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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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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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Price EJ, Baer AN. How to treat Sjögren's syndrome. Rheumatology (Oxford) 2019; 60:2574-2587. [PMID: 30770917 DOI: 10.1093/rheumatology/key363] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 10/03/2018] [Indexed: 01/03/2023] Open
Abstract
SS is a chronic, autoimmune disease of unknown aetiology for which there is no known curative treatment. Although dryness of the eyes and mouth are the classically described features, patients often experience drying of other mucosal surfaces and systemic manifestations, including fatigue and arthralgia. There is an association with other autoimmune diseases, especially thyroid disease, coeliac disease and primary biliary cholangitis. Systemic features may affect up to 70% and include inflammatory arthritis, skin involvement, haematological abnormalities, neuropathies, interstitial lung disease and a 5-10% lifetime risk of B cell lymphoma. Treatment should aim to empower patients to manage their condition; conserve, replace and stimulate secretions; prevent damage; and suppress underlying systemic disease activity.
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Affiliation(s)
- Elizabeth J Price
- Department of Rheumatology, Great Western Hospital NHS Foundation Trust, Swindon, UK
| | - Alan N Baer
- Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Gallo A, Martellucci S, Fusconi M, Pagliuca G, Greco A, De Virgilio A, De Vincentiis M. Sialendoscopic management of autoimmune sialadenitis: a review of literature. ACTA OTORHINOLARYNGOLOGICA ITALICA 2018; 37:148-154. [PMID: 28516978 PMCID: PMC5463523 DOI: 10.14639/0392-100x-1605] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 12/12/2016] [Indexed: 12/24/2022]
Abstract
Autoimmune diseases of major salivary glands include Sjögren's syndrome and a complex of disorders classified as immunoglobulin G4-related diseases. These pathologies are characterised by an autoimmune reaction mediated by T-helper lymphocytes that targets the ducts of exocrine glands in Sjögren's syndrome and glandular parenchyma in immunoglobulin G4-related diseases. Immunoglobulin G4-related diseases represent recently introduced multi-organ diseases that also involve the salivary glands. However, the morbid conditions once known as Mikulicz's disease and Kuttner's tumour were recently considered as two variants of immunoglobulin G4-related diseases affecting the major salivary glands ( immunoglobulin G4-related sialadenitis). This review briefly summarises the pathogenesis and clinical features of autoimmune diseases of the major salivary glands, focusing on the diagnostic and therapeutic role of sialendoscopy.
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Affiliation(s)
- A Gallo
- Department of Surgical Biotechnologies and Science, ENT Section "Sapienza" University of Rome, Italy
| | - S Martellucci
- Department of Surgical Biotechnologies and Science, ENT Section "Sapienza" University of Rome, Italy
| | - M Fusconi
- Department of Sensorial Organs, ENT Section "Sapienza" University of Rome, Italy
| | - G Pagliuca
- Department of Surgical Biotechnologies and Science, ENT Section "Sapienza" University of Rome, Italy
| | - A Greco
- Department of Sensorial Organs, ENT Section "Sapienza" University of Rome, Italy
| | - A De Virgilio
- Department of Sensorial Organs, ENT Section "Sapienza" University of Rome, Italy
| | - M De Vincentiis
- Department of Sensorial Organs, ENT Section "Sapienza" University of Rome, Italy
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Sumida T, Azuma N, Moriyama M, Takahashi H, Asashima H, Honda F, Abe S, Ono Y, Hirota T, Hirata S, Tanaka Y, Shimizu T, Nakamura H, Kawakami A, Sano H, Ogawa Y, Tsubota K, Ryo K, Saito I, Tanaka A, Nakamura S, Takamura E, Tanaka M, Suzuki K, Takeuchi T, Yamakawa N, Mimori T, Ohta A, Nishiyama S, Yoshihara T, Suzuki Y, Kawano M, Tomiita M, Tsuboi H. Clinical practice guideline for Sjögren's syndrome 2017. Mod Rheumatol 2018; 28:383-408. [PMID: 29409370 DOI: 10.1080/14397595.2018.1438093] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences. METHODS The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. RESULTS The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. CONCLUSION The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.
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Affiliation(s)
- Takayuki Sumida
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan
| | - Naoto Azuma
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,c Division of Rheumatology, Department of Internal Medicine , Hyogo College of Medicine , Hyogo , Japan
| | - Masafumi Moriyama
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,d Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences , Kyushu University , Fukuoka , Japan
| | - Hiroyuki Takahashi
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan
| | - Hiromitsu Asashima
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan
| | - Fumika Honda
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan
| | - Saori Abe
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan
| | - Yuko Ono
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,d Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences , Kyushu University , Fukuoka , Japan
| | - Tomoya Hirota
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan
| | - Shintaro Hirata
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,e The First Department of Internal Medicine , School of Medicine, University of Occupational and Environmental Health, Japan , Fukuoka , Japan.,f Department of Clinical Immunology and Rheumatology , Hiroshima University Hospital , Hiroshima , Japan
| | - Yoshiya Tanaka
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,e The First Department of Internal Medicine , School of Medicine, University of Occupational and Environmental Health, Japan , Fukuoka , Japan
| | - Toshimasa Shimizu
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,g Unit of Translational Medicine, Department of Immunology and Rheumatology , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Hideki Nakamura
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,g Unit of Translational Medicine, Department of Immunology and Rheumatology , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Atsushi Kawakami
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,g Unit of Translational Medicine, Department of Immunology and Rheumatology , Nagasaki University Graduate School of Biomedical Sciences , Nagasaki , Japan
| | - Hajime Sano
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,c Division of Rheumatology, Department of Internal Medicine , Hyogo College of Medicine , Hyogo , Japan
| | - Yoko Ogawa
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,h Department of Ophthalmology , School of Medicine, Keio University , Tokyo , Japan
| | - Kazuo Tsubota
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,h Department of Ophthalmology , School of Medicine, Keio University , Tokyo , Japan
| | - Koufuchi Ryo
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,i Department of Pathology , Tsurumi University School of Dental Medicine , Kanagawa , Japan
| | - Ichiro Saito
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,i Department of Pathology , Tsurumi University School of Dental Medicine , Kanagawa , Japan
| | - Akihiko Tanaka
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,d Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences , Kyushu University , Fukuoka , Japan
| | - Seiji Nakamura
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,d Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences , Kyushu University , Fukuoka , Japan
| | - Etsuko Takamura
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,j Department of Ophthalmology , Tokyo Women's Medical University, School of Medicine , Tokyo , Japan
| | - Masao Tanaka
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,k Department of Advanced Medicine for Rheumatic Diseases , Kyoto University Graduate School of Medicine , Kyoto , Japan
| | - Katsuya Suzuki
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,l Division of Rheumatology, Department of Internal Medicine , School of Medicine, Keio University , Tokyo , Japan
| | - Tsutomu Takeuchi
