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De Vita S, Isola M, Baldini C, Goules AV, Chatzis LG, Quartuccio L, Zabotti A, Giovannini I, Donati V, Ferro F, Rizzo MT, Manfrè V, Pegolo E, Voulgarelis M, Zaja F, Fanin R, Masaoutis C, Rontogianni D, Fotiadis DI, Ponzoni M, Tzioufas AG. Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording. Rheumatology (Oxford) 2022; 62:1586-1593. [PMID: 36063040 PMCID: PMC10072883 DOI: 10.1093/rheumatology/keac470] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/11/2022] [Accepted: 08/11/2022] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. METHODS A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. RESULTS PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. CONCLUSION A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.
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Affiliation(s)
- Salvatore De Vita
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Miriam Isola
- Institute of Statistics, Department of Medical Area, University of Udine, Udine, Italy
| | - Chiara Baldini
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Andreas V Goules
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
| | - Loukas G Chatzis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
| | - Luca Quartuccio
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Alen Zabotti
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Ivan Giovannini
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Valentina Donati
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Francesco Ferro
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Maria Teresa Rizzo
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Valeria Manfrè
- Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy
| | - Enrico Pegolo
- Institute of Anatomic Pathology, Department of Medical and Biological Sciences, University of Udine, University Hospital of Santa Maria della Misericordia, Udine, Italy
| | - Michael Voulgarelis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
| | - Francesco Zaja
- Department of Hematology, DSM University of Trieste, Trieste, Italy
| | - Renato Fanin
- Hematology and SCT Unit, Università di Udine, Azienda Sanitaria-Universitaria Integrata Santa Maria Misericordia, Udine, Italy
| | - Christos Masaoutis
- Department of Pathology, Evangelismos General Hospital of Athens, Athens, Greece
| | - Dimitra Rontogianni
- Department of Pathology, Evangelismos General Hospital of Athens, Athens, Greece
| | - Dimitrios I Fotiadis
- Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, Ioannina, GR, 45110, Greece.,Department of Biomedical Research, Institute of Molecular Biology and Biotechnology-FORTH, GR 45110 Ioannina, Greece
| | - Maurilio Ponzoni
- Pathology Unit, San Raffaele Scientific Institute, Milan, Italy; Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Institute for Autoimmune Systemic and Neurological Diseases, Athens, Greece
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Jousse-Joulin S, D'Agostino MA, Hočevar A, Naredo E, Terslev L, Ohrndorf S, Iagnocco A, Schmidt WA, Finzel S, Alavi Z, Bruyn GAW. Response to: 'Ultrasonographic damages of major salivary glands are associated with cryoglobulinemic vasculitis and lymphoma in primary Sjogren's syndrome: are the ultrasonographic features of the salivary glands new prognostic markers in Sjogren's syndrome?' by Coiffier et al. Ann Rheum Dis 2021; 80:e112. [PMID: 31601631 DOI: 10.1136/annrheumdis-2019-216327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 09/18/2019] [Indexed: 12/21/2022]
Affiliation(s)
| | | | - Alojzija Hočevar
- Rheumatology, Universitiy Medical Centre Ljubljana, Ljubljana, Slovenia
| | | | - Lene Terslev
- Rheumatology, Glostrup University Hospital, Copenhagen, Denmark
| | - Sarah Ohrndorf
- Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Annamaria Iagnocco
- Scienze Cliniche e Biologiche, Università degli Studi di Torino, Rome, Italy
| | - Wolfgang A Schmidt
- Rheumatology, Medical Centre for Rheumatology Berlin Buch, Berlin, Germany
| | - Stephanie Finzel
- Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
| | - Zarrin Alavi
- INSERM, CIC 1412, Brest University Hospital, Brest, France
| | - George A W Bruyn
- MC Group Hospitals, Lelystad, The Netherlands
- Reumakliniek Flevoland, Lelystad, The Netherlands
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3
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Ruiz-Ordoñez I, Piedrahita JM, Arévalo JA, Agualimpia A, Tobón GJ. Lymphomagenesis predictors and related pathogenesis. J Transl Autoimmun 2021; 4:100098. [PMID: 33889831 PMCID: PMC8050773 DOI: 10.1016/j.jtauto.2021.100098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 11/23/2022] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disease characterised by a wide range of clinical manifestations and complications, including B-cell lymphoma. This study aims to describe the predictors associated with lymphomagenesis in patients with Sjögren's syndrome, emphasising the pathophysiological bases that support this association. We performed a review of the literature published through a comprehensive search strategy in PubMed/MEDLINE, Scopus, and Web of science. Forty publications describing a total of 45,208 patients with SS were retrieved. The predictors were grouped according to their pathophysiological role in the lymphoproliferation process. Also, some new biomarkers such as MicroRNAs, P2X7 receptor-NLRP3 inflammasome, Thymic stromal lymphopoietin, and Three-prime repair exonuclease 1 (TREX1) were identified. The knowledge of the pathophysiology allows the discrimination of markers that participate in the initial stages. Considering that the lymphoproliferation process includes the progression of lymphoma towards more aggressive subtypes, it is essential to recognise biomarkers associated with a worse prognosis.
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Affiliation(s)
- Ingrid Ruiz-Ordoñez
- Fundación Valle del Lili, Centro de Investigaciones Clínicas, Cra 98 No. 18-49, Cali, 760032, Colombia
- Universidad Icesi, Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Cali, Colombia
| | - Juan-Manuel Piedrahita
- Universidad Icesi, Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Cali, Colombia
- Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia
| | - Javier-Andrés Arévalo
- Universidad Icesi, Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Cali, Colombia
- Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia
| | - Andrés Agualimpia
- Universidad Icesi, Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Cali, Colombia
- Fundación Valle del Lili, Unidad de Reumatología, Cra 98 No. 18-49, Cali. 760032, Colombia
| | - Gabriel J Tobón
- Universidad Icesi, Centro de Investigación en Reumatología, Autoinmunidad y Medicina Traslacional, Cali, Colombia
- Fundación Valle del Lili, Unidad de Reumatología, Cra 98 No. 18-49, Cali. 760032, Colombia
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Traianos EY, Locke J, Lendrem D, Bowman S, Hargreaves B, Macrae V, Tarn JR, Ng WF. Serum CXCL13 levels are associated with lymphoma risk and lymphoma occurrence in primary Sjögren's syndrome. Rheumatol Int 2020; 40:541-548. [PMID: 32047959 PMCID: PMC7069897 DOI: 10.1007/s00296-020-04524-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/21/2020] [Indexed: 12/19/2022]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease characterised by an increased risk for non-Hodgkin lymphoma (NHL) development. Ectopic germinal centre (GC) in the salivary gland is associated with increased NHL risk in pSS, and the chemokine CXCL13 is implicated in B-cell migration and GC formation. Serum CXCL13 concentrations were quantified by ELISA in 48 healthy individuals, 273 pSS patients without NHL (pSS-nonL), and 38 pSS patients with NHL (pSS-NHL+) from the United Kingdom Primary Sjögren's Syndrome Registry cohort. PSS-nonL patients were stratified into low risk (LR), moderate risk (MR) and high risk (HR) groups according to the lymphoma risk score proposed by Fragkioudaki et al. Differences in serum CXCL13 levels among groups were analysed using the Wilcoxon method. Also, changes in serum CXCL13 over a time period of at least 1 year and a median 4 years were assessed for 200 pSS-nonL and 8 pSS-NHL+ patients. In addition, associations of serum CXCL13 with B-cell and inflammatory markers were investigated by correlation analyses and logistic regression. Serum CXCL13 levels were higher in all pSS groups compared to controls (p < 0.0001), and in pSS-NHL+ compared to pSS-nonL patients (p = 0.0204). LR patients had lower CXCL13 levels than MR patients (p < 0.0001) and pSS-NHL+ patients (p = 0.0008). CXCL13 levels remained stable over the study period for all pSS groups. CXCL13 was associated (p < 0.0005) with Immunoglobulin G (IgG), B-cell activating factor, β2 microglobulin, combined free light chains, κ and λ light chains, anti-Ro/SSA, anti-La/SSB, and erythrocyte sedimentation rate. IgG and C3 controlled for age and gender were significantly associated with NHL risk in pSS. Serum CXCL13 levels were elevated in pSS-NHL+ and MR patients compared to LR patients and remained stable over time. Further study is required to investigate the role of CXCL13 in pSS-associated NHL risk.
