Correspondence: Fabiola Atzeni,
| | - Francesco Gozza
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Giacomo Cafaro
- Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Carlo Perricone
- Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elena Bartoloni
- Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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23
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Vargas JFDC, Skare T, Gehlen ML, Moreira ATR. Subconjunctival adalimumab for treatment of dry eye disease in Sjögren’s syndrome. REVISTA BRASILEIRA DE OFTALMOLOGIA 2022. [DOI: 10.37039/1982.8551.20220003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Chen G, Che L, Cai X, Zhu P, Ran J. Bioinformatic Analysis Identifies Biomarkers and Treatment Targets in Primary Sjögren's Syndrome Patients with Fatigue. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7697558. [PMID: 35075430 PMCID: PMC8783724 DOI: 10.1155/2022/7697558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/23/2021] [Indexed: 11/17/2022]
Abstract
We aim to identify the common genes, biological pathways, and treatment targets for primary Sjögren's syndrome patients with varying degrees of fatigue features. We select datasets about transcriptomic analyses of primary Sjögren's syndrome (pSS) patients with different degrees of fatigue features and normal controls in peripheral blood. We identify common differentially expressed genes (DEGs) to find shared pathways and treatment targets for pSS patients with fatigue and design a protein-protein interaction (PPI) network by some practical bioinformatic tools. And hub genes are detected based on the PPI network. We perform biological pathway analysis of common genes by Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Lastly, potential treatment targets for pSS patients with fatigue are found by the Enrichr platform. We discovered that 27 DEGs are identified in pSS patients with fatigue features and the severe fatigued pSS-specific gene is RTP4. DEGs are mainly localized in the mitochondria, endosomes, endoplasmic reticulum, and cytoplasm and are involved in the biological process by which interferon acts on cells and cells defend themselves against viruses. Molecular functions mainly involve the process of RNA synthesis. The DEGs of pSS are involved in the signaling pathways of viruses such as hepatitis C, influenza A, measles, and EBV. Acetohexamide PC3 UP, suloctidil HL60 UP, prenylamine HL60 UP, and chlorophyllin CTD 00000324 are the four most polygenic drug molecules. PSS patients with fatigue features have specific gene regulation, and chlorophyllin may alleviate fatigue symptoms in pSS patients.
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Affiliation(s)
- Guangshu Chen
- Department of Endocrinology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Li Che
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Xingdong Cai
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Ping Zhu
- Department of Endocrinology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
| | - Jianmin Ran
- Department of Endocrinology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, China
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25
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Saraux A, Devauchelle-Pensec V. Primary Sjögren's syndrome: new beginning for evidence-based trials. Lancet 2022; 399:121-122. [PMID: 34861169 DOI: 10.1016/s0140-6736(21)02644-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/29/2022]
Affiliation(s)
- Alain Saraux
- Department of Rheumatology, Centre Hospitalier Universitaire de la Cavale Blanche, Brest, France; Université de Brest, INSERM UMR 1227, Labex Immunotherapy, Graft, Oncology, Brest 29609, France.
| | - Valérie Devauchelle-Pensec
- Department of Rheumatology, Centre Hospitalier Universitaire de la Cavale Blanche, Brest, France; Université de Brest, INSERM UMR 1227, Labex Immunotherapy, Graft, Oncology, Brest 29609, France
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26
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Bhatt M, Shende P. Modulated approaches for strategic transportation of proteins and peptides via ocular route. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Targeted Therapy for Primary Sjögren's Syndrome: Where are We Now? BioDrugs 2021; 35:593-610. [PMID: 34731460 DOI: 10.1007/s40259-021-00505-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2021] [Indexed: 10/19/2022]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy characterized by dryness symptoms. This review briefly describes recent advances in the targeted therapies for pSS. Biologics evaluated for pSS treatment mainly include B cell-depleting agents, inhibitors of B cell activation, and agents that target co-signaling molecules or proinflammatory cytokines. Small molecule inhibitors that target signaling pathways have also been evaluated. However, current evidence for the efficacy of targeted therapies in pSS is still sparse. Although ianalumab (an anti-B cell-activating factor [BAFF]-receptor antibody) and iscalimab (an anti-CD40 antibody) are promising biologics for pSS, their efficacy still needs to be evaluated in larger clinical trials. For other biologics, clinical trials have found no differences versus placebo in the change from baseline in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score and fatigue score. Possible causes of the disappointing outcomes mainly include the inefficacy of those evaluated biologics in treating pSS, the high heterogeneous nature of pSS, irreversible exocrine glandular failure at advanced disease stages, inappropriate recruitment strategy in clinical trials, and outcome measures. Early diagnosis and glandular function-centered outcome measures may help to improve the current situation in the systemic therapy of pSS.