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,l Division of Rheumatology, Department of Internal Medicine , School of Medicine, Keio University , Tokyo , Japan
| | - Noriyuki Yamakawa
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,m Department of Rheumatology and Clinical Immunology , Kyoto University Graduate School of Medicine , Kyoto , Japan.,n Department of Rheumatology , Kyoto-Katsura Hospital , Kyoto , Japan
| | - Tsuneyo Mimori
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,m Department of Rheumatology and Clinical Immunology , Kyoto University Graduate School of Medicine , Kyoto , Japan
| | - Akiko Ohta
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,o Division of Public Health, Department of Social Medicine , Saitama Medical University , Saitama , Japan
| | - Susumu Nishiyama
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,p Kurashiki Medical Center , Okayama , Japan
| | - Toshio Yoshihara
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,q Department of Otorhinolaryngology , Tokyo Women's Medical University , Tokyo , Japan
| | - Yasunori Suzuki
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,r Division of Rheumatology, Department of Cardiovascular and Internal Medicine , Kanazawa University Graduate School of Medicine , Ishikawa , Japan
| | - Mitsuhiro Kawano
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,r Division of Rheumatology, Department of Cardiovascular and Internal Medicine , Kanazawa University Graduate School of Medicine , Ishikawa , Japan
| | - Minako Tomiita
- b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan.,s Department of Allergy and Rheumatology , Chiba Children's Hospital , Chiba , Japan
| | - Hiroto Tsuboi
- a Department of Internal Medicine , University of Tsukuba , Ibaraki , Japan.,b Clinical Practice Guideline Committee for Sjögren's Syndrome, The Research Team for Autoimmune Diseases, The Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW) , Tokyo , Japan
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Corden A, Handelman B, Yin H, Cotrim A, Alevizos I, Chiorini JA. Neutralizing antibodies against adeno-associated viruses in Sjögren's patients: implications for gene therapy. Gene Ther 2017; 24:241-244. [PMID: 28150697 PMCID: PMC5810933 DOI: 10.1038/gt.2017.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 11/12/2016] [Accepted: 11/29/2016] [Indexed: 01/07/2023]
Abstract
One potential setback to the use of gene therapy for the treatment of Sjögren's syndrome is the presence of neutralizing antibodies (nAb) against adeno-associated virus (AAV) serotypes. In order to evaluate the efficacy of this treatment option, nAb titers were measured in both healthy individuals and Sjögren's patients. Several serotypes with known transduction activity in mouse salivary glands were tested and only AAV5 showed a statistically significant change in the prevalence of nAbs between Sjögren's and healthy participants. Both groups showed a higher rate of nAbs for AAV2 compared with most of the other serotypes tested, except for bovine AAV (BAAV). Although a similar rate of seropositivity was seen against BAAV and AAV2, the percentage of samples with high titer was significantly lower with BAAV. Furthermore, the majority of positive samples exhibited low nAb titers in the primary Sjögren's syndrome (pSS) group for all serotypes except for AAV2. AAV5 was the only serotype that showed a statistically significant shift in the percentage of medium or high neutralizing titer. Based on these results, many serotypes are viable vectors in a gene therapy approach and pSS patients do not have a statistically significant higher rate of seropositivity or titer compared with healthy donors.
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Affiliation(s)
- A Corden
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - B Handelman
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - H Yin
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - A Cotrim
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - I Alevizos
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - J A Chiorini
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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Betül Türkoğlu E, Tuna S, Alan S, İhsan Arman M, Tuna Y, Ünal M. Effect of Systemic Infliximab Therapy in Patients with Sjögren's Syndrome. Turk J Ophthalmol 2015; 45:138-141. [PMID: 27800220 PMCID: PMC5082270 DOI: 10.4274/tjo.48379] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 11/20/2014] [Indexed: 01/18/2023] Open
Abstract
Objectives: To investigate the effect of systemic infliximab therapy on tear function tests and the ocular surface in patients with Sjögren’s syndrome secondary to various autoimmune diseases. Materials and Methods: This prospective study included 22 eyes of 22 patients with Sjögren’s syndrome who began treatment with systemic infliximab. Tear film break-up time (TBUT), anesthetized Schirmer’s 1 test, fluorescein staining test, and Ocular Surface Disease Index (OSDI) scores were recorded before treatment and in the 3rd and 6th months of treatment. Results: In the 3rd month of infliximab therapy, no significant changes were observed in Schirmer’s values, TBUT, fluorescein staining, or OSDI scores (p=0.260, p=0.357, p=0.190 and p=0.07, respectively). In the 6th month of infliximab therapy, no significant changes were observed in TBUT, fluorescein staining, Schirmer’s value or OSDI scores (p=0.510, p=0.320, p=0.220 and p=0.344, respectively). Conclusion: Infliximab therapy, which is commonly used in systemic autoimmune diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and ankylosing spondylitis, did not show a positive effect on ocular surface and tear function tests.
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Affiliation(s)
- Elif Betül Türkoğlu
- Akdeniz University Faculty of Medicine, Department of Ophthalmology, Antalya, Turkey
| | - Serpil Tuna
- Akdeniz University Faculty of Medicine, Department of Physical Therapy and Rehabilitation, Antalya, Turkey
| | - Sevil Alan
- Akdeniz University Faculty of Medicine, Department of Dermatology, Antalya, Turkey
| | - Mehmet İhsan Arman
- Akdeniz University Faculty of Medicine, Department of Physical Therapy and Rehabilitation, Antalya, Turkey
| | - Yaşar Tuna
- Akdeniz University Faculty of Medicine, Department of Gastroenterology, Antalya, Turkey
| | - Mustafa Ünal
- Akdeniz University Faculty of Medicine, Department of Ophthalmology, Antalya, Turkey
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Gasparyan AY, Ayvazyan L, Akazhanov NA, Kitas GD. Self-correction in biomedical publications and the scientific impact. Croat Med J 2014; 55:61-72. [PMID: 24577829 PMCID: PMC3944419 DOI: 10.3325/cmj.2014.55.61] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 02/15/2014] [Indexed: 01/17/2023] Open
Abstract
AIM To analyze mistakes and misconduct in multidisciplinary and specialized biomedical journals. METHODS We conducted searches through PubMed to retrieve errata, duplicate, and retracted publications (as of January 30, 2014). To analyze publication activity and citation profiles of countries, multidisciplinary, and specialized biomedical journals, we referred to the latest data from the SCImago Journal and Country Rank database. Total number of indexed articles and values of the h-index of the fifty most productive countries and multidisciplinary journals were recorded and linked to the number of duplicate and retracted publications in PubMed. RESULTS Our analysis found 2597 correction items. A striking increase in the number of corrections appeared in 2013, which is mainly due to 871 (85.3%) corrections from PLOS One. The number of duplicate publications was 1086. Articles frequently published in duplicate were reviews (15.6%), original studies (12.6%), and case reports (7.6%), whereas top three retracted articles were original studies (10.1%), randomized trials (8.8%), and reviews (7%). A strong association existed between the total number of publications across countries and duplicate (rs=0.86, P<0.0001) and retracted items (rs=0.812, P<0.0001). A similar trend was found between country-based h-index values and duplicate and retracted publications. CONCLUSION The study suggests that the intensified self-correction in biomedicine is due to the attention of readers and authors, who spot errors in their hub of evidence-based information. Digitization and open access confound the staggering increase in correction notices and retractions.