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Affiliation(s)
- Emmanuella Young Traianos
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - James Locke
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Dennis Lendrem
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | | | - Ben Hargreaves
- NIHR Newcastle Biomedical Research Center, Newcastle upon Tyne, UK
| | - Victoria Macrae
- NIHR Newcastle Biomedical Research Center, Newcastle upon Tyne, UK
| | - UK primary Sjögren’s syndrome registry
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
- Univesity Hospital Birmingham, Birmingham, UK
- NIHR Newcastle Biomedical Research Center, Newcastle upon Tyne, UK
| | - Jessica Rachael Tarn
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
| | - Wan-Fai Ng
- Musculoskeletal Research Group, Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH UK
- NIHR Newcastle Biomedical Research Center, Newcastle upon Tyne, UK
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5
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Gorodetskiy VR, Probatova NA, Vasilyev VI. Characteristics of diffuse large B-cell lymphoma in patients with primary Sjögren's syndrome. Int J Rheum Dis 2020; 23:540-548. [PMID: 32100426 PMCID: PMC7187201 DOI: 10.1111/1756-185x.13800] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/19/2019] [Accepted: 01/13/2020] [Indexed: 12/15/2022]
Abstract
Aim Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing diffuse large B‐cell lymphoma (DLBCL), which is an aggressive and heterogeneous non‐Hodgkin lymphoma. This study aimed to characterize DLBCLs in patients with pSS. Method We identified 18 patients with DLBCL and pSS over a 22‐year period. Based on the 2016 WHO guidelines, we characterized DLBCL based on immunohistochemical tests using a broad panel of antibodies, and an Epstein‐Barr virus (EBV) test using in situ hybridization. Results The median time from initial pSS symptom onset to the DLBCL diagnosis was 20.5 years and the median time from the pSS diagnosis until the DLBCL diagnosis was 14 years. After the lymphoma diagnosis, the median overall survival was 3 months (range: 0‐212 months) and the 5‐year overall survival rate was 37.5%. Thirteen DLBCLs were re‐classified as DLBCL, not otherwise specified (NOS) in nine cases; EBV‐positive DLBCL, NOS in two cases; and T‐cell/histiocyte‐rich large B‐cell lymphoma in two cases. Five cases of DLBCLs were not re‐classified because their EBV status was unknown. The Hans algorithm, which uses a combination of staining for CD10, BCL6, and MUM1, was used to classify the DLBCLs into the germinal center B‐cell (GCB) subtype for three cases and the non‐GCB subtype for nine cases. Conclusion These results indicate that DLBCL tends to occur late in pSS cases and is mainly related to the non‐GCB subtype of DLBCL.
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Affiliation(s)
| | | | - Vladimir Ivanovich Vasilyev
- Department of Intensive Methods of Therapy, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
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6
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Noureldine HA, Nour-Eldine W, Hodroj MH, Noureldine MHA, Taher A, Uthman I. Hematological malignancies in connective tissue diseases. Lupus 2020; 29:225-235. [PMID: 31933408 DOI: 10.1177/0961203319899986] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic inflammation has profound tumor-promoting effects. Inflammatory cells are the key players in immunosurveillance against tumors, and immunosuppression is known to increase the risk of tumors. Autoimmune diseases, which manifest as loss of self-tolerance and chronic immune dysregulation, provide a perfect environment for tumor development. Aside from managing the direct inflammatory consequences of autoimmune pathogenesis, cancer risk profiles should be considered as a part of a patient's treatment. In this review, we describe the various associations of malignancies with autoimmune diseases, specifically systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome, as well as discuss the mechanisms contributing to the pathogenesis of both disorders.
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Affiliation(s)
- H A Noureldine
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - W Nour-Eldine
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - M H Hodroj
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - M H A Noureldine
- Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children's Hospital, Saint Petersburg, USA
| | - A Taher
- Division of Hematology and Medical Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - I Uthman
- Division of Rheumatology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Primary Pulmonary Diffuse Large B-Cell Lymphoma Presenting as an Endobronchial Lesion: The Youngest Adult Patient in the Literature. CURRENT HEALTH SCIENCES JOURNAL 2019; 45:425-428. [PMID: 32110447 PMCID: PMC7014988 DOI: 10.12865/chsj.45.04.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/20/2019] [Indexed: 12/02/2022]
Abstract
A 20-year-old female patient was admitted to hospital with complaints of chest and back pain in September 2018. There was a cavitary lesion in the upper zone of the left lung in the chest X-ray. Thorax CT revealed an irregular contoured and shaped mass with 87x67x79 mm sizes, in the upper lobe of the left lung lying to paramediastinal area. Since there was a doubt about malignancy, positron emission tomography (PET) was performed; there was a cavitary lesion in the left upper lobe with high FDG uptake (SUVmax: 23.2). Bronchoscopic examination revealed an endobronchial lesion with nearly complete occlusion in the apicoposterior segment of the left upper lobe. Bronchoalveolar lavage (BAL) performed in this session for acid-fast bacilli (AFB) was negative. The patient was diagnosed as primary pulmonary diffuse large B-cell lymphoma (DLBCL) by histopathological and immunohistochemical evaluation of endobronchial biopsy specimens. Following the final diagnosis of Bronchus-Associated Lymphoid Tissue Lymphoma (BALTOMA), the patient was referred to the department of haematology, and chemotherapy was planned for therapy. Since DLBCL is extremely rare, and uncommonly presenting with an endobronchial lesion, we want to present this patient as the youngest adult case of primary endobronchial BALT lymphoma in the literature.
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Li ZY, Kim S, Huang S, Mian R. Multicentric Castleman disease with TAFRO syndrome and Sjögren's. Clin Case Rep 2019; 7:2388-2392. [PMID: 31893065 PMCID: PMC6935625 DOI: 10.1002/ccr3.2502] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 09/11/2019] [Accepted: 09/17/2019] [Indexed: 12/19/2022] Open
Abstract
We describe a patient with Castleman's disease with TAFRO syndrome and concurrent Sjögren's syndrome and investigate whether the autoimmune process may have accelerated the onset of her Castleman's disease. Patient was treated with R-CVP therapy with remission of symptoms although there is no current standard treatment.
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Affiliation(s)
- Zi Ying Li
- Department of Internal MedicineUniversity of California, San Francisco-FresnoFresnoCAUSA
| | - Shirley Kim
- Department of Internal MedicineUniversity of California, San Francisco-FresnoFresnoCAUSA
| | - SiYi Huang
- Department of Internal MedicineUniversity of California, San Francisco-FresnoFresnoCAUSA
| | - Raza Mian
- Department of Internal MedicineUniversity of California, San Francisco-FresnoFresnoCAUSA
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De Vita S, Gandolfo S. Predicting lymphoma development in patients with Sjögren's syndrome. Expert Rev Clin Immunol 2019; 15:929-938. [PMID: 31347413 DOI: 10.1080/1744666x.2019.1649596] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Introduction: The issue of predicting lymphoma in primary Sjögren's syndrome (pSS) starts from its clinical and biologic essence, i.e., an autoimmune exocrinopathy with sicca syndrome, inflammation and lymphoproliferation of MALT (mucosa-associated lymphoid tissue) in exocrine glands. Areas covered: The two major predictors to be firstly focused are persistent salivary gland (SG) swelling and cryoglobulinemic vasculitis with related features as purpura and low C4, or the sole serum cryoglobulinemia repeatedly detected. They are pathogenetically linked and reflect a heavier MALT involvement by histopathology, with the expansion of peculiar rheumatoid factor (RF)-positive clones/idiotypes. Other predictors include lymphadenopathy, splenomegaly, neutropenia, lymphopenia, serum beta2-microglobulin, monoclonal immunoglobulins, light chains, and RF. Composite indexes/scores may also predict lymphoma. Expert opinion: Prediction at baseline needs amelioration, and must be repeated in the follow-up. Careful clinical characterization, with harmonization and stratification of large cohorts, is a relevant preliminary step. Validated and new biomarkers are needed in biologic fluids and tissues. SG echography with automatic scoring could represent a future imaging biomarker, still lacking. Scoring MALT involvement in pSS, as an additional tool to evaluate disease activity and possibly to predict lymphoma, is welcomed. All these efforts are now ongoing within the HarmonicSS project and in other research initiatives in pSS.