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Tian Y, Yang H, Liu N, Li Y, Chen J. Advances in Pathogenesis of Sjögren's Syndrome. J Immunol Res 2021; 2021:5928232. [PMID: 34660815 PMCID: PMC8516582 DOI: 10.1155/2021/5928232] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/01/2021] [Accepted: 09/08/2021] [Indexed: 01/09/2023] Open
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology that mainly involves exocrine glands. Patients present with dry mouth and eyes, fever, arthralgia, and other systemic symptoms. In severe cases, the quality of life of patients is affected. At present, there is no cure for SS, and the treatment options are extremely limited. In recent years, studies of patients and animal models have identified abnormalities of immune cell function and cytokines to be involved in SS. A systematic review of the literature may clarify the etiology and pathogenesis of SS, as well as provide a theoretical basis for the development of new drugs for the treatment of SS.
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Affiliation(s)
- Yao Tian
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
| | - Hongyi Yang
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
| | - Na Liu
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
| | - Yan Li
- Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jie Chen
- Department of Science and Techonology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
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29
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Seror R, Nocturne G, Mariette X. Current and future therapies for primary Sjögren syndrome. Nat Rev Rheumatol 2021; 17:475-486. [PMID: 34188206 DOI: 10.1038/s41584-021-00634-x] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2021] [Indexed: 02/06/2023]
Abstract
Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics.
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Affiliation(s)
- Raphaèle Seror
- Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France
| | - Gaetane Nocturne
- Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France
| | - Xavier Mariette
- Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France.
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30
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Vitali C, Minniti A, Pignataro F, Maglione W, Del Papa N. Management of Sjögren's Syndrome: Present Issues and Future Perspectives. Front Med (Lausanne) 2021; 8:676885. [PMID: 34164418 PMCID: PMC8215198 DOI: 10.3389/fmed.2021.676885] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 04/06/2021] [Indexed: 12/15/2022] Open
Abstract
In view of the new possibilities for the treatment of primary Sjögren's syndrome (pSS) given by the availability of new biotechnological agents targeting the various molecular and cellular actors of the pathological process of the disease, classification criteria aimed at selecting patients to be enrolled in therapeutic trials, and validated outcome measures to be used as response criteria to these new therapies, have been developed and validated in the last decades. Unfortunately, the therapeutic trials so far completed with these new treatments have yielded unsatisfactory or only partially positive results. The main issues that have been evoked to justify the poor results of the new therapeutic attempts are: (i) the extreme variability of the disease phenotypes of the patients enrolled in the trials, which are dependent on different underlying patterns of biological mechanisms, (ii) the fact that the disease has a long indolent course, and that most of the enrolled patients might already have irreversible clinical features. The advances in the research of new disease biomarkers that can better distinguish the different clinical phenotypes of patients and diagnose the disease in an earlier phase are also discussed.
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Affiliation(s)
- Claudio Vitali
- Rheumatology Outpatient Clinics, "Mater Domini" Humanitas Hospital, Castellanza, Italy
| | | | | | - Wanda Maglione
- Department of Rheumatology, ASST G. Pini-CTO, Milan, Italy
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Felten R, Devauchelle-Pensec V, Seror R, Duffau P, Saadoun D, Hachulla E, Pierre Yves H, Salliot C, Perdriger A, Morel J, Mékinian A, Vittecoq O, Berthelot JM, Dernis E, Le Guern V, Dieudé P, Larroche C, Richez C, Martin T, Zarnitsky C, Blaison G, Kieffer P, Maurier F, Dellal A, Rist S, Andres E, Contis A, Chatelus E, Sordet C, Sibilia J, Arnold C, Tawk MY, Aberkane O, Holterbach L, Cacoub P, Saraux A, Mariette X, Meyer N, Gottenberg JE. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis 2021; 80:329-338. [PMID: 33208345 DOI: 10.1136/annrheumdis-2020-218467] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVES No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications. METHODS Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment. RESULTS 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14). CONCLUSION Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo. TRIAL REGISTRATION NUMBER NCT01782235.