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Affiliation(s)
- Armen Yuri Gasparyan
- Armen Yuri Gasparyan, Departments of Rheumatology and Research and Development, Dudley Group NHS Foundation Trust, Russells Hall Hospital, North Block, Clinical Research Unit, Dudley, West Midlands, DY1 2HQ, United Kingdom,
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Hofauer B, Bas M, Manour N, Knopf A. Effekt liposomaler Lokaltherapie auf die Sicca-Symptomatik des primären Sjögren-Syndroms. HNO 2013; 61:921-7. [DOI: 10.1007/s00106-013-2736-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Yoon KC. Topical biological agents targeting cytokines for the treatment of dry eye disease. World J Ophthalmol 2013; 3:16-19. [DOI: 10.5318/wjo.v3.i2.16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Revised: 07/26/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
Because inflammation plays a key role in the pathogenesis of dry eye disease and Sjögren’s syndrome, topical anti-inflammatory agents such as corticosteroids and cyclosporine A have been used to treat inflammation of the ocular surface and lacrimal gland. Systemic biological agents that target specific immune molecules or cells such as tumor necrosis factor (TNF)-α, interferone-α, interleukin (IL)-1, IL-6, or B cells have been used in an attempt to treat Sjögren’s syndrome. However, the efficacy of systemic biological agents, other than B-cell targeting agents, has not yet been confirmed in Sjögren’s syndrome. Several studies have recently evaluated the efficacy of topical administration of biological agents targeting cytokines in the treatment of dry eye disease. Topical blockade of IL-1 by using IL-1 receptor antagonist could ameliorate clinical signs and inflammation of experimental dry eye. Using a mouse model of desiccating stress-induced dry eye, we have demonstrated that topical application of a TNF-α blocking agent, infliximab, could improve tear production and ocular surface irregularity, decrease inflammatory cytokines and Th-1 CD4+ cells on the ocular surface, and increase goblet cell density in the conjunctiva. Although controversy still remains, the use of topical biological agents targeting inflammatory cytokines may be a promising therapy for human dry eye disease.
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Steinfeld SD, Demols P, Salmon I, Kiss R, Appelboom T. Notice of retraction of two articles (“Infliximab in patients with primary Sjögren's syndrome: A pilot study” and “Infliximab in patients with primary Sjögren's syndrome: one-year followup”). ACTA ACUST UNITED AC 2013. [DOI: 10.1002/art.37942] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
PURPOSE To investigate the efficacy of a topical anti-tumor necrosis factor-α agent, infliximab, in a mouse model of experimental dry eye (EDE). METHODS EDE was induced in C57BL/6 mice, with or without topical treatment consisting of balanced salt solution or 0.001%, 0.01%, or 0.1% infliximab solutions. Tear volume and corneal smoothness were measured on days 5 and 10 after treatment. Levels of interleukin (IL)-1β, IL-6, IL-17, and interferon γ (IFN-γ) were measured in the conjunctiva using a multiplex immunobead assay 10 days after treatment. Periodic acid-Schiff staining, immunohistochemistry, and flow cytometry were also performed 10 days after treatment. RESULTS Mice treated with 0.01% or 0.1% infliximab showed a significant improvement in tear volume and corneal smoothness compared with controls. The 0.01% and 0.1% infliximab-treated groups showed decreased levels of conjunctival IL-1β, IL-6, IL-17, and interferon γ and a decreased staining intensity of tumor necrosis factor-α. The density of conjunctival goblet cells was higher, whereas the number of CD4*CXCR3* T cells was lower, in the 0.01% and 0.1% infliximab-treated groups compared with the EDE and balanced salt solution control groups. However, there was no significant difference in all parameters between the 0.001% infliximab-treated group and control group. CONCLUSIONS : Topical application of infliximab can improve tear production and ocular surface irregularity, decrease inflammatory cytokines and cells on the ocular surface, and increase conjunctival goblet cell density. These results suggest that topical infliximab eye drops at a concentration of 0.01% and 0.1% may be useful for the treatment of dry eye disease.
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Reksten TR, Brokstad KA, Jonsson R, Brun JG, Jonsson MV. Implications of long-term medication of oral steroids and antimalarial drugs in primary Sjögren's syndrome. Int Immunopharmacol 2011; 11:2125-9. [PMID: 21964047 DOI: 10.1016/j.intimp.2011.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 08/30/2011] [Accepted: 09/13/2011] [Indexed: 01/07/2023]
Abstract
BACKGROUND Immunomodulating drugs are commonly used in treating patients with autoimmune diseases but with very different outcomes. We aimed to investigate differences in cytokine and autoantibody levels with regard to patient characteristics in patients with primary Sjögren's syndrome (pSS) receiving oral steroids or antimalarial drugs (AM) after a longer period of time. METHODS Serum samples from 141 patients fulfilling the revised EU-US criteria and 99 healthy controls were analysed for 25 cytokines and 8 autoantibodies. RESULTS AM-patients had lowered levels of IL-5, IL-10, IL-13 and IFN-γ, though non-significantly. Use of prednisolone was associated with reduced levels of IL-15, IL-2, IL-4, IL-12p40, TNF-α, MIP-1α and MIP-1β (p<0.05), and a trend towards decreased levels of IL-1RA and IL-1β was observed. No associations were seen between AM and antibody levels. Significantly higher protein levels of anti-Ro-52 and anti-Ro-60 were observed in the patients taking prednisolone (p<0.05). The proportion of patients positive for anti-Ro-52 and anti-La-48 did not differ significantly in the groups taking and not taking prednisolone, but a difference was seen for anti-Ro-60 (p<0.05). CONCLUSIONS Prednisolone is a potent anti-inflammatory and immunosuppressive drug commonly used in autoimmune diseases. Our study shows that oral steroids are associated with reduced levels of several pro-inflammatory cytokines, but increased levels of pSS specific autoantibodies. The association between steroid use and increased antibody levels is not readily explained by known steroid effects, and should therefore be confirmed in further studies. Lower levels of pro-inflammatory cytokines indicate a beneficial effect of oral steroids in this patient group.
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Affiliation(s)
- Tove Ragna Reksten
- Broegelmann Research Laboratory, Gade Institute, University of Bergen, Bergen, Norway.
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Meiners PM, Vissink A, Kallenberg CGM, Kroese FGM, Bootsma H. Treatment of primary Sjögren's syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point? Expert Opin Biol Ther 2011; 11:1381-94. [PMID: 21819314 DOI: 10.1517/14712598.2011.605352] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION In vitro and in vivo experimental data have suggested new immunopathogenic mechanisms in primary Sjögren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. Amongst these new treatment modalities, monoclonal antibodies specific for the B-cell surface molecule CD20 have been shown to be the most promising treatment option to date. AREAS COVERED A search of the Pubmed, MEDLINE, EMBASE, Cochrane and Ovid databases was performed to review literature on the efficacy and safety profile of anti-CD20 therapy in pSS patients. EXPERT OPINION A single course of the chimeric humanized anti-CD20 antibody rituximab was effective in reducing disease activity in pSS patients for about six to nine months. Retreatment of responders resulted in a similar effect to initial treatment. When combined with corticosteroids during infusion, rituximab was shown to be a safe drug to administer. Thus, anti-CD20 therapy can be considered an effective treatment option in pSS patients. However, large randomized controlled trials with anti-CD20 therapy, for example rituximab, are warranted in order to: 1) assess long-term effects of such treatment, 2) determine which pSS patients will benefit most from anti-CD20 treatment and 3) assess which retreatment schedule should be followed.