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Affiliation(s)
- Salvatore De Vita
- Rheumatology Clinic, Udine University Hospital, Department of Medical Area, University of Udine , Udine , Italy
| | - Saviana Gandolfo
- Rheumatology Clinic, Udine University Hospital, Department of Medical Area, University of Udine , Udine , Italy
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10
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Nocturne G. [Sjögren's syndrome update: Clinical and therapeutic aspects]. Rev Med Interne 2019; 40:433-439. [PMID: 31027874 DOI: 10.1016/j.revmed.2019.03.329] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/07/2019] [Accepted: 03/21/2019] [Indexed: 12/16/2022]
Abstract
Sjögren's syndrome (SS) is a systemic orphan disease. It is characterized by the involvement of epithelial tissues leading to the term of autoimmune epithelitis. New classification criteria have been developed in 2016. New scores have also been developed: a patient-reported outcome called ESSPRI and a score assessing systemic activity of the disease called ESSDAI. These new tools are very helpful to better stratify patients and to customize the management of this very heterogeneous disease. Among the autoimmune diseases, SS is associated with the highest risk of lymphoma. Five to ten percent of the patients will have a B cell lymphoma mostly a low-grade lymphoma developing from mucosa-associated lymphoid tissue (MALT). Major advances have been made in this field: pathogeny is better understood, new predictors are available and progresses have been made in the management of this severe complication. Research in the field of SS is very dynamic as illustrated by the high number of therapeutic trials. There is hope that these innovations, reviewed in the present article, will have potential significant repercussions for the patients in the next few years.
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Affiliation(s)
- G Nocturne
- Department of Rheumatology, hôpitaux universitaires Paris-Sud, AP-HP, 94270 Le Kremlin-Bicêtre, France; Inserm U1184, Center for immunology of viral infections and autoimmune diseases, Université Paris-Sud, 94270 Le Kremlin-Bicêtre, France.
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11
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Nocturne G, Pontarini E, Bombardieri M, Mariette X. Lymphomas complicating primary Sjögren's syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford) 2019; 60:3513-3521. [PMID: 30838413 PMCID: PMC8328496 DOI: 10.1093/rheumatology/kez052] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/09/2019] [Indexed: 12/31/2022] Open
Abstract
Lymphoma development is the most serious complication of SS and the main factor impacting on mortality rate in patients with this condition. Lymphomas in SS are most commonly extranodal non-Hodgkin B-cell lymphomas of the mucosa-associated lymphoid tissue and frequently arise in salivary glands that are the target of a chronic inflammatory autoimmune process. Extensive work on lymphomagenesis in SS has established that the progression towards B-cell lymphoma is a multistep process related to local chronic antigenic stimulation of B cells. These neoplastic B cells in SS frequently derived from autoreactive clones, most commonly RF-producing B cells, which undergo uncontrolled proliferation and malignant escape. In this review, we highlight the most important recent findings that have enhanced our understanding of lymphoma development in SS, with particular reference to the close link between autoimmunity and lymphomagenesis. We also discuss how the identification of key factors involved in B-cell malignancies may impact on our ability to identify at early stages patients at increased risk of lymphoma with potential significant repercussions for the clinical management of SS patients. Finally, we identified the most promising areas of current and further research with the potential to provide novel basic and translational discoveries in the field. The questions of finding new biomarkers, developing a validated score for predicting lymphoma occurrence and assessing if a better control of disease activity will decrease the risk of lymphoma in primary SS will be the enthralling questions of the next few years.
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Affiliation(s)
- Gaetane Nocturne
- Department of Rheumatology, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, Centre for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR1184, Le Kremlin Bicêtre, France
| | - Elena Pontarini
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Michele Bombardieri
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Xavier Mariette
- Department of Rheumatology, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, Centre for Immunology of Viral Infections and Autoimmune Diseases, INSERM UMR1184, Le Kremlin Bicêtre, France
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Dei-Adomakoh YA, Quarcoopome L, Abrahams AD, Segbefia CI, Dey DI. Sjögren's and plasma cell variant Castleman disease: a case report. Ghana Med J 2018; 52:61-65. [PMID: 30013261 DOI: 10.4314/gmj.v52i1.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Castleman disease is a rare cause of lymphoid hyperplasia and may result in localized symptoms or an aggressive, multisystem disorder. It can mimic other diseases like lymphoma or tuberculosis. It classically presents as a mediastinal mass that involves the lymphatic tissue primarily but can also affect extra lymphatic sites including the lungs, larynx, parotid glands, pancreas, meninges, and muscles. In HIV and HHV8-negative patients with idiopathic multi-centric Castleman disease, pathogenesis may involve autoimmune mechanisms. We highlight and report a case of a 34-year-old Ghanaian female who was successfully diagnosed and managed for Sjögren's as well as plasma cell variant Castleman disease with combination chemotherapy and rituximab followed by eighteen months maintenance therapy with pulse chlorambucil and prednisolone and three monthly rituximab.
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Affiliation(s)
- Yvonne A Dei-Adomakoh
- Department of Haematology, University of Ghana School of Biomedical and Allied Health Sciences, PO Box GP 4236, Accra, Ghana
| | | | - Afua D Abrahams
- Department of Pathology, University of Ghana School of Biomedical and Allied Health Sciences, PO Box GP 4236, Accra, Ghana
| | - Catherine I Segbefia
- Department of Child Health, University of Ghana School of Medicine & Dentistry, Accra, Ghana
| | - Dzifa I Dey
- Department of Medicine & Therapeutics, University of Ghana School of Medicine and Dentistry, Accra, Ghana
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13
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Chiu YH, Chung CH, Lin KT, Lin CS, Chen JH, Chen HC, Huang RY, Wu CT, Liu FC, Chien WC. Predictable biomarkers of developing lymphoma in patients with Sjögren syndrome: a nationwide population-based cohort study. Oncotarget 2018; 8:50098-50108. [PMID: 28177920 PMCID: PMC5564832 DOI: 10.18632/oncotarget.15100] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
Sjögren syndrome (SS) is commonly known to be correlated with lymphoma. This study included 16,396 individuals in the SS cohort and 65,584 individuals in the non-SS cohort, all of whom were enrolled in the Taiwan National Health Insurance database between 2000 and 2010. We evaluated the risk factors of non-Hodgkin's lymphoma (NHL) in the primary SS cohort by applying a Cox multivariable proportional-hazards model. We increased the correlation of patients with SS and NHL, with an adjusted HR of 4.314 (95% CI 2.784 – 6.685). Of the 16,396 SS patients, 66 individuals had salivary gland slices without NHL development, while the other 16,330 individuals that did not have salivary gland slices revealed 30 individuals that developed NHL. Of the 16,396 SS patients, 128 individuals underwent immunomodulator agent therapy (including hydroxychloroquine, azathioprine, cyclosporine, methotrexate, and rituximab) without NHL development. None of the 30 individuals that developed NHL from SS received immunomodulator agents. We found that patients with SS were at an increased risk of developing NHL, with the most common NHL subgroup being diffused large B-cell lymphoma. SS patients who were candidates for salivary gland slices or immunomodulator agents were associated with a lower risk of developing lymphoma over time. We recommend that patients at a higher risk upon diagnosis of SS receive close follow-up and aggressive treatment.