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Affiliation(s)
- Renaud Felten
- Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
| | | | - Raphaèle Seror
- Rheumatology, Université Paris-Sud BU Kremlin-Bicêtre, Le Kremlin-Bicetre, Île-de-France, France
| | - Pierre Duffau
- Internal Medicine, CHU de Bordeaux, Bordeaux, Aquitaine, France
| | - David Saadoun
- University Hospital Pitié Salpêtrière, Paris, Île-de-France, France
| | - Eric Hachulla
- Internal Medicine, Regional and University Hospital Centre Lille Internal Medicine Service, Lille, Hauts-de-France, France
| | - Hatron Pierre Yves
- Internal Medicine, Regional and University Hospital Centre Lille Internal Medicine Service, Lille, Hauts-de-France, France
| | - Carine Salliot
- Rheumatology, Regional Hospital Centre Orleans La Source Hospital, Orleans, Centre, France
| | - Aleth Perdriger
- Rheumatology, University Hospital Centre Rennes, Rennes, Bretagne, France
| | - Jacques Morel
- CHU Lapeyronie, Montpellier, Languedoc-Roussillon, France
| | - Arsène Mékinian
- Internal Medicine, Hospital Saint-Antoine, Paris, Île-de-France, France
| | - Olivier Vittecoq
- Rheumatology, University Hospital Centre Rouen, Rouen, Normandie, France
| | | | | | | | - Philippe Dieudé
- Rheumatology, Hôpital Bichat Claude-Bernard, Paris, Île-de-France, France
| | - Claire Larroche
- Internal Medicine, Hospital Avicenne, Bobigny, Île-de-France, France
| | - Christophe Richez
- Rheumatology, CHU Bordeaux GH Pellegrin, Bordeaux, Aquitaine, France
| | - Thierry Martin
- Internal Medicine, CHU Strasbourg, Strasbourg, Alsace, France
| | - Charles Zarnitsky
- Rheumatology, Hôpital Jacques Monod, Montivilliers, Normandy, France
| | | | - Pierre Kieffer
- Internal Medicine, CH Mulhouse, Mulhouse, Grand Est, France
| | - François Maurier
- Internal Medicine, Sainte Blandine Hospital, Metz, Lorraine, France
| | - Azeddine Dellal
- Rheumatology, GHI Le Raincy-Montfermeil, Montfermeil, Île-de-France, France
| | - Stephanie Rist
- Rheumatology, Regional Hospital Centre Orleans La Source Hospital, Orleans, Centre, France
| | - Emmanuel Andres
- Internal Medicine, CHU Strasbourg, Strasbourg, Alsace, France
| | - Anne Contis
- Internal Medicine, CHU de Bordeaux, Bordeaux, Aquitaine, France
| | - Emmanuel Chatelus
- Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
| | - Christelle Sordet
- Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
| | - Jean Sibilia
- Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
| | | | - Mira Y Tawk
- DRCI, CHU Strasbourg, Strasbourg, Alsace, France
| | | | - Lise Holterbach
- Public Health, Methods in Clinical Research Team, Hopitaux universitaires de Strasbourg, Strasbourg, Alsace, France
| | - Patrice Cacoub
- University Hospital Pitié Salpêtrière, Paris, Île-de-France, France
| | - Alain Saraux
- Rheumatology, Hospital Cavale-Blanche, Brest, Bretagne, France
| | - Xavier Mariette
- Rheumatology, Université Paris-Sud BU Kremlin-Bicêtre, Le Kremlin-Bicetre, Île-de-France, France
| | - Nicolas Meyer
- Public Health, Methods in Clinical Research Team, Hopitaux universitaires de Strasbourg, Strasbourg, Alsace, France
| | - Jacques-Eric Gottenberg
- Rheumatology, CHU Strasbourg, Centre National de Référence des maladies auto-immunes et systémiques rares Est/Sud-Ouest (RESO), Strasbourg, Alsace, France
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Padern G, Duflos C, Ferreira R, Assou S, Guilpain P, Maria ATJ, Goulabchand R, Galea P, Jurtela M, Jorgensen C, Pers YM. Identification of a Novel Serum Proteomic Signature for Primary Sjögren's Syndrome. Front Immunol 2021; 12:631539. [PMID: 33708222 PMCID: PMC7942395 DOI: 10.3389/fimmu.2021.631539] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/04/2021] [Indexed: 12/13/2022] Open
Abstract
Context Primary Sjögren's syndrome (pSS) is a complex heterogeneous autoimmune disease (AID) which can mimic rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Our exploratory study investigated serum biomarkers that may discriminate pSS from RA and SLE. Methods Serum concentrations of 63 biomarkers involved in immune cell trafficking, inflammatory response, cellular movement, and cell-to-cell signaling were measured in AID patients, included prospectively into the study at the Montpellier University Hospital. A multivariate analysis by multiple logistic regression was performed, and discriminative power assessed using logistic regression adjusted on significant demographic factors. Results Among the 95 patients enrolled, 42 suffered from pSS, 28 from RA, and 25 from SLE. Statistical analysis showed that concentrations of BDNF (OR = 0.493 with 95% CI [0.273-0.891]; p = 0.0193) and I-TAC/CXCL11 (OR = 1.344 with 95% CI [1.027-1.76]; p = 0.0314) can significantly discriminate pSS from RA. Similarly, greater concentrations of sCD163 (OR = 0.803 with 95% CI [0.649-0.994]; p = 0.0436), Fractalkine/CX3CL1 (OR = 0.534 with 95% CI [0.287-0. 991]; p = 0.0466), MCP-1/CCL2 (OR = 0.839 with 95% CI [0.732-0.962]; p = 0.0121), and TNFa (OR = 0.479 with 95% CI [0.247-0.928]; p = 0.0292) were associated with SLE diagnosis compared to pSS. In addition, the combination of low concentrations of BDNF and Fractalkine/CX3CL1 was highly specific for pSS (specificity 96.2%; positive predictive value 80%) compared to RA and SLE, as well as the combination of high concentrations of I-TAC/CXCL11 and low concentrations of sCD163 (specificity 98.1%; positive predictive value 75%). Conclusion Our study highlights biomarkers potentially involved in pSS, RA, and SLE pathophysiology that could be useful for developing a pSS-specific diagnostic tool.