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Affiliation(s)
- Petra M Meiners
- University of Groningen, University Medical Center Groningen, Department of Oral and Maxillofacial Surgery, The Netherlands
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Abstract
INTRODUCTION Primary Sjögren's syndrome (PSS) is a relatively common immune-mediated condition characterized by oral and ocular dryness, fatigue, musculoskeletal pain and poor health-related quality of life. Other extra-glandular organs can also be affected and PSS is associated with a markedly increased risk of lymphoma. Furthermore, the health-economic cost for PSS is substantial. There is currently no effective treatment available. With better understanding of the pathophysiology of PSS and advances in technologies, it is now possible to develop biological therapies to target specific molecules or molecular pathways that are important in PSS pathogenesis. Indeed, a limited number of biological therapies have already been tested in PSS with mixed successes. AREAS COVERED Published data on the use of biological therapies in PSS, the possible roles for other biological therapies and the potential challenges for their use. EXPERT OPINION The use of biological agents targeting key cellular and molecular pathways in PSS pathogenesis represents a promising therapeutic strategy. Clinical trials assessing the efficacy of biological therapies in PSS should be encouraged but patient selection and outcome measures used in these studies must be carefully considered to ensure that the true effects of biological therapies on the outcomes of PSS are being appropriately evaluated.
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Affiliation(s)
- Wan-Fai Ng
- University of Newcastle, Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle upon Tyne, NE2 4HH, UK.
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Akpek EK, Lindsley KB, Adyanthaya RS, Swamy R, Baer AN, McDonnell PJ. Treatment of Sjögren's syndrome-associated dry eye an evidence-based review. Ophthalmology 2011; 118:1242-52. [PMID: 21459453 DOI: 10.1016/j.ophtha.2010.12.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2009] [Revised: 11/29/2010] [Accepted: 12/14/2010] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Outcomes-based review of reported treatment options for patients with dry eye secondary to Sjögren's syndrome (SS). CLINICAL RELEVANCE Dry eye affects many individuals worldwide. Significant proportion of patients with dry eye has underlying SS, a progressive autoimmune condition. The few suggested guidelines for the treatment of dry eye are mostly based on severity of symptoms and/or clinical findings rather than on outcomes analysis, and do not differentiate SS from other causes of dry eye. METHODS AND LITERATURE REVIEW: A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by ≥4 review authors. RESULTS The searches identified 3559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. CONCLUSIONS In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The efficacy of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye.
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Affiliation(s)
- Esen Karamursel Akpek
- The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Kallenberg CGM, Vissink A, Kroese FGM, Abdulahad WH, Bootsma H. What have we learned from clinical trials in primary Sjögren's syndrome about pathogenesis? Arthritis Res Ther 2011; 13:205. [PMID: 21371351 PMCID: PMC3157640 DOI: 10.1186/ar3234] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sjögren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS.
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Affiliation(s)
- Cees G M Kallenberg
- Department of Rheumatology and Clinical Immunology, AA21, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands.
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Tobón GJ, Saraux A, Pers JO, Youinou P. Emerging biotherapies for Sjögren's syndrome. Expert Opin Emerg Drugs 2010; 15:269-82. [PMID: 20384543 DOI: 10.1517/14728211003702392] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE OF THE FIELD Sjögren's syndrome (SS) is an autoimmune epithelitis. This exocrinopathy is frequently associated with extraglandular complications, and the patients are at risk of developing B cell lymphoma. Given the lack of disease-modifying drugs, and the fact that SS is a quintessential B-cell mediated disease, attention has recently been focused on biotherapies. AREAS COVERED IN THIS REVIEW Despite negative grounds, TNF-alpha antagonists have been tested in the disease, and proven not be efficient. However, B-cell depleting therapy using anti-CD20 antibodies such as rituximab, which is a chimeric mAb, has shown promise in the field, while anti-CD22 mAb seems to be less active. WHAT THE READER WILL GAIN New treatments against the B-cell activating factor of the TNF family are about to be tested, or replaced by receptor immunoglobulin decay protein. TAKE HOME MESSAGE B-cell depleting therapies seem promising in SS, but no data are, thus far, available on treatments targeting B-cell activating factor of the TNF family.
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Affiliation(s)
- Gabriel J Tobón
- Université de Brest, Université Européenne de Bretagne, Laboratory of Immunology, CHU Morvan, BP824, F29609 Brest, France
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Enríquez-de-Salamanca A, Calonge M. Cytokines and chemokines in immune-based ocular surface inflammation. Expert Rev Clin Immunol 2010; 4:457-67. [PMID: 20477574 DOI: 10.1586/1744666x.4.4.457] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Altered levels of several cytokines and chemokines have been found in different types of inflammatory ocular surface diseases, such as allergy or dry-eye syndrome. It has also been demonstrated that epithelial cells play a key role in the persistence and even initiation of chronic mucosal inflammation. The recent development of 'multiplex detection' technologies has facilitated the identification of specific patterns of expression of these molecules in some ocular immune-based inflammatory disorders. Analysis of these molecules in tissues, cells (in vivo and in vitro) and tears has revealed that not only inflammatory cells but also epithelial and fibroblast resident cells are sources of these molecules. The purpose of this review is to summarize recent studies in this field.
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Affiliation(s)
- Amalia Enríquez-de-Salamanca
- IOBA (Institute of Applied Opthalmobiology), Ocular Surface Group, Campus Miguel Delibes, University of Valladolid, Valladolid, Spain.
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Fauchais AL, Ouattara B, Gondran G, Lalloue F, Petit D, Ly K, Lambert M, Launay D, Loustaud-Ratti V, Bezanahari H, Liozon E, Hachulla E, Jauberteau MO, Vidal E, Hatron PY. Articular manifestations in primary Sjogren's syndrome: clinical significance and prognosis of 188 patients. Rheumatology (Oxford) 2010; 49:1164-72. [DOI: 10.1093/rheumatology/keq047] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Ng WF, Bowman SJ. Primary Sjogren's syndrome: too dry and too tired. Rheumatology (Oxford) 2010; 49:844-53. [PMID: 20147445 DOI: 10.1093/rheumatology/keq009] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Chronic fatigue is one of the most prevalent and debilitating symptoms in primary SS (pSS). Approximately 70% of pSS patients suffer from disabling fatigue, which is associated with reduced health-related quality of life. In this article, we review the instruments used for evaluating pSS-related fatigue, our current understanding of the underlying psychosocial and physiological mechanisms of fatigue in pSS and the therapeutic strategies that have been studied in the management of fatigue in pSS.
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Affiliation(s)
- Wan-Fai Ng
- Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcaste upon Tyne NE2 4HH, UK.