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Affiliation(s)
- Yu-Hsiang Chiu
- Department of Internal Medicine, Division of Rheumatology/Immunology/Allergies, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Kuen-Tze Lin
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chin-Sheng Lin
- Department of Internal Medicine, Division of Cardiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jia-Hong Chen
- Department of Internal Medicine, Division of Hematology/Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsiang-Cheng Chen
- Department of Internal Medicine, Division of Rheumatology/Immunology/Allergies, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ren-Yeong Huang
- Department of Periodontology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Tsung Wu
- Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Feng-Cheng Liu
- Department of Internal Medicine, Division of Rheumatology/Immunology/Allergies, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan
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Minami D, Ando C, Sato K, Moriwaki K, Sugahara F, Nakasuka T, Iwamoto Y, Fujiwara K, Shibayama T, Yonei T, Sato T. Multiple Mucosa-associated Lymphoid Tissue Lymphoma of the Trachea. Intern Med 2017; 56:2907-2911. [PMID: 28943536 PMCID: PMC5709637 DOI: 10.2169/internalmedicine.8269-16] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mucosa-associated lymphoid tissue lymphoma is a common type of primary pulmonary carcinoma, but the presence of polypoid nodules is extremely rare. We herein report two cases with multiple nodules in the trachea. One case involved polypoid nodules and airway stenosis mimicking asthma; the other case had concurrent nontuberculous mycobacterial infection. The diagnosis of both cases was confirmed by bronchoscopy. The two cases were sensitive to radiotherapy and chemotherapy, respectively.
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Affiliation(s)
- Daisuke Minami
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Chihiro Ando
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Ken Sato
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Kaori Moriwaki
- Department of Respiratory Medicine, Hiroshima City Asa Citizens Hospital, Japan
| | - Fumihiro Sugahara
- Department of Respiratory Medicine, Hiroshima City Asa Citizens Hospital, Japan
| | - Takamasa Nakasuka
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Yoshitaka Iwamoto
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Keiichi Fujiwara
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Takuo Shibayama
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Toshiro Yonei
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
| | - Toshio Sato
- Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Japan
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15
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Titsinides S, Nikitakis N, Piperi E, Sklavounou A. MALT Lymphoma of Minor Salivary Glands in a Sjögren's Syndrome Patient: a Case Report and Review of Literature. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2017; 8:e5. [PMID: 28496965 PMCID: PMC5423310 DOI: 10.5037/jomr.2017.8105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 03/20/2017] [Indexed: 12/24/2022]
Abstract
Background Sjögren’s syndrome is a chronic systemic disease, characterized by lymphocytic infiltration and destruction mainly of the salivary and lacrimal glands, resulting in xerostomia and xeropthalmia. Sjögren’s syndrome patients have a 44-fold excess risk for the development of non-Hodgkin’s lymphoma particularly mucosa-associated lymphoid tissue (MALT) lymphoma, prevalently affecting the major salivary glands. In this report, a rare case of MALT lymphoma of minor salivary glands in a patient with Sjögren’s syndrome is described. A review of the published cases of MALT lymphoma located in the minor salivary glands of patients with Sjögren’s syndrome is provided. Methods In a 64-year-old female patient previously diagnosed with Sjögren’s syndrome, an asymptomatic soft tissue mass at the palate was noticed, exhibiting rapid enlargement within one month. With a main differential diagnosis of salivary gland neoplasm or lymphoproliferative lesion, a partial biopsy was performed accompanied by proper immunohistochemical analysis. Results A final diagnosis of MALT lymphoma was rendered and the patient was referred for further multidisciplinary evaluation. Gastric endoscopy and biopsy revealed a Helicobacter pylori-negative gastric MALT lymphoma, while spleen involvement and bone marrow infiltration were also identified. Patient was classified as having stage IV disseminated disease and a standard chemotherapy protocol was administered; the treatment was well tolerated and resulted in complete remission. Conclusions This case emphasizes the need for close monitoring of patients with Sjögren’s syndrome by oral medicine specialists, which, besides ensuring proper management of xerostomia and its sequelae, may also lead to early recognition of lymphoma development.
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Affiliation(s)
- Savvas Titsinides
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, AthensGreece
| | - Nikolaos Nikitakis
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, AthensGreece
| | - Evangelia Piperi
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, AthensGreece
| | - Alexandra Sklavounou
- Department of Oral Medicine and Pathology, School of Dentistry, National and Kapodistrian University of Athens, AthensGreece
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16
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Marginal zone lymphoma: Associated autoimmunity and auto-immune disorders. Best Pract Res Clin Haematol 2017; 30:65-76. [DOI: 10.1016/j.beha.2016.07.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 07/09/2016] [Indexed: 12/20/2022]
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17
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Fragkioudaki S, Mavragani CP, Moutsopoulos HM. Predicting the risk for lymphoma development in Sjogren syndrome: An easy tool for clinical use. Medicine (Baltimore) 2016; 95:e3766. [PMID: 27336863 PMCID: PMC4998301 DOI: 10.1097/md.0000000000003766] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The heightened risk of non-Hodgkin lymphoma (NHL) development in primary Sjogren syndrome (SS) is well established. Several adverse clinical and laboratory predictors have been described. In the current work, we aimed to formulate a predictive score for NHL development, based on clinical, serological, and histopathological findings at the time of SS diagnosis. In the present case-control study of 381 primary SS patients and 92 primary SS patients with concomitant NHL, clinical, serological, and histopathological variables at the time of SS diagnosis were retrospectively recorded. For the identification of predictors for NHL development univariate and multivariate models were constructed. Salivary gland enlargement (SGE), lymphadenopathy, Raynaud phenomenon, anti-Ro/SSA or/and anti-La/SSB autoantibodies, rheumatoid factor (RF) positivity, monoclonal gammopathy, and C4 hypocomplementemia were shown to be independent predictors for NHL development. On the basis of the number of independent risk factors identified, a predictive risk score for NHL development was formulated. Thus, patients presenting with ≤2 risk factors had a 3.8% probability of NHL development, those with 3 to 6 risk factors 39.9% (OR (95%CI): 16.6 [6.5-42.5], P < 0.05), while in the presence of all 7 risk factors the corresponding probability reached 100% (OR [95%CI]: 210.0 [10.0-4412.9], P < 0.0001). In conclusion, an easy to use diagnostic scoring tool for NHL development in the context of SS is presented. This model is highly significant for the design of early therapeutic interventions in high risk SS patients for NHL development.
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Affiliation(s)
| | - Clio P. Mavragani
- Department of Physiology
- Department of Pathophysiology
- Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Haralampos M. Moutsopoulos
- Department of Pathophysiology
- Joint Academic Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Anaya JM, Ramirez-Santana C, Alzate MA, Molano-Gonzalez N, Rojas-Villarraga A. The Autoimmune Ecology. Front Immunol 2016; 7:139. [PMID: 27199979 PMCID: PMC4844615 DOI: 10.3389/fimmu.2016.00139] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 03/29/2016] [Indexed: 12/21/2022] Open
Abstract
Autoimmune diseases (ADs) represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation). As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology). In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics) to favor or protect against autoimmunity and its outcomes. Herein, we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status (SES), gender and sex hormones, vitamin D, organic solvents, and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.