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Affiliation(s)
- Guillaume Padern
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Claire Duflos
- Clinical Research and Epidemiology Unit, CHU Montpellier, Montpellier University, Montpellier, France
| | - Rosanna Ferreira
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Said Assou
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Philippe Guilpain
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Internal Medicine and Multi-Organic Diseases Department, Hôpital Saint Éloi, CHU Montpellier, Montpellier, France
| | - Alexandre Thibault Jacques Maria
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
- Internal Medicine and Multi-Organic Diseases Department, Hôpital Saint Éloi, CHU Montpellier, Montpellier, France
| | - Radjiv Goulabchand
- Internal Medicine Department, Caremeau University Hospital, Nîmes, France
| | - Pascale Galea
- BioRad Laboratory, Research and Development Department, Montpellier, France
| | - Maja Jurtela
- Clinical Research and Epidemiology Unit, CHU Montpellier, Montpellier University, Montpellier, France
| | - Christian Jorgensen
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Yves-Marie Pers
- IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
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Chatzis L, Vlachoyiannopoulos PG, Tzioufas AG, Goules AV. New frontiers in precision medicine for Sjogren's syndrome. Expert Rev Clin Immunol 2021; 17:127-141. [PMID: 33478279 DOI: 10.1080/1744666x.2021.1879641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: Sjögren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed.Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.
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Affiliation(s)
- Loukas Chatzis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas V Goules
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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van Beers JJ, Damoiseaux JG. Immune Monitoring upon Treatment with Biologics in Sjögren's Syndrome: The What, Where, When, and How. Biomolecules 2021; 11:116. [PMID: 33467204 PMCID: PMC7830440 DOI: 10.3390/biom11010116] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/25/2022] Open
Abstract
Over the years, a wide variety of therapeutic antibodies has been successfully introduced in the auto-immunology clinic, and many more are on the way. Many of these treatments address either a pathogenic circulating molecule or a cell-bound molecule. Whereas addressing the former target results in neutralization of the soluble factor and binding to the latter target either inhibits cellular function or induces selective cell death. If this targeted molecule or cell is part of the immune system, this therapy evokes a state of immunodeficiency with infections as a possible consequence. Therefore, immune monitoring is needed to prevent such adverse side effects of immunotherapy. In this paper, different immunotherapies used in Sjögren's syndrome, as well as different approaches to monitoring the immune system, are discussed.
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Affiliation(s)
- Joyce J.B.C. van Beers
- Central Diagnostic Laboratory Maastricht University Medical Center, Laboratory Specialist in Medical Immunology and Clinical Chemistry, 6202 AZ Maastricht, The Netherlands
| | - Jan G.M.C. Damoiseaux
- Central Diagnostic Laboratory Maastricht University Medical Center, Laboratory Specialist in Medical Immunology, 6202 AZ Maastricht, The Netherlands;
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35
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Srivastava A, Makarenkova HP. Innate Immunity and Biological Therapies for the Treatment of Sjögren's Syndrome. Int J Mol Sci 2020; 21:E9172. [PMID: 33271951 PMCID: PMC7730146 DOI: 10.3390/ijms21239172] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/11/2022] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disorder affecting approximately 3% of the population in the United States. This disease has a female predilection and affects exocrine glands, including lacrimal and salivary glands. Dry eyes and dry mouths are the most common symptoms due to the loss of salivary and lacrimal gland function. Symptoms become more severe in secondary SS, where SS is present along with other autoimmune diseases like systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. It is known that aberrant activation of immune cells plays an important role in disease progression, however, the mechanism for these pathological changes in the immune system remains largely unknown. This review highlights the role of different immune cells in disease development, therapeutic treatments, and future strategies that are available to target various immune cells to cure the disease.
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Affiliation(s)
| | - Helen P. Makarenkova
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA;
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36
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Cohen PL, McCulloch A. Fingolimod reduces salivary infiltrates and increases salivary secretion in a murine Sjögren's model. J Autoimmun 2020; 115:102549. [PMID: 33059968 PMCID: PMC7683371 DOI: 10.1016/j.jaut.2020.102549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/29/2020] [Accepted: 10/02/2020] [Indexed: 10/23/2022]
Abstract
Sjögren's Syndrome (SjS) is a chronic, systemic autoimmune disease causing xerostomia, xerophthalmia, and systemic symptoms. The principal pathological finding in SjS is the accumulation of lymphocytes in exocrine glandular tissue and elsewhere, leading to secretory dysfunction and other abnormalities. A rational therapeutic approach might be to interfere with lymphocyte migration to the periphery from central lymphoid tissues. We thus examined in an animal model of SjS the effects of Fingolimod (FTY720, Gilenya™), which interferes with migration of lymphocytes to peripheral sites. Fingolimod induces sequestration of lymphocytes in lymphoid organs by altering lymphocyte expression of sphingosine-1-phosphate receptors. In the C57Bl/6. NOD.Aec1Aec2 (AEC) model of SjS, Fingolimod reduced circulating T and B cell numbers. Treatment of AEC mice with Fingolimod increased salivary output and decreased the size of salivary gland infiltrates. Oral Fingolimod thus merits further consideration in the management of SjS in humans.