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Vosters JL, Yin H, Roescher N, Kok MR, Tak PP, Chiorini JA. Local expression of tumor necrosis factor-receptor 1:immunoglobulin G can induce salivary gland dysfunction in a murine model of Sjögren's syndrome. Arthritis Res Ther 2009; 11:R189. [PMID: 20003451 PMCID: PMC3003528 DOI: 10.1186/ar2888] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Revised: 11/10/2009] [Accepted: 12/14/2009] [Indexed: 12/20/2022] Open
Abstract
Introduction Tumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions. Although tumor necrosis factor inhibitors have demonstrated great utility in treating other autoimmune diseases, such as rheumatoid arthritis, there are conflicting results in Sjögren's syndrome. The aim of this study was to assess the effect of a locally expressed tumor necrosis factor inhibitor on the salivary gland function and histopathology in an animal model of Sjögren's syndrome. Methods Using in vivo adeno associated viral gene transfer, we have stably expressed soluble tumor necrosis factor-receptor 1-Fc fusion protein locally in the salivary glands in the Non Obese Diabetic model of Sjögren's syndrome. Pilocarpine stimulated saliva flow was measured to address the salivary gland function and salivary glands were analyzed for focus score and cytokine profiles. Additionally, cytokines and autoantibody levels were measured in plasma. Results Local expression of tumor necrosis factor-receptor 1:immunoglobulin G fusion protein resulted in decreased saliva flow over time. While no change in lymphocytic infiltrates or autoantibody levels was detected, statistically significant increased levels of tumor growth factor-β1 and decreased levels of interleukin-5, interleukin-12p70 and interleukin -17 were detected in the salivary glands. In contrast, plasma levels showed significantly decreased levels of tumor growth factor-β1 and increased levels of interleukin-4, interferon-γ, interleukin-10 and interleukin-12p70. Conclusions Our findings suggest that expression of tumor necrosis factor inhibitors in the salivary gland can have a negative effect on salivary gland function and that other cytokines should be explored as points for therapeutic intervention in Sjögren's syndrome.
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Affiliation(s)
- Jelle L Vosters
- Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
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Knopf A, Pickhard A, Stark T, Schulz S, Scherer EQ. [Recurrent abcesses of the parotid gland in Sjögren's syndrome]. HNO 2009; 57:959-63. [PMID: 19696974 DOI: 10.1007/s00106-009-1903-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
We report on a 48-year old female patient suffering from recurrent suppurative sialo-adenitis. Resections of both parotid and the left submandibular glands had to be performed due to abscesses. The woman had suffered from recurrent swelling of the salivary glands as well as xerostomia and xerophthalmia for years. Sjögren's syndrome was diagnosed with a delay of 17 years. The current case implicates recurrent bacterial suppurative sialo-adenitis caused by longstanding Sjögren's syndrome. In every case rheumatic disorders have to be considered in the differential diagnosis of recurrent suppurative parotitis. A detailed anamnesis, ultrasound, a differential hemogram, testing for rheumatoid factor and anti-nuclear antibodies (ANA) as well as SS-A and SS-B ENAs can give early information years before Sjögren's syndrome becomes clinically apparent.
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Affiliation(s)
- A Knopf
- Hals-Nasen-Ohren-Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675, München, Deutschland.
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Régent A, Mouthon L. [Anti-TNFalpha therapy in systemic autoimmune and/or inflammatory diseases]. Presse Med 2009; 38:761-73. [PMID: 19349142 DOI: 10.1016/j.lpm.2009.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2009] [Accepted: 02/16/2009] [Indexed: 01/08/2023] Open
Abstract
TNFalpha plays a crucial role in the physiopathology of a large number of auto-immune and/or inflammatory systemic diseases. In addition to authorized indications including rheumatoid arthritis, ankylosing spondylitis, Crohn disease, ulcerative colitis, psoriatic arthritis and plaque psoriasis, TNFalpha blockers have been tested in a wide range of auto-immune and/or inflammatory diseases. TNFalpha blockers might be an option in refractory ANCA-associated vasculitis, sarcoïdosis, adult onset Still disease, Behçet disease, AA amyloïdosis and TRAPS. However, pertaining to the limited number of prospective randomized trails available, the small number of patients included and the poor methodology, it is difficult to define their place in the therapeutic strategy in these conditions. The therapeutic effect of TNFalpha blockers is often suspensive and disease flares are frequently observed during sustained treatment, as in the case of Behçet's disease. Published data do not support the use of TNFalpha blockers in connective tissue diseases.
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Affiliation(s)
- Alexis Régent
- UPRES EA 4058, Université Paris Descartes, Faculté de Médecine, F-75005 Paris, France
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Carsons SE. Issues Related to Clinical Trials of Oral and Biologic Disease-Modifying Agents for Sjögren's Syndrome. Rheum Dis Clin North Am 2008; 34:1011-23, x. [DOI: 10.1016/j.rdc.2008.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
Sjogren's syndrome (SS) is a chronic autoimmune disorder affecting mainly middle-aged women. It is characterized by lymphocytic infiltration and destruction of the exocrine glands (mainly the salivary and lacrimal glands), resulting in dry mouth and eyes. Symptoms of SS are chronic and sometimes devastating, compromising the quality of life at a major extent. Despite its autoimmune nature, evidence for the use of immunosuppressive agents, which are the mainstay of therapy of diseases of autoimmune origin, is limited. Keratoconjunctivitis sicca (KCS), the main ocular manifestation of SS, is managed with tear substitutes, as well as local and systemic stimulators of tear secretion and supportive surgical procedures. Management of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline are the cornerstone of current therapy in SS. Corticosteroids, cyclophoshamide, and nucleoside analogues are reserved for severe extraglandular manifestations of SS. The role of anti-B-cell therapy is a promising option for glandular and extraglandular manifestations of the disease, as well as for the management of SS-associated lymphoma.
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Nakayamada S, Saito K, Umehara H, Ogawa N, Sumida T, Ito S, Minota S, Nara H, Kondo H, Okada J, Mimori T, Yoshifuji H, Sano H, Hashimoto N, Sugai S, Tanaka Y. Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial. Mod Rheumatol 2007; 17:464-9. [PMID: 18084697 DOI: 10.1007/s10165-007-0627-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2007] [Accepted: 06/22/2007] [Indexed: 10/22/2022]
Abstract
This multicenter clinical trial was performed to evaluate the efficacy and safety of mizoribine for the treatment of Sjögren's syndrome. Fifty-nine patients with a definite diagnosis of Sjögren's syndrome received 150;Smg of mizoribine daily for 16 weeks. The salivary secretion volume was determined at baseline, at weeks 8 and 16 after the start of the study treatment by the Saxon test, and clinical manifestations were assessed by the investigator and the patients using a 10-cm visual analog scale (VAS). Adverse drug reactions were reported in 18 patients, of whom 6 patients had to discontinue the study due to such adverse reactions; however, no serious adverse drug reactions definitely related to the study drug were noted. The salivary secretion volume, the rate of change in salivary secretion, the patients' own assessments of dry mouth and dry eyes, the investigators' assessment of oral sicca symptoms, and the investigators' overall assessment improved following the treatment regimen with statistical significance at week 16 after the start of treatment in comparison to the baseline values. These results suggested that mizoribine may be effective in producing a subjective and objective amelioration of the glandular symptoms in patients with Sjögren's syndrome, without observing any serious adverse effects related to this drug.
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Affiliation(s)
- Shingo Nakayamada
- First Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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Rigopoulos D, Korfitis C, Gregoriou S, Katsambas AD. Infliximab in dermatological treatment: beyond psoriasis. Expert Opin Biol Ther 2007; 8:123-33. [DOI: 10.1517/14712598.8.1.123] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Jonsson R, Bolstad AI, Brokstad KA, Brun JG. Sjögren's syndrome--a plethora of clinical and immunological phenotypes with a complex genetic background. Ann N Y Acad Sci 2007; 1108:433-47. [PMID: 17894008 DOI: 10.1196/annals.1422.046] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Primary Sjögren's syndrome is a complex autoimmune disorder, considered to represent an ideal disease with which to study the mechanisms underlying autoimmunity because its manifestations are both organ specific and systemic in nature. The characteristic histologic finding in target organs is a progressive focal infiltration of mononuclear lymphoid cells, replacing glandular epithelium (lymphoepithelial lesion). This involvement has been re-emphasized in the 2002 revised EU criteria for Sjögren's syndrome. Moreover, ectopic secondary lymphoid follicles in Sjögren's syndrome contain all elements of relevance for driving an autoimmune response. A number of cytokines and chemokines are involved and particularly B cell activating factor seems to direct the lifespan of infiltrating B cells by enhancing their proliferation and maturation. The recent discovery of clinical benefit after B cell depletion also highlights the pivotal role of B cells in Sjögren's syndrome. A major challenge in Sjögren's syndrome will be to stratify the disease process including genetic and environmental triggers. Identification of novel genetic and molecular markers may lead to the development of better diagnostic and prognostic tools in Sjögren's syndrome including its systemic complications. This minor review will cover the current knowledge on classification, pathogenesis, multiplex findings, potential candidate genes, gene profiling results, and novel therapy approaches. New hypotheses behind the complexity of Sjögren's syndrome are expected to follow.