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Affiliation(s)
- Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Carolina Ramirez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Maria A Alzate
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Nicolas Molano-Gonzalez
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Adriana Rojas-Villarraga
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
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19
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Clinical picture, outcome and predictive factors of lymphoma in Sjӧgren syndrome. Autoimmun Rev 2015; 14:641-9. [DOI: 10.1016/j.autrev.2015.03.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 03/16/2015] [Indexed: 12/12/2022]
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20
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Mandal S, Pile K, Chacko RT, Danda D. Malignancy and autoimmunity: causally or casually related? Int J Rheum Dis 2014; 17:601-5. [DOI: 10.1111/1756-185x.12536] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Santoshkumar Mandal
- Department of Clinical Immunology and Rheumatology; Christian Medical College and Hospital; Vellore India
| | - Kevin Pile
- Department of Medicine; University of Western Sydney; Sydney Australia
| | - Raju Titus Chacko
- Department of Medical Oncology; Christian Medical College and Hospital; Vellore India
| | - Debashish Danda
- Department of Clinical Immunology and Rheumatology; Christian Medical College and Hospital; Vellore India
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21
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Nocturne G, Mariette X. Sjögren Syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol 2014; 168:317-27. [PMID: 25316606 DOI: 10.1111/bjh.13192] [Citation(s) in RCA: 193] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary Sjögren Syndrome (pSS) is an autoimmune disease associated with an increased risk of lymphoma. Lymphomas complicating pSS are mostly low-grade B cell non-Hodgkin lymphomas, predominantly of marginal zone histological type. Mucosal localization is predominant, notably mucosa-associated lymphoid tissue lymphomas. Lymphomas often develop in organs where pSS is active, such as salivary glands. Germinal centre (GC)-like structures, high TNFSF13B (BAFF) and Flt3-ligand (FLT3LG) levels and genetic impairment of TNFAIP3 are new predictors of lymphoma development. These new findings allow a better understanding of the pathogenic mechanisms leading to lymphoma. We propose the following scenario: auto-immune B cells with rheumatoid factor (RF) activity are continuously stimulated by immune complexes containing antibodies against more specific auto-antigens, such as SSA/Ro, SSB/La or others. Germline abnormality of TNFAIP3 leads to a decreased control of the NF-kB pathway and thus promotes survival of B cells and oncogenic mutations especially in GC structure. Moreover, B cells are stimulated by a positive loop of activation induced by BAFF secretion. Thus, lymphomagenesis associated with pSS exemplifies the development of antigen-driven B-cell lymphoma. The control of disease activity by a well-targeted immunosuppressor is the primary objective of the management of the patient in order to repress chronic B cell stimulation.
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22
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Quartuccio L, Isola M, Baldini C, Priori R, Bartoloni E, Carubbi F, Gregoraci G, Gandolfo S, Salvin S, Luciano N, Minniti A, Alunno A, Giacomelli R, Gerli R, Valesini G, Bombardieri S, De Vita S. Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study. Scand J Rheumatol 2014; 44:36-41. [DOI: 10.3109/03009742.2014.923931] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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23
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Identification of lymphoma predictors in patients with primary Sjögren’s syndrome: a systematic literature review and meta-analysis. Rheumatol Int 2014; 35:17-26. [DOI: 10.1007/s00296-014-3051-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 05/16/2014] [Indexed: 12/23/2022]
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24
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Biomarkers of lymphoma in Sjögren’s syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: Results of a multicenter study. J Autoimmun 2014; 51:75-80. [DOI: 10.1016/j.jaut.2013.10.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/08/2013] [Accepted: 10/13/2013] [Indexed: 11/24/2022]
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25
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Tobón GJ, Saraux A, Gottenberg JE, Quartuccio L, Fabris M, Seror R, Devauchelle-Pensec V, Morel J, Rist S, Mariette X, De Vita S, Youinou P, Pers JO. Role of Fms-like tyrosine kinase 3 ligand as a potential biologic marker of lymphoma in primary Sjögren's syndrome. ACTA ACUST UNITED AC 2014; 65:3218-27. [PMID: 23982978 DOI: 10.1002/art.38129] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 08/08/2013] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Patients with primary Sjögren's syndrome (SS) are at greater risk of developing lymphoma. This study was undertaken to evaluate whether the Fms-like tyrosine kinase 3 ligand (Flt-3L) might be associated with lymphoma in primary SS. METHODS Serum levels of Flt-3L were measured in 369 patients with primary SS from the French Assessment of Systemic Signs and Evolution of Sjögren's Syndrome study cohort and in 10 patients with primary SS at the time of lymphoma diagnosis in an Italian cohort. Associations between increased levels of Flt-3L and a history of lymphoma, history of previously diagnosed criteria related to a high risk of lymphoma, and greater extent of disease activity were evaluated. RESULTS Among patients with primary SS, higher levels of Flt-3L were significantly associated with a history of lymphoma (P = 0.0001). Previous markers for risk of lymphoma development, such as presence of purpura, low levels of C4, presence of lymphocytopenia, low levels of IgM, high levels of β2 -microglobulin, and a higher primary SS disease activity score, were all associated with higher levels of Flt-3L. The levels of Flt-3L were also increased in serum obtained from patients with primary SS at the time of lymphoma diagnosis. Furthermore, the Flt-3L levels were elevated in the serum of 6 patients up to 94 months (mean 46 months) prior to the diagnosis of lymphoma. Receiver operating characteristic curve analysis showed that an Flt-3L level of 175 pg/ml was the ideal cutoff value for demonstrating an association with lymphoma (specificity 97.5%, sensitivity 44%, negative predictive value 97%). CONCLUSION Flt-3L is associated with lymphoma in primary SS, and constitutes a good biologic marker. Higher levels of this cytokine are present several years before the diagnosis of lymphoma, and may be useful as a predictive marker of lymphoproliferative disorders in primary SS.
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Affiliation(s)
- Gabriel J Tobón
- EA 2216, Université de Brest, and Université Européenne de Bretagne, Brest, France
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Giannouli S, Voulgarelis M. Predicting progression to lymphoma in Sjögren's syndrome patients. Expert Rev Clin Immunol 2014; 10:501-12. [DOI: 10.1586/1744666x.2014.872986] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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27
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Aktan Köşker T, Erten S, Erden E. Lymphoma Associated with Sjögren's Syndrome. Turk J Haematol 2014; 30:416-7. [PMID: 24385835 PMCID: PMC3874966 DOI: 10.4274/tjh-2013.0156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 06/20/2013] [Indexed: 12/01/2022] Open
Affiliation(s)
- Tuğba Aktan Köşker
- Atatürk Education and Research Hospital, Internal Medicine, Ankara, Turkey
| | - Sükran Erten
- Atatürk Education and Research Hospital, Department of Rheumatology, Ankara, Turkey
| | - Esra Erden
- Ankara University Medical Faculty, Department of Pathology, Ankara, Turkey
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Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol 2013; 9:544-56. [PMID: 23857130 DOI: 10.1038/nrrheum.2013.110] [Citation(s) in RCA: 280] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Primary Sjögren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.
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Affiliation(s)
- Gaëtane Nocturne
- Service de Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud, INSERM U1012, 78 rue du Général Leclerc, Le Kremlin Bicêtre, France
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29
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Pers JO, Youinou P. Are the B cells cast with the leading part in the Sjogren's syndrome scenario? Oral Dis 2013; 20:529-37. [PMID: 23837848 DOI: 10.1111/odi.12153] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 05/29/2013] [Accepted: 05/29/2013] [Indexed: 02/03/2023]
Abstract
The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunity. In practice, B cells have turned quite attractive as a target for biotherapy. For example, treatment with anti-CD20 Ab has afforded some benefits in this disease, while BAFF blockers are still on the way, but should expand our armamentarium for treating SS. With such B-cell-directed biotherapies in mind, we delineate herein the distinguishing traits of B lymphocytes in SS.