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Affiliation(s)
- Philip L Cohen
- Departments of Medicine, Lewis Katz School of Medicine at Temple University, 3322 North Broad Street, Room 201, Philadelphia, PA, 19140, USA.
| | - Amanda McCulloch
- Microbiology/Immunology, Lewis Katz School of Medicine at Temple University, 3322 North Broad Street, Room 201, Philadelphia, PA, 19140, USA
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37
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Seror R, Bowman S. Outcome Measures in Primary Sjögren's Syndrome. Arthritis Care Res (Hoboken) 2020; 72 Suppl 10:134-149. [PMID: 33091252 DOI: 10.1002/acr.24331] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/19/2020] [Indexed: 11/09/2022]
Affiliation(s)
- Raphaèle Seror
- Hôpital Bicêtre Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale U1012, Le Kremlin Bicêtre, France
| | - Simon Bowman
- Milton Keynes University Hospital, Milton Keynes, United Kingdom, and University Hospitals Birmingham and University of Birmingham, Birmingham, United Kingdom
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38
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Romano C, Esposito S, Ferrara R, Cuomo G. Tailoring biologic therapy for real-world rheumatoid arthritis patients. Expert Opin Biol Ther 2020; 21:661-674. [PMID: 33147106 DOI: 10.1080/14712598.2021.1847268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Introduction: The cornerstone of rheumatoid arthritis (RA) therapy relies on the treat-to-target strategy, which aims at dampening inflammation as soon as possible in order to achieve persistent low disease activity or, ideally, remission, according to validated disease activity measures. Traditional disease-modifying antirheumatic drugs (DMARDs) may be chosen in monotherapy or in combination as first-line therapy; in case of an unsatisfactory response after a 3-6-month trial, biologic therapy may be commenced.Areas covered: Real-life RA patients may present with concomitant comorbidities/complications or be in peculiar physiological states which raise more than one question as to which biotherapy may be more well suited considering the whole clinical picture. Therefore, a thorough literature search was performed to identify the most appropriate biologic therapy in each setting considered in this review.Expert opinion: Here we provide suggestions for the use of biologic drugs having a predictable better outcome in specific real-world conditions, so as to ideally profile the patient to the best of the current knowledge.
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Affiliation(s)
- Ciro Romano
- Department of Medicine, Clinical Immunology Outpatient Clinic, "Luigi Vanvitelli" University of Campania, Naples, Italy
| | - Sergio Esposito
- Department of Medicine, Clinical Immunology Outpatient Clinic, "Luigi Vanvitelli" University of Campania, Naples, Italy
| | - Roberta Ferrara
- Department of Medicine, Clinical Immunology Outpatient Clinic, "Luigi Vanvitelli" University of Campania, Naples, Italy
| | - Giovanna Cuomo
- Department of Medicine, Clinical Immunology Outpatient Clinic, "Luigi Vanvitelli" University of Campania, Naples, Italy
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39
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Biologic therapy in Sjögren's syndrome. Clin Rheumatol 2020; 40:2143-2154. [PMID: 33106929 DOI: 10.1007/s10067-020-05429-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/06/2020] [Accepted: 09/22/2020] [Indexed: 01/19/2023]
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease with complex and diverse clinical manifestations. It is characterized by lymphocyte infiltration of exocrine glands such as the salivary gland and lacrimal gland leading to insufficient secretion of the gland, manifested as dry mouth and dry eyes. In addition, it can involve extraglandular organs and cause systemic damage. The pathogenesis of SS is still unclear. At present, symptomatic treatment is the mainstay and there is a lack of effective therapy. With the development of molecular pathways underlying the pathogenesis of SS, more and more novel biological agents are used to treat SS. We summarized and analyzed the existing evidences on the efficacy of biological treatment of SS and their targets. Analysis of the efficacy of biological therapy and improvement of treatment strategies can help to give full play to its therapeutic advantages.
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40
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Parisis D, Chivasso C, Perret J, Soyfoo MS, Delporte C. Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy. J Clin Med 2020; 9:E2299. [PMID: 32698400 PMCID: PMC7408693 DOI: 10.3390/jcm9072299] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3-3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the "autoimmune epithelitis" still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin's lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.
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Affiliation(s)
- Dorian Parisis
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
- Department of Rheumatology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Clara Chivasso
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
| | - Jason Perret
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
| | | | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
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41
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Abstract
Introduction: Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease characterized by a complex and not yet completely elucidated etiopathogenesis, where autoimmune manifestations coexist with different degree of lymphoproliferation, resulting in multiple possible scenarios extremely heterogeneous from patient to patient. Although considerable progress has been made in the identifications of potential novel therapeutic targets in recent years, the biological complexity of pSS, combined to such heterogeneous clinical manifestations, makes the treatment of pSS, even today, a great challenge. Areas covered: A therapy specifically approved for pSS is still lacking. In recent years, several novel promising agents are being tested in pSS. Based on a deep revision of drugs evaluated for pSS therapy, it is striking that several clinical trials, some of them testing very promising agents, failed. Expert opinion: a renewal of clinical trial design, including the definition of novel inclusion criteria and outcome measures, together with the development of a stratification model of pSS patients and the advance in the definition of pathogenetic mechanisms underlying peculiar pSS subsets, represent preliminary and crucial steps to overcome the current therapeutic impasse in pSS.