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Affiliation(s)
- Roland Jonsson
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway.
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Thanou-Stavraki A, James JA. Primary Sjogren's syndrome: current and prospective therapies. Semin Arthritis Rheum 2007; 37:273-92. [PMID: 17714766 DOI: 10.1016/j.semarthrit.2007.06.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2007] [Revised: 06/05/2007] [Accepted: 06/17/2007] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To summarize data on existing and experimental therapies for primary Sjogren's syndrome (pSS), referring both to sicca syndrome and to other systemic disease manifestations. METHODS Relevant English and non-English articles acquired through Medline were reviewed. RESULTS pSS usually has a benign clinical course, centered on sicca features and general musculoskeletal manifestations, and is managed symptomatically. However, a subset of patients develops more severe extraglandular disease that warrants close monitoring and aggressive treatment. For dry eyes and mouth, nonpharmacologic measures to preserve secretions, and tear and saliva substitutes, offer some symptomatic relief. Muscarinic agonists and topical cyclosporine yield well-documented improvement in ocular sicca features. Although traditional antirheumatic drugs are used empirically for polyarthritis and other Sjogren's symptoms, their efficacy in pSS overall and as disease-modifying agents is limited. For the potential severe, nonexocrine manifestations complicating pSS, standard high-dose immunosuppression is used. Among the biologic agents already examined in pSS, those targeting tumor necrosis factor (TNF)-alpha failed to demonstrate significant benefit. Nonetheless, rituximab and other B-cell-depleting therapies appear promising. CONCLUSIONS Treatment of pSS patients with severe extraglandular disease should differ from that of patients with predominantly sicca features and/or general muscoloskeletal manifestations. pSS treatment is mainly symptomatic, primarily directed against sicca complaints. The traditional anti-rheumatic agents show limited efficacy in the systemic process and use of systemic TNF-alpha inhibitors has been very disappointing. B cell depleting treatments and other newer biologic therapies appear more promising.
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Affiliation(s)
- Aikaterini Thanou-Stavraki
- Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA
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Meijer JM, Pijpe J, Bootsma H, Vissink A, Kallenberg CGM. The future of biologic agents in the treatment of Sjögren's syndrome. Clin Rev Allergy Immunol 2007; 32:292-7. [PMID: 17992596 PMCID: PMC2071970 DOI: 10.1007/s12016-007-8005-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The gain in knowledge regarding the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of Sjögren's syndrome (SS) and the current availability of various biological agents (anti-TNF-alpha, IFN- alpha, anti-CD20, and anti-CD22) have resulted in new strategies for therapeutic intervention. In SS, various phase I and II studies have been performed to evaluate these new strategies. Currently, B cell-directed therapies seem to be more promising than T cell-related therapies. However, large, randomized, placebo-controlled clinical trials are needed to confirm the promising results of these early studies. When performing these trials, special attention has to be paid to prevent the occasional occurrence of the severe side effects.
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Affiliation(s)
- Jiska M Meijer
- Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, The Netherlands.
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Salivary dysfunction associated with systemic diseases: systematic review and clinical management recommendations. ACTA ACUST UNITED AC 2007; 103 Suppl:S57.e1-15. [PMID: 17379156 DOI: 10.1016/j.tripleo.2006.11.010] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2006] [Accepted: 11/08/2006] [Indexed: 01/29/2023]
Abstract
OBJECTIVES The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. STUDY DESIGN Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. RESULTS Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. CONCLUSIONS These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.
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Lodde BM, Baum BJ, Tak PP, Illei G. Experience with experimental biological treatment and local gene therapy in Sjogren's syndrome: implications for exocrine pathogenesis and treatment. Ann Rheum Dis 2006; 65:1406-13. [PMID: 16880196 PMCID: PMC1798364 DOI: 10.1136/ard.2006.052761] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2006] [Indexed: 12/13/2022]
Abstract
Sjögren's syndrome is an autoimmune exocrinopathy, mainly affecting the lacrimal and salivary glands, and resulting in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown, and only palliative treatment is currently available. Data obtained from experimental animal and human studies using biological agents or gene therapeutics can offer insight into the disease process of Sjögren's syndrome. This article reviews the current literature on these approaches and assesses the lessons learnt about the pathogenesis of Sjögren's syndrome.
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Affiliation(s)
- B M Lodde
- Gene Therapy and Therapeutics Branch/NIDCR, National Institutes of Health, 10 Center Drive, Building 10, Room 1N114, Bethesda, MD 20892-1190, USA
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Tomiak C, Dörner T. [Sjögren's syndrome. Current aspects from a rheumatological point of view]. Z Rheumatol 2006; 65:505-17; quiz 518-9. [PMID: 17004051 DOI: 10.1007/s00393-006-0101-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Sjögren's syndrome is an autoimmune disease of the exocrine glands characterized by the leading symptoms of keratoconjunctivitis and stomatitis sicca based on a complex pathogenesis. The prevalence is about 0.5-1%; primary Sjögren's syndrome is differentiated from secondary Sjögren's syndrome associated with other autoimmune disorders. The diagnosis is established by the presence of subjective complaints and objective evidence of sicca symptoms, anti-Ro(SSA)/La(SSB) antibodies, and/or focal lymphocytic infiltration of the glandular tissue. In addition to the typical sicca symptomatology, which is managed symptomatically by substitution and stimulation therapy, some patients exhibit extraglandular manifestations. Complaints involving the musculoskeletal system and inner ear dominate and are treated by the rheumatologist. The indication for base therapy is tailored to individual needs, but the efficacy of this approach has not been established in studies. About 5-10% of the patients with primary Sjögren's syndrome develop a B-cell non-Hodgkin's lymphoma. The disease requires interdisciplinary management including, among others, ophthalmologists, dentists, and otorhinolaryngologists, depending on the clinical picture.
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Affiliation(s)
- C Tomiak
- Reha-Zentrum Bad Aibling, Deutsche Rentenversicherung Bund, Rheumazentrum - AHB, Kolbermoorer Strasse 56, 83043 Bad Aibling, Deutschland.
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Abstract
Sjögren's syndrome (SS) is a chronic inflammatory and lymphoproliferative autoimmune disease of unknown aetiology. It is characterised by progressive mononuclear cell infiltration of the salivary and lacrimal glands and a decreased glandular secretion, resulting in dryness of the mouth and eyes (xerostomia and keratoconjunctivitis sicca, respectively). Dendritic cells (DC) are considered to be the most potent antigen-presenting cells. Because of their central role in initiating an immune response while maintaining tolerance, impaired function of these cells might lead to the break of peripheral tolerance and initiation of immune responses to self-antigens. This review will focus on the possible role of DC in SS.