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Affiliation(s)
- J O Pers
- EA2216, Research Unit of Immunopathology, University of Brest, Brest, France
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30
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Malignant lymphoma in primary Sjögren's syndrome: an update on the pathogenesis and treatment. Semin Arthritis Rheum 2013; 43:178-86. [PMID: 23816048 DOI: 10.1016/j.semarthrit.2013.04.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 03/27/2013] [Accepted: 04/11/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Sjögren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. Its association with lymphoma is well documented. Our aim was to systematically review the molecular, clinical, histopathologic, and therapeutic aspects of these SS-related malignant lymphoproliferations. METHODS The literature was searched for original articles published between 1968 and 2012 focusing on the risk factors for lymphoma development in Sjögren's syndrome using MEDLINE and PubMed. The search terms we used were "Sjögren's syndrome," "lymphoma," and "risk factors." All papers identified were English-language, full-text papers. RESULTS A low-grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the commonest lymphoid neoplasia in SS. The majority of SS-associated lymphomas are characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. Although the transition from a chronic inflammatory condition to malignant lymphoma is a multistep process that is yet poorly understood, there is increasing evidence that chronic antigenic stimulation by an exoantigen or autoantigens plays an essential role in the development of SS-associated lymphoproliferation. CONCLUSIONS This review discusses the pathogenetic aspects of lymphomagenesis in SS. Recent advances in the treatment of lymphoma in SS are also stated.
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31
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Dong L, Chen Y, Masaki Y, Okazaki T, Umehara H. Possible Mechanisms of Lymphoma Development in Sjögren's Syndrome. ACTA ACUST UNITED AC 2013; 9:13-22. [PMID: 23853604 PMCID: PMC3706954 DOI: 10.2174/1573395511309010003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 04/28/2013] [Accepted: 05/02/2013] [Indexed: 02/08/2023]
Abstract
Primary Sjögren's syndrome (pSS) is a systemic as well as an organ-specific autoimmune disease characterized by lymphocytic infiltration of the glandular epithelial tissue. SS patients have been reported to be at highest risk of developing lymphoproliferative neoplasms, when compared with patients with other rheumatoid diseases. Factors such as cytokine stimulation, environmental factors, viral infection and genetic events as well as vitamin deficiency may contribute to the development of lymphoma. Over the past few decades, numerous efforts have been made to assess the relationship between lymphoma and SS. These include epidemiological surveys, molecular biologic assessments of clonality and well-linked register cohort studies evaluating the predictive value of clinical, laboratory and histological findings. Nevertheless, the mechanisms and factors predictive of lymphoma development in pSS patients remain to be defined. This review summarizes updated knowledge on the incidence of and risk factors for lymphoma development in pSS patients, as well as discussing the most recent findings on the development and treatment of lymphoma in pSS patients and the possible mechanism of lymphoma development.
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Affiliation(s)
- Lingli Dong
- Department of Hematology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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Yoon RG, Kim MY, Song JW, Chae EJ, Choi CM, Jang S. Primary endobronchial marginal zone B-cell lymphoma of bronchus-associated lymphoid tissue: CT findings in 7 patients. Korean J Radiol 2013; 14:366-74. [PMID: 23483549 PMCID: PMC3590354 DOI: 10.3348/kjr.2013.14.2.366] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 09/05/2012] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To investigate CT and (18)F-flurodeoxyglucose ((18)F-FDG) positron-emission tomography/CT findings of primary endobronchial marginal zone B-cell lymphoma of the bronchus-associated lymphoid tissue (BALT). MATERIALS AND METHODS From June 2006 through April 2012, seven patients (six female, one male; age range, 21-61 years; mean age, 49 years) were examined who were pathologically diagnosed with the primary endobronchial marginal zone B-cell lymphoma of BALT. We evaluated the locations and characteristics of the lesions on CT and (18)F-FDG-PET/CT scans. The lesions were classified into the following three patterns: 1) solitary intraluminal nodule; 2) several tiny nodular protrusions; and 3) diffuse wall thickening. RESULTS A solitary intraluminal nodule was observed in four patients (57.1%), several tiny nodular protrusion in two patients (28.6%), and diffuse wall thickening in one patient (14.3%). The lesions were categorized into 3 major locations: confined to the trachea (n = 3), confined to the lobar bronchus (n = 2), and diffuse involvement of the trachea and both main bronchi (n = 2). All lesions demonstrated homogeneous iso-attenuation as compared with muscle on pre- and post-enhancement scans. Secondary findings in the lungs (n = 3; 42.9%) included postobstructive lobar atelectasis (n = 1), air trapping (n = 1), and pneumonia (n = 1). On (18)F-FDG-PET/CT (n = 5), 4 lesions showed homogeneous uptake with maximum standardized uptake values (mSUV), ranging 2.3-5.7 (mean mSUV: 3.3). One lesion showed little FDG uptake. CONCLUSION Primary endobronchial marginal zone B-cell lymphoma of the BALT manifests as three distinct patterns on CT, with the solitary intraluminal nodule presenting as the main pattern. Most lesions demonstrate homogeneous but weak FDG uptake on (18)F-FDG-PET/CT.
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Affiliation(s)
- Ra Gyoung Yoon
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul 138-736, Korea
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Baer AN, Gourin CG, Westra WH, Cox DP, Greenspan JS, Daniels TE. Rare diagnosis of IgG4-related systemic disease by lip biopsy in an international Sjögren syndrome registry. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 115:e34-9. [PMID: 23146570 DOI: 10.1016/j.oooo.2012.07.485] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Revised: 07/09/2012] [Accepted: 07/19/2012] [Indexed: 12/24/2022]
Abstract
IgG4-related disease has been recently defined as a distinct clinic-pathologic entity, characterized by dense IgG-4 plasmacytic infiltration of diverse organs, fibrosis, and tumefactive lesions. Salivary and lacrimal glands are a target of this disease and, when affected, may clinically resemble Küttner tumor, Mikulicz disease, or orbital inflammatory pseudotumor. In some patients, the disease is systemic, with metachronous involvement of multiple organs, including the pancreas, aorta, kidneys, and biliary tract. We report a 66-year-old man who presented with salivary gland enlargement and severe salivary hypofunction and was diagnosed with IgG4-related disease on the basis of a labial salivary gland biopsy. Additional features of his illness included a marked peripheral eosinophilia, obstructive pulmonary disease, and lymphoplasmacytic aortitis. He was evaluated in the context of a research registry for Sjögren syndrome and was the only 1 of 2594 registrants with minor salivary gland histopathologic findings supportive of this diagnosis.
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Affiliation(s)
- Alan N Baer
- Department of Medicine (Rheumatology), Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
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Abstract
Autoantibodies are extremely promising diagnostic and prognostic biomarkers of cancer, and have the potential to promote early diagnosis and to make a large impact by improving patient outcome and decreasing mortality. Moreover, autoantibodies may be useful reagents in the identification of subjects at risk for cancer, bearing premalignant tissue changes. Great efforts are being made in many laboratories to validate diagnostic panels of autoantibodies with high sensitivity and specificity that could be useful in a clinical setting. It is likely that prospective studies of sufficiently large cohorts of patients and controls using high-throughput technology may allow the identification of biomarkers with diagnostic significance, and perhaps of discrete antigen phenotypes with clinical significance. The identification of TAAs may also be essential for the development of anticancer vaccines, because autoantibodies found in cancer sera target molecules involved in signal transduction, cell-cycle regulation, cell proliferation, and apoptosis, playing important roles in carcinogenesis. On this basis, molecular studies of antigenantibody systems in cancer promise to yield valuable information on the carcinogenic process. TAAs identified by serum antibodies in cancer sera can be natural immunogenic molecules, useful as targets for cancer immunotherapy. An important problem encountered in the practice of medicine is the identification of healthy individuals in the general population who unknowingly are at high risk of developing cancer. For the rheumatologist, a related problem is the identification of those patients with rheumatic diseases who are at high risk for developing a malignant process. These problems encountered in the fields of cancer and the rheumatic diseases can in the future be helped by new diagnostic instruments based on antibodies. The need for promoting the early diagnosis of cancer is a recognized major public health problem in need of significant research support for the validation of multiple promising but inconclusive studies, with the intention of producing diagnostic panels of autoantibodies in various types of cancers. Cancer developing in patients with rheumatic diseases is also an important problem requiring prospective longterm follow-up studies of patients with rheumatic diseases, particularly because some of the new biologic therapies seem to increase the cancer risk. It is possible that a panel of autoantibodies common to patients with cancer and the rheumatic diseases may prove to be of value in the identification of those patients with ADs at high risk for neoplasms.