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Affiliation(s)
- Saviana Gandolfo
- a Rheumatology Clinic, Udine University Hospital, Department of Medical Area , University of Udine , Udine , Italy
| | - Salvatore De Vita
- a Rheumatology Clinic, Udine University Hospital, Department of Medical Area , University of Udine , Udine , Italy
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Pilson Q, Smith S, Jefferies CA, Ní Gabhann-Dromgoole J, Murphy CC. miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome. Sci Rep 2020; 10:7484. [PMID: 32366870 PMCID: PMC7198540 DOI: 10.1038/s41598-020-64422-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 12/11/2019] [Indexed: 01/15/2023] Open
Abstract
In primary Sjögren’s syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3’ untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.
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Affiliation(s)
- Qistina Pilson
- Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.,Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland
| | - Siobhan Smith
- School of Pharmacy and Biomolecular Sciences (PBS) and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Caroline A Jefferies
- Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, California, 90048, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, California, 90048, USA
| | - Joan Ní Gabhann-Dromgoole
- School of Pharmacy and Biomolecular Sciences (PBS) and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.,Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Conor C Murphy
- Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland. .,Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.
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van den Hoogen LL, van Laar JM. Targeted therapies in systemic sclerosis, myositis, antiphospholipid syndrome, and Sjögren's syndrome. Best Pract Res Clin Rheumatol 2020; 34:101485. [PMID: 32067925 DOI: 10.1016/j.berh.2020.101485] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Targeted therapies using biological disease-modifying antirheumatic drugs (bDMARDs) and small molecule synthetic drugs have revolutionized rheumatological practice. Initially developed for the treatment of immune arthritis (rheumatoid arthritis, psoriatic arthritis, and spondylarthritis), both bDMARDs and small molecule synthetic drugs are now increasingly entering the space of connective tissue disease (CTD) treatment. Recent clinical trial data in systemic sclerosis (SSc) have been particularly encouraging with positive effects on outcomes having been observed with nintedanib preventing the decline of lung function in patients with SSc-related interstitial lung disease. Randomized trials targeting B-cells by rituximab in primary Sjogren's syndrome have led to mixed results. Novel strategies to target B-cells in primary Sjögren's syndrome including ianalumab and belimumab are underway and will hopefully result in clear treatment effects. Inflammatory idiopathic myositis (polymyositis (PM) and dermatomyositis (DM)) and antiphospholid syndrome are proving to be more difficult to tackle but are nonetheless the subject of ongoing studies. To what extent new compounds can replace more traditional immunosuppressive drugs remains to be determined, but if the experience in immune arthritis has taught us anything it is that combination therapy may be the way to go.
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Affiliation(s)
- Lucas L van den Hoogen
- Dept of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht University, the Netherlands.
| | - Jacob M van Laar
- Dept of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht University, the Netherlands.
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Kollert F, Fisher BA. Equal rights in autoimmunity: is Sjögren’s syndrome ever ‘secondary’? Rheumatology (Oxford) 2020; 59:1218-1225. [DOI: 10.1093/rheumatology/keaa009] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/16/2019] [Accepted: 12/23/2019] [Indexed: 12/31/2022] Open
Abstract
Abstract
Sjögren’s syndrome (SjS) accompanied by other systemic autoimmune rheumatic connective tissue diseases has historically been termed ‘secondary’ in contrast to ‘primary’ SjS as a standalone entity. However, it is a matter of a long-standing debate whether the prefixes ‘primary’ and ‘secondary’, including a temporal component, are obsolete in the terminology of SjS. We review the history and the pathophysiological, chronological, genetic, histological and clinical data underlying the concept of ‘secondary’ SjS. There are important unintended consequences of the nomenclature; notably ‘secondary’ SjS has been much less researched and is often excluded from clinical trials. We argue for further research, a change in terminology and more stringent classification. Further we highlight possible opportunities for trials in SjS and other systemic autoimmune diseases that might contribute to an advance in care for all patients with SjS.
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Affiliation(s)
- Florian Kollert
- Department of Rheumatology, Immunology, and Allergology, Inselspital, University Hospital Bern, Bern, Switzerland
| | - Benjamin A Fisher
- Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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45
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Toward better outcomes in Sjögren's syndrome: The promise of a stratified medicine approach. Best Pract Res Clin Rheumatol 2020; 34:101475. [PMID: 32005417 DOI: 10.1016/j.berh.2019.101475] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Sjögren's syndrome is a systemic autoimmune disease defined by its targeted inflammation of the salivary and lacrimal glands, resulting in dry mouth and eyes in the majority and persistent or recurrent salivary gland enlargement in a minority of those affected. Involvement of major organs, an increased risk of lymphoma, and autoantibodies against ubiquitous cellular ribonucleoproteins define some of its systemic features. Those affected have a high symptom burden and the development of disease-modifying therapies is thus an urgent need. A stratified medicine approach offers promise as a means of targeting specific therapies to patients for whom the mechanism of action is most relevant. Implementation of this approach will require an understanding of the pathophysiological processes underlying different patient subsets, and then identifying or developing a drug that targets this pathway. Such therapies would be most effective if implemented early in the disease course before the advent of adverse outcomes or glandular damage. This review will provide a disease overview followed by an analysis of the feasibility of a stratified medicine approach, focusing on the disease heterogeneity, predictors of disease progression and adverse outcomes, and recent advances in the development of relevant outcome measures and new therapies.