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Affiliation(s)
- P Vogelsang
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, N-5021 Bergen, Norway
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HSIA EC, RULEY KM, RAHMAN MU. Infliximab (RemicadeR): from bench to clinical practice. A paradigm shift in rheumatology practice. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1479-8077.2006.00185.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Abstract
Sjogren's syndrome is an autoimmune exocrinopathy that predominantly affects salivary and lachrymal glands, leading to dry eyes and mouth. The most common clinical problems faced by the rheumatologist are those of dry eyes and mouth, parotid swelling, fatigue and extraglandular manifestations. The first stage in management is to make an accurate diagnosis based on the American/European consensus criteria. The most frequent differential diagnoses are dry eyes and mouth symptoms, a variant of chronic fatigue syndrome and fibromyalgia, and sialosis, which causes a non-inflammatory enlargement of the parotid glands. The mainstay of treatment for the sicca symptoms is local therapy, and that for the milder systemic symptoms is hydroxychloroquine. Steroids and immunosuppressive drugs are reserved for more severe extraglandular disease. In spite of intensive research in other systemic treatments including biologic therapies, there is limited evidence to support their use in routine clinical practice.
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Affiliation(s)
- P J Venables
- Kennedy Institute Division, Imperial College, London, UK.
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Jonsson MV, Delaleu N, Brokstad KA, Berggreen E, Skarstein K. Impaired salivary gland function in NOD mice: Association with changes in cytokine profile but not with histopathologic changes in the salivary gland. ACTA ACUST UNITED AC 2006; 54:2300-5. [PMID: 16802370 DOI: 10.1002/art.21945] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVE To characterize the chronologic disease course and possible interrelationships between salivary gland inflammation, hyposalivation, and cytokine levels in NOD mice, a model for Sjögren's syndrome (SS). METHODS NOD mice of different ages were used to mimic different disease stages of SS. Histopathologic findings and rates of salivary secretion were compared between 8-week-old, 17-week-old, and 24-week-old female mice. In addition, 10 cytokines were analyzed in serum and saliva obtained from NOD and BALB/c mice. RESULTS In NOD mice, the salivary flow rate did not change between 8 weeks and 17 weeks of age, while a significant decrease in the salivary flow rate occurred between 17 weeks and 24 weeks of age (P < 0.001). In contrast, significant histopathologic changes in the salivary glands occurred before 17 weeks of age. Chronic inflammatory cell infiltrates were characterized by T and B cell infiltration. Interestingly, in one-third of the mice, proliferating cells were observed in the focal infiltrates. Significant changes in the levels of interleukin-2 (IL-2), IL-5, and granulocyte-macrophage colony-stimulating factor in serum, and in the levels of IL-4 and tumor necrosis factor alpha (TNFalpha) in saliva occurred contemporarily with the decrease in salivary flow. Correlation analyses revealed a negative association between salivary secretion and the levels of IL-4, interferon-gamma, and TNFalpha in saliva obtained from NOD mice, while the correlation with inflammatory changes in the glands was consistently weak. CONCLUSION Consistent with previous findings, our results indicate at least 2 phases of SS-like disease in NOD mice. Hyposalivation was preceded by inflammatory changes in the salivary glands, whereas abrupt changes in secretion occurred without significant progression of inflammation. Changes in cytokine levels are an indication of the mechanisms involved in the adaptive immune response in the transition from early to overt disease.
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Hansen A, Lipsky PE, Dörner T. Immunopathogenesis of primary Sjögren's syndrome: implications for disease management and therapy. Curr Opin Rheumatol 2005; 17:558-65. [PMID: 16093833 DOI: 10.1097/01.bor.0000172801.56744.c3] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Recent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögren's syndrome. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as their implications for clinical handling and therapeutic options. RECENT FINDINGS It becomes increasingly apparent that certain disturbances of the immune system (i.e. B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator) play a central role in this entity. Whether this is a primary abnormality or the result of predisposing factors or infectious, e.g. viral, agents remains uncertain. New insights into the pathogenesis also provide candidates for better diagnosis and classification of disease severity, such as flow cytometric analysis, measurement of soluble cell surface molecules, autoantibodies, cytokines, and ligands (B-cell-activating factor/B-lymphocyte stimulator). Whether B-cell-directed therapies (i.e. blocking B-cell-activating factor/B-lymphocyte stimulator, anti-CD20 therapy) will have an impact on primary Sjögren's syndrome needs to be shown in clinical trials. Alternative therapeutic approaches such as organ-targeted gene transfer are in development but must be carefully evaluated for safety and efficacy in preclinical models that resemble human primary Sjögren's syndrome. SUMMARY The pathogenesis of primary Sjögren's syndrome is complex and the factors initiating and driving autoimmunity in this entity are largely unknown. Recent studies provide new insights into potential pathogenetic mechanisms of the disease and, thereby, the chance for improved strategies in disease management and therapy.
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Affiliation(s)
- Arne Hansen
- Charité University Medicine Berlin, Germany.
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Zoukhri D. Effect of inflammation on lacrimal gland function. Exp Eye Res 2005; 82:885-98. [PMID: 16309672 PMCID: PMC1361268 DOI: 10.1016/j.exer.2005.10.018] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2005] [Revised: 10/06/2005] [Accepted: 10/17/2005] [Indexed: 12/21/2022]
Abstract
The lacrimal gland is the main contributor to the aqueous layer of the tear film. It secretes proteins, electrolytes and water, which helps to nourish and protect the ocular surface. Lacrimal gland secretion is primarily under neural control, which is achieved through a neural reflex arc. Stimuli to the ocular surface activate afferent sensory nerves in the cornea and conjunctiva. This in turn activates efferent parasympathetic and sympathetic nerves in the lacrimal gland to stimulate secretion. Sex steroid hormones are also important regulators of lacrimal gland functions. A decrease or lack of lacrimal gland secretion is the leading cause of aqueous tear deficient dry eye syndrome (DES). It has been suggested that DES is an inflammatory disorder that affects the ocular surface and the lacrimal gland. In several pathological instances, the lacrimal gland can become a target of the immune system and show signs of inflammation. This can result from autoimmune diseases (Sjögren's syndrome), organ transplantation (graft versus host disease), or simply as a result of aging. The hallmarks of lacrimal gland inflammation are the presence of focal lymphocytic infiltrates and increased production of proinflammatory cytokines. The mechanisms leading to lacrimal gland dysfunction are still poorly understood. Apoptosis, production of autoantibodies, hormonal imbalance, alterations in signaling molecules, neural dysfunction, and increased levels of proinflammatory cytokines have been proposed as possible mediators of lacrimal gland insufficiency in disease states.
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Affiliation(s)
- Driss Zoukhri
- Department of General Dentistry, Tufts University School of Dental Medicine, Boston, MA, USA.