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De Vita S, Quartuccio L, Salvin S, Corazza L, Zabotti A, Fabris M. Cryoglobulinaemia related to Sjogren's syndrome or HCV infection: differences based on the pattern of bone marrow involvement, lymphoma evolution and laboratory tests after parotidectomy. Rheumatology (Oxford) 2011; 51:627-33. [PMID: 22210656 DOI: 10.1093/rheumatology/ker407] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE The relationship of cryoglobulinaemia with lymphoproliferation of mucosa-associated lymphoid tissue (MALT) as risk factors for lymphoma evolution in SS remains to be clarified. The different biologic background of SS-related cryoglobulinaemia as compared with cryoglobulinaemia linked to HCV infection was clarified by different clinical and biologic approaches. METHODS B-cell clonal expansion was analysed in the bone marrow of 27 consecutive cases with primary SS and mixed cryoglobulinaemia, HCV unrelated, in comparison with 55 HCV-related patients with cryoglobulinaemic vasculitis (CV) without SS. The results were related to the possible occurrence and localization of B-cell lymphoma in the single case. Secondly, the prevalence of mixed cryoglobulinaemia was investigated in 41 unselected patients with primary SS showing either parotid myoepithelial sialadenitis (MESA) or a frank B-cell non-Hodgkin's lymphoma. Thirdly, the levels of serum cryoglobulins and RF were followed in one patient with primary SS, CV and parotid B-cell lymphoma of MALT after bilateral subtotal parotidectomy. RESULTS A polyclonal pattern of B expansion in the bone marrow was significantly more frequent in SS-related (19/27 cases) than in HCV-related cryoglobulinaemia (19/55) (P = 0.003). Cryoglobulins were positive in a fraction of patients with SS and malignant lymphoma or with parotid MESA (13/18 and 7/23, respectively), whereas MALT involvement by the lymphoproliferative disorder was the rule. Finally, the levels of serum cryoglobulins and RF markedly decreased in the SS patient undergoing bilateral subtotal parotidectomy. CONCLUSION Lymphoproliferation of MALT appears as the biologic background of cryoglobulinaemia in SS, differently from HCV-related cryoglobulinaemia.
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Affiliation(s)
- Salvatore De Vita
- Rheumatology Clinic, Department of Medical and Biological Sciences, University Hospital 'S. Maria della Misericordia', Piazzale Santa Maria Misericordia 1, 33100 Udine, Italy.
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Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun 2011; 38:J109-19. [PMID: 22079680 DOI: 10.1016/j.jaut.2011.10.003] [Citation(s) in RCA: 224] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 10/24/2011] [Indexed: 11/21/2022]
Abstract
A large number of autoimmune diseases (ADs) are more prevalent in women. The more frequent the AD and the later it appears, the more women are affected. Many ideas mainly based on hormonal and genetic factors that influence the autoimmune systems of females and males differently, have been proposed to explain this predominance. These hypotheses have gained credence mostly because many of these diseases appear or fluctuate when there are hormonal changes such as in late adolescence and pregnancy. Differences in X chromosome characteristics between men and women with an AD have led researchers to think that the genetic background of this group of diseases also relates to the genetic determinants of gender. These hormonal changes as well as the genetic factors that could explain why women are more prone to develop ADs are herein reviewed.
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Solans-Laqué R, López-Hernandez A, Bosch-Gil JA, Palacios A, Campillo M, Vilardell-Tarres M. Risk, predictors, and clinical characteristics of lymphoma development in primary Sjögren's syndrome. Semin Arthritis Rheum 2011; 41:415-23. [PMID: 21665245 DOI: 10.1016/j.semarthrit.2011.04.006] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Revised: 03/21/2011] [Accepted: 04/03/2011] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To assess the risk and predictors of lymphoma development in a large cohort of patients with primary Sjögren's syndrome (pSS). METHODS Cox-regression analyses were used to study the predictive value of clinical and laboratory findings at pSS diagnosis, and Kaplan-Meier survival curves to compare survival probability between patients who developed lymphoma and the total cohort. Expected risk for lymphoma was calculated by comparison with the background population. RESULTS Eleven (4.5%) from 244 patients developed a non-Hodgkin lymphoma (NHL). Diffuse large B-cell and mucosa-associated lymphoid tissue lymphomas occurred at a similar frequency. Three (27.3%) patients died: 2 due to transformation from mucosa-associated lymphoid tissue to diffuse large B-cell. Purpura (HR 8.04, 95% confidence interval [CI] 2.33-27.67), parotidomegaly (HR 6.75, 95%CI 1.89-23.99), anemia (HR 3.43, 95%CI 1.04-11.35), leukopenia (HR 8.70, 95%CI 2.38-31.82), lymphocytopenia (HR 16.47, 95%CI 3.45-78.67), hypergammaglobulinemia (HR 4.06, 95%CI 1.06-15.58), low C3 (HR 36.65, 95%CI 10.65-126.18), and low C4 (HR 39.70, 95%CI 8.85-126.18) levels at pSS diagnosis were significant predictors of NHL development, but only hypocomplementemia and lymphocytopenia were independent risk factors. Hypocomplementemia was related to earlier development of NHL and higher mortality. The cumulative risk of developing lymphoma ranged from 3.4% in the first 5 years to 9.8% at 15 years. Standardized incidence ratio (95%CI) for NHL development was 15.6 (95%CI 8.7-28.2). CONCLUSIONS Patients with pSS have a 16-fold increased risk of developing lymphoma. This risk increases with time. Hypocomplementemia and lymphocytopenia at pSS diagnosis are the strongest predictors. Survival is clearly reduced in patients with hypocomplementemia. Indolent lymphomas tend to evolve over time toward a more aggressive histologic type.
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Affiliation(s)
- Roser Solans-Laqué
- Internal Medicine Department of Vall d'Hebron University Hospital, Barcelona, Spain.
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Abstract
Sjögren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. The involvement of these glands is characterized by focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Immunologically-activated or apoptotic glandular epithelial cells that expose autoantigens in genetically predisposed individuals might drive autoimmune-mediated tissue injury. Alterations in several immune mediators, such as upregulation of type I interferon-regulated genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23-type 17 T-helper cell pathway, have been reported. Extension of the pathological process that affects the exocrine glands into periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic findings that involve the lungs, liver or kidneys. These manifestations develop as a result of lymphocytic invasion or an immune-complex-mediated process, or both, and present as skin vasculitis coupled with peripheral neuropathy or glomerulonephritis (or both). Patients with systemic extraepithelial manifestations display low serum levels of the complement component C4 and mixed type II cryoglobulins, and show an increased risk of developing non-Hodgkin lymphoma, thereby reflecting an overall worse prognosis with higher mortality rates than those without extraepithelial manifestations.
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WATANABE MAIKO, NANIWA TAIO, HARA MASAKI, ARAKAWA TOSHINAO, MAEDA TOMOYO. Pulmonary Manifestations in Sjögren’s Syndrome: Correlation Analysis Between Chest Computed Tomographic Findings and Clinical Subsets with Poor Prognosis in 80 Patients. J Rheumatol 2009; 37:365-73. [DOI: 10.3899/jrheum.090507] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective. Sjögren’s syndrome (SS) has a varied clinical spectrum and has been associated with various chest computed tomography (CT) findings. We sought to delineate the characteristic CT features in various subsets of SS, especially poor prognosis subsets.Methods. Retrospectively identified 80 never-smoker SS patients [56 primary SS (1-SS), 24 secondary SS (2-SS)] who underwent chest CT at our institution during a 3-year period from 2004 through 2007 were included in this study. Chest CT findings were qualitatively and semiquantitatively analyzed with comparison between 1-SS and 2-SS, and correlation with anti-SSB/La seropositivity and the presence of clonally derived lymphoproliferative disorder (cLPD), which are known to be pathognomonic and prognostic clinical features of SS patients.Results. All patients were women with median age of 60 years. Anti-SSB/La antibodies were found in 17 primary SS patients and 4 2-SS patients. Eleven patients with cLPD were identified and all of them had 1-SS. The most frequent CT finding in both types of patients was interlobular septal thickening. Secondary SS was associated with a significantly greater frequency and extent of honeycombing versus 1-SS. Univariate and multivariate analysis showed a significant association between honeycombing and 2-SS. In patients with 1-SS and in the SS group as a whole, we observed independent and significant associations between cysts and anti-SSB/La seropositivity or cLPD.Conclusion. Cysts are significantly associated with anti-SSB/La seropositivity and cLPD. The presence of lung cysts revealed by chest CT might be a prognostic clinical feature, a clue, or a predictor of cLPD in patients with SS.