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46
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Usuba FS, Saad CGS, Aikawa NE, Novaes P, Moraes JCB, Santo RM, Carvalho JF, Bonfá E, Alves MR. Improvement of conjunctival cytological grade and tear production in Ankylosing Spondylitis patients under TNF inhibitors: a long-term follow-up. Sci Rep 2020; 10:334. [PMID: 31942038 PMCID: PMC6962203 DOI: 10.1038/s41598-019-57266-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/26/2019] [Indexed: 01/12/2023] Open
Abstract
Dry eye disease can compromise the patient’s quality of life. Few studies assessed the ocular surface (OS) in Ankylosing Spondylitis (AS) patients. This study aimed to evaluate the clinical and cytological findings of the OS in patients with AS, classify dry eye disease (DED) severity grade and conjunctival impression cytology (IC), and the effects of TNF inhibitors (TNFi) in a one-year follow-up. A baseline (BL) evaluation included 36 AS patients and 39 healthy controls. They fulfilled the Ocular Surface Index Disease questionnaire and underwent the Schirmer I test, break-up time, vital staining, and conjunctival IC. A DED severity grade, as well as IC rating, was applied. Fourteen of these patients received TNFi and analysis of ocular and systemic AS disease parameters occurred at BL and three months (3 M), and 12 months (12 M) after treatment. The AS patients presented a higher frequency of DED (p = 0.01), a worse score of severity (p = 0.001), and a higher frequency of altered IC (p = 0.007) when compared to controls. The 14 patients under TNFi presented an improvement in all the clinical disease activity parameters throughout the one-year treatment (p < 0.05) even as a concomitant increase in the Schirmer test (p = 0.04), and a significant amelioration in the altered IC to a normal IC (p = 0.006). DED is a frequent and under-diagnosed ocular disease in AS patients. The long-term parallel improvement of disease activity and OS parameters in AS patients receiving TNFi suggests that the OS can be an additional target of systemic inflammation in AS.
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Affiliation(s)
- Fany Solange Usuba
- Ophthalmology Department, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
| | - Carla Gonçalves Schahin Saad
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Nadia Emi Aikawa
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Priscila Novaes
- Ophthalmology Department, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Julio Cesar Bertacini Moraes
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Ruth Miyuki Santo
- Ophthalmology Department, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Jozelio Freire Carvalho
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Eloisa Bonfá
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Milton Ruiz Alves
- Ophthalmology Department, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Mavragani CP, Moutsopoulos HM. Sjögren's syndrome: Old and new therapeutic targets. J Autoimmun 2019; 110:102364. [PMID: 31831255 DOI: 10.1016/j.jaut.2019.102364] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 11/10/2019] [Indexed: 02/09/2023]
Abstract
Sjögren's syndrome (SS) is a prototype autoimmune disease characterized by oral and ocular mucosal dryness following chronic inflammation of salivary and lachrymal glands, respectively. Profound B cell hyperactivity along with systemic manifestations including fatigue, musculoskeletal complaints, features related to hepatic, pulmonary, renal and nervous system involvement, as well as lymphoma development can be also present. Despite that activation of both innate and adaptive immune pathways has been long well documented in SS pathogenesis, systemic immunosuppression in SS, in contrast to other autoimmune diseases, has been largely inefficacious. Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited. Recent advances in dissecting the molecular pathways underlying SS pathogenesis led to an expanding number of novel biological compounds directed towards type I interferon system, antigen presentation, costimulatory pathways, B and T cell activation, as well as germinal center formation. While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results from administration of other kinase inhibitors, a transmembrane activator and calcium-modulator and cytophilin ligand interactor TACI fusion protein (RC18), as well as low dose recombinant interleukin-2 to expand T-regulatory cells are currently awaited.