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Moen K, Kvalvik AG, Hellem S, Jonsson R, Brun JG. The long-term effect of anti TNF-α treatment on temporomandibular joints, oral mucosa, and salivary flow in patients with active rheumatoid arthritis: A pilot study. ACTA ACUST UNITED AC 2005; 100:433-40. [PMID: 16182164 DOI: 10.1016/j.tripleo.2005.05.060] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2005] [Revised: 05/03/2005] [Accepted: 05/23/2005] [Indexed: 11/21/2022]
Abstract
OBJECTIVE The objective of this study was to evaluate the long-term effects of anti-TNF-alpha treatment on temporomandibular joints (TMJs), oral mucosa, and salivary flow in RA. STUDY DESIGN Seventeen patients received infusions of TNF-alpha blocking agents after 0, 2, and 6 weeks, and then every 8 weeks until week 54 (follow-up). Clinical dysfunction index (Di) for the TMJ system, salivary flow, disease activity score (DAS28), and other medical assessments were calculated at weeks 0 and 54. RESULTS Median Di was 5.0 (range 0-21) at baseline and 1.0 (range 0-6) (P = .001) at follow-up. Mean salivary flow was 3.2 mL/15 minutes at baseline and 4.6 at follow-up (P = .055). Two (11.7%) of the patients developed oral candidiasis during the period of treatment. The median DAS28 was 6.2 (range, 4.7-7.7) at baseline and 4.1 (range, 1.6-6.8) at follow-up (P = .001). CONCLUSION We conclude that anti-TNF-alpha blocking treatments have beneficial effects on oral as well as general manifestations of RA.
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Affiliation(s)
- Ketil Moen
- Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Norway.
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Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands, primarily the salivary and lacrimal glands. It has been suggested that exogenous agents may trigger SS in genetically predisposed individuals. However, at present, the etiology of SS is far from being understood, and no direct evidence for any of these triggers has been presented. The salivary and lacrimal glands from patients with SS harbor unique and highly selected T- and B-cell populations. Disturbance in glandular cell apoptosis may be one possible explanation for the sicca symptoms in SS. However, discrepancies between glandular destruction and salivary flow give rise to processes causing glandular dysfunction preceding or triggering glandular cell destruction. Recent reports suggested autoantibodies inhibiting neuronal innervation of acinar cells and defective water transport to be implicated in salivary secretion deficiency observed in SS. Several types of autoantibodies have been suggested to contribute to the pathogenesis of SS. However, how the tolerance to these structures is broken down is unknown at present. Studies on B-cell activating factor indicated that diminished apoptosis and disturbed B-cell maturation could be responsible for the occurrence of autoreactive B-cells and B-cell hyperreactivity. B-cell activation may also provide a basis for lymphoma development observed in up to 5% of the patients with SS.
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Affiliation(s)
- Nicolas Delaleu
- Clinic for Geriatric and Special Care Dentistry, University of Zürich, Zürich, Switzerland.
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45
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Ramos-Casals M, Tzioufas AG, Font J. Primary Sjögren's syndrome: new clinical and therapeutic concepts. Ann Rheum Dis 2005; 64:347-54. [PMID: 15498797 PMCID: PMC1755414 DOI: 10.1136/ard.2004.025676] [Citation(s) in RCA: 178] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Sicca features are the central clinical manifestations of Sjögren's syndrome (SS), but recent studies have confirmed that primary SS has a systemic expression, including extraglandular manifestations. Patients with a predominantly extraepithelial expression should be managed differently from patients with predominantly periepithelial or sicca limited disease. In coming years treatment will be based on muscarinic agonists for sicca features and immunosuppressive/biological agents for extraglandular features.
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Affiliation(s)
- M Ramos-Casals
- Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain.
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Ramos-Casals M, Tzioufas AG, Font J. Síndrome de Sjögren. Nuevas perspectivas terapéuticas. Med Clin (Barc) 2005; 124:111-5. [PMID: 15710099 DOI: 10.1157/13070854] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- Manuel Ramos-Casals
- Servicio de Enfermedades Autoinmunes Sistémicas, Hospital Clínic de Barcelona, Barcelona, Spain.
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Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR. Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. ACTA ACUST UNITED AC 2004; 50:2240-5. [PMID: 15248223 DOI: 10.1002/art.20299] [Citation(s) in RCA: 194] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To assess the safety and potential efficacy of etanercept in the treatment of Sjögren's syndrome (SS). METHODS This pilot study was a 12-week randomized, double-blind, placebo-controlled trial of etanercept, with 14 subjects in each group. Patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Patients met the American-European Consensus Group criteria for SS. The primary outcome required at least 20% improvement from baseline values for at least 2 of the following 3 domains: subjective or objective measures of dry mouth, subjective or objective measures of dry eyes, and IgG level or erythrocyte sedimentation rate (ESR). RESULTS Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS secondary to rheumatoid arthritis. Baseline measures did not differ between the 2 groups. Three etanercept-treated patients and 1 placebo-treated patient did not complete the trial. Five etanercept-treated patients and 3 placebo-treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. At 12 weeks, the ESR had decreased in the etanercept group compared with baseline (P = 0.004); however, the mean reduction was only 18.6%. CONCLUSION We found no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly for 12 weeks was clinically efficacious in SS. A larger trial will be necessary to definitively address the efficacy of etanercept in the treatment of SS.
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Affiliation(s)
- Vidya Sankar
- National Institutes of Health, Bethesda, Maryland, USA.
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Abstract
When salivary output is reduced chronically to a significant extent, there is a marked increase in dental caries. As the role of saliva in protection of the oral hard tissue is well recognized, there have long been efforts to enhance salivary function in conditions with associated secretory hypofunction. The rationale is that by stimulating salivary output, caries and other oral complications will be reduced or eliminated. The most widely used method for increasing salivary function is a combination of masticatory and gustatory stimulation. A large number of systemic agents have also been proposed as secretagogues, but only a few have shown consistent salivary enhancing properties in well-designed, controlled trials. Pilocarpine has been shown to improve symptoms of oral dryness and to increase salivary output in patients with Sjögren's syndrome and postradiation xerostomia. Recently, cevimeline has shown significant salivary enhancement in Sjögren's syndrome. Pilocarpine and cevimeline have a similar mechanism of action, side effect profile and duration of activity. No secretagogues have been linked directly in clinical trials to either caries prevention or a reduction in the existing caries rate of salivary dysfunction patients. Improved secretagogues are needed, with fewer side effects, increased duration of activity and greater potency. Future research directions include gene therapeutic approaches to direct salivary growth and differentiation or modify remaining tissues to promote secretion, creation of a biocompatible artificial salivary gland and salivary transplantation. With improved secretagogues, the effects of conditions that result in reduced salivary function and increased caries will be ameliorated.
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Affiliation(s)
- Philip C Fox
- Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA.
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50
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Abstract
Salivary gland disease gives rise to salivary gland enlargement, pain, and prolonged xerostomia (dry mouth). Xerostomia is the most common long-standing problem for the majority of affected patients. There are many causes of dry mouth, with long-standing xerostomia being a particular problem in Sjögren's syndrome and after radiation to the head and neck region. Xerostomia is usually managed with saliva substitutes, but a large number of potential systemic therapies of long-standing xerostomia now exist. Some-particularly immunosuppressants-are of fundamental interest for the potential reduction of gland damage in Sjögren's syndrome but as yet are of limited clinical usefulness. Others, particularly pilocarpine and cevimeline, are, or have the potential to be, clinically useful in stimulating salivation by virtue of their action on cholinergic receptors.
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Affiliation(s)
- S R Porter
- Department of Oral Medicine, Eastman Dental Institute for Oral Health Care Sciences, University College London, University of London, England.
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