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Affiliation(s)
- Clio P Mavragani
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Andréu Sánchez JL, Fernández Castro M, del Campo Fontecha PD, Corominas H, Narváez García FJ, Gómez de Salazar JR, Rua-Figueroa Í, Abad Hernández MÁ, Álvarez Rivas MN, Montes JDP, Francisco Hernández FM, Gantes Pedraza MÁ, Greco Merino MG, Hernández MV, Navarro Compán MV, Solarte JAP, Romero Bueno FI, Park HS, Sivera Mascaró F. Recomendaciones SER sobre la utilización de fármacos biológicos en el síndrome de Sjögren primario. ACTA ACUST UNITED AC 2019; 15:315-326. [DOI: 10.1016/j.reuma.2018.10.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 10/09/2018] [Accepted: 10/31/2018] [Indexed: 12/15/2022]
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Brito-Zerón P, Retamozo S, Kostov B, Baldini C, Bootsma H, De Vita S, Dörner T, Gottenberg JE, Kruize AA, Mandl T, Ng WF, Seror R, Tzioufas AG, Vitali C, Bowman S, Mariette X, Ramos-Casals M. Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjögren's syndrome. RMD Open 2019; 5:e001064. [PMID: 31749986 PMCID: PMC6827762 DOI: 10.1136/rmdopen-2019-001064] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/26/2019] [Accepted: 09/29/2019] [Indexed: 12/18/2022] Open
Abstract
Objective To evaluate current evidence on the efficacy and safety of topical and systemic medications in patients with primary Sjögren syndrome (SjS) to inform European League Against Rheumatism treatment recommendations. Methods The MEDLINE, EMBASE and Cochrane databases were searched for case-control/prospective cohort studies, randomised controlled trials (RCTs) and systematic reviews. Results Current evidence in primary SjS patients fulfilling the 2002 criteria is based on the data from 9 RCTs, 18 prospective cohort studies and 5 case-control studies. Two Cochrane systematic literature reviews (SLRs) have reported that topical treatments for dry mouth and dry eye are safe and effective. Ocular cyclosporine A was safe and effective in two RCTs including 1039 patients with dry eye syndrome. Two Cochrane SLRs on serum tear drops and plugs showed inconsistency in possible benefits, both for symptoms and objective measures. Five RCTs reported significant improvements in oral dryness and salivary flow rates for pilocarpine and cevimeline. An RCT showed no significant placebo-differences for hydroxychloroquine 400 mg/day for the primary outcome (visual analogue scale (VAS) composite of dryness, fatigue and pain). We identified seven RCTs carried out in primary SjS patients. RCTs using infliximab, anakinra and baminercept found no placebo-differences for the primary outcomes. The two largest RCTs randomised 255 patients to receive rituximab or placebo and reported no significant results in the primary outcome (VAS composite), while prospective studies suggested efficacy in systemic disease. Conclusion The current evidence supporting the use of the main topical therapeutic options of primary SjS is solid, while limited data from RCTs are available to guide systemic therapies.
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Affiliation(s)
- Pilar Brito-Zerón
- Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA-Sanitas, Barcelona, Spain
- Laboratory of Autoimmune Diseases Josep Font, CELLEX, IDIBAPS, Barcelona, Spain
| | - Soledad Retamozo
- Department of Rheumatology, Instituto Modelo de Cariología Privado S.R.L, Instituto Universitario de Ciencias Biomédicas de Córdoba, Cordoba, Argentina
- Instituto De Investigaciones En Ciencias De La Salud (INICSA), Universidad Nacional de Córdoba (UNC), Cordoba, Argentina
| | - Belchin Kostov
- Research Primary Healthcare Transversal Research Group, CAP Les Corts, CAPSBE, IDIBAPS, Barcelona, Spain
- Statistics and Operations Research Department, Universitat Politecnica de Catalunya, Barcelona, Spain
| | - Chiara Baldini
- Rheumatology Unit, Universita degli Studi di Pisa, Pisa, Italy
| | - Hendrika Bootsma
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Salvatore De Vita
- Clinic of Rheumatology, University Hospital Santa Maria della Misericordia, Udine, Italy
| | - Thomas Dörner
- Department of Medicine/Rheumatology and Clinical Immunology and DRFZ, Charité Universitätsmedizin Berlin Campus Charite Mitte, Berlin, Germany
| | - Jacques-Eric Gottenberg
- Department of Rheumatology, Strasbourg University Hospital, National Reference Center for Rare Systemic Autoimmune Diseases, CNRS, IBMC, UPR 3572, Université de Strasbourg, Strasbourg, France
| | - Aike A. Kruize
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Thomas Mandl
- Department of Rheumatology, Skane University Hospital Malmö, Lund University, Lund, Sweden
| | - Wan-Fai Ng
- NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Raphaele Seror
- Department of Rheumatology, Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Le Kremlin-Bicetre, France
- Center for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR 1184, Université Paris-Sud, Université Paris-Saclay, Paris, France
| | - Athanasios G. Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Simon Bowman
- Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Xavier Mariette
- Department of Rheumatology, Assistance Publique – Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Le Kremlin-Bicetre, France
- Center for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR 1184, Université Paris-Sud, Université Paris-Saclay, Paris, France
| | - Manuel Ramos-Casals
- Laboratory of Autoimmune Diseases Josep Font, CELLEX, IDIBAPS, Barcelona, Spain
- Department of Autoimmune Diseases, ICMiD, Hospital Clinic de Barcelona, Barcelona, Spain
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Abstract
The prevalence of primary Sjögren's syndrome (pSS) is between 1:100 and 1:1000 and it is therefore the most common connective tissue disease. Nevertheless, it can be difficult to diagnose pSS as the symptoms are frequently unspecific and diagnostic markers are lacking in many patients. In addition, only few controlled therapeutic studies of pSS have been carried out so that the optimal management is not yet clear. Meanwhile, outcome parameters to monitor clinical improvement have been developed and a large number of therapeutic studies are currently being performed. This review article summarizes the current diagnostic and treatment options for pSS.
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Affiliation(s)
- Torsten Witte
- Klinik für Immunologie und Rheumatologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.
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