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Shen L, Suresh L, Li H, Zhang C, Kumar V, Pankewycz O, Ambrus JL. IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans. Clin Immunol 2009; 130:304-12. [DOI: 10.1016/j.clim.2008.10.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2008] [Revised: 10/07/2008] [Accepted: 10/08/2008] [Indexed: 11/29/2022]
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Illes A, Varoczy L, Papp G, Wilson PC, Alex P, Jonsson R, Kovacs T, Konttinen YT, Zeher M, Nakken B, Szodoray P. Aspects of B-cell non-Hodgkin's lymphoma development: a transition from immune-reactivity to malignancy. Scand J Immunol 2009; 69:387-400. [PMID: 19508370 DOI: 10.1111/j.1365-3083.2009.02237.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The development of B-cell lymphomas is an intricate interplay among various pathogenic factors, leading to a multi-step process, encompassing various stages of B-cell maturation. Besides genetic abnormalities, a variety of environmental and microbial factors, as well as disproportional immune-regulatory processes lead to the malignant transformation. Yet, little is known about the exact chain of events, which lead from the physiological polyclonal B-cell activation as a response to exogenous antigens through oligoclonality to a monoclonal, uncontrolled, malignant B-cell proliferation. The aim of the present review was to summarize the potential harmful steps in the development of B-cell lymphomas, according to conventional and novel theories, and to depict therapeutic regimens presently in use as well as to envision future drug developments, beneficial in the battle against this lymphoid malignancy.
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Affiliation(s)
- A Illes
- Division of Immune-Hematology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
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Voulgarelis M, Moutsopoulos HM. Mucosa-associated lymphoid tissue lymphoma in Sjögren's syndrome: risks, management, and prognosis. Rheum Dis Clin North Am 2009; 34:921-33, viii. [PMID: 18984412 DOI: 10.1016/j.rdc.2008.08.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Sjögren's syndrome is a chronic inflammatory disease primarily affecting the exocrine glands. Its association with lymphoma is well documented, with salivary extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue type being the most common and constituting a major disease complication. These neoplasms are antigen-stimulated B-cell lymphomas characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. This article presents a review of the literature and discusses the clinical, histopathologic, therapeutic, and prognostic aspects of these tumors in Sjögren's syndrome. In addition, it highlights the predictor markers of lymphoma development.
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Affiliation(s)
- Michael Voulgarelis
- Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
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Nam-Cha SH, San-Millán B, Mollejo M, García-Cosio M, Garijo G, Gomez M, Warnke RA, Jaffe ES, Piris MA. Light-chain-restricted germinal centres in reactive lymphadenitis: report of eight cases. Histopathology 2008; 52:436-44. [PMID: 18315596 DOI: 10.1111/j.1365-2559.2008.02965.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
AIMS Light-chain-restricted germinal centres are generally associated with the existence of a neoplastic lymphoproliferative disorder. The aim was to present a series of cases with persistent lymph node enlargement that featured some germinal centres showing light chain immunoglobulin restriction. METHODS AND RESULTS A series of six reactive lymphadenitis and two Castleman's disease cases was analysed by immunohistochemistry, IgH-polymerase chain reaction (PCR) and microdissected PCR. In all cases some germinal centres contained a population of plasma cells and plasmacytoid germinal centre cells showing light chain immunoglobulin restriction. In three cases the monotypic cells also showed distinct Bcl-2 expression. Two of the cases showed a predominant IgH rearrangement on a florid polyclonal background and one had an IgH monoclonal rearrangement, as revealed by PCR. Microdissected germinal centre PCR revealed a dominant repeated band in one of three cases and in another case a non-repeated clonal peak was observed. One of the patients developed a follicular lymphoma, which became evident from a subsequent biopsy. CONCLUSIONS These findings may be a manifestation of an underlying disorder in the regulation of the immune response, or an exaggeration of the germinal centre oligoclonal nature. This should be taken into account in the differential diagnosis of follicular hyperplasia.
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Affiliation(s)
- S H Nam-Cha
- Lymphoma Group, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
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Tzioufas AG, Voulgarelis M. Update on Sjögren's syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol 2008; 21:989-1010. [PMID: 18068857 DOI: 10.1016/j.berh.2007.09.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Sjögren's syndrome is a chronic inflammatory process that primarily involves the exocrine glands. Its clinical manifestations range from autoimmune exocrinopathy to extraglandular (systemic) involvement affecting the lungs, kidneys, blood vessels, and muscles; it can occur alone (primary Sjögren's syndrome) or in association with other autoimmune diseases (secondary Sjögren's syndrome). In recent years, clinical and laboratory observations have highlighted the central role of the epithelial cell and it has been suggested that the etiological name of the disease should be 'autoimmune epithelitis'. The extraglandular manifestations of the disease are divided in two groups: (1) lung, kidney (interstitial nephritis), and liver involvement as a result of lymphocytic invasion in epithelial tissues; and (2) skin vasculitis, peripheral neuropathy, and glomerulonephritis, with low C4 levels, which is the result of immune complex disease, are associated with increased morbidity and high risk for lymphoma. The diagnosis of the disease is based on the classification criteria, raised by the American-European Study Group and which have been built on the European preliminary classification criteria, developed in 1992. The association of Sjögren's syndrome with lymphoma is well documented as in approximately 5% of patients the benign autoimmune process is transformed into a lymphoid malignancy. The salivary extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue type are the most common lymphoma in Sjögren's syndrome. These tumors are antigen-stimulated B-cell lymphomas and are characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. Among the clinical and serological parameters that have been associated with lymphoma development in patients with Sjögren's syndrome, the presence of palpable purpura, low C4 and mixed monoclonal cryoglobulinemia constitute the main predictive markers; patients displaying these risk factors should be monitored closely. The purpose of this review is to discuss the clinical picture, the diagnostic procedure, and the malignant lymphoproliferation in the disease.
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Clinical, immunologic, and molecular factors predicting lymphoma development in Sjogren's syndrome patients. Clin Rev Allergy Immunol 2008; 32:265-74. [PMID: 17992593 DOI: 10.1007/s12016-007-8001-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Among autoimmune diseases, Sjogren's syndrome (SS) displays the highest incidence of non-Hodgkin lymphoma (NHL) development with the salivary extranodal marginal zone B cell lymphomas being the most common type. The majority of SS-associated NHLs are characterized by localized stage, indolent clinical course, and recurrence in other extranodal sites. Although the transition from a chronic inflammatory condition to malignant lymphoma is a multistep process yet poorly understood, there is increasing evidence that chronic antigenic stimulation by an exoantigen or autoantigens plays an essential role in the development of SS associated lymphoproliferation. Additional molecular oncogenic events such as microsatellite instability, loss of the B cell cycle control, and the forced overproduction of specific B cell biologic stimulators seem to contribute to the emergence and progression of the malignant overgrowth. Among the clinical and serological parameters that have been associated with lymphoma development in SS patients, the presence of palpable purpura, low C4, and mixed monoclonal cryoglobulinemia constitute the main predictive markers, and patients displaying these risk factors should be monitored closely.
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Systemic Sclerosis and Malignancy. South Med J 2008; 101:12-3. [DOI: 10.1097/smj.0b013e31815d3cd2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Konno A, Takiguchi M, Takada K, Usami T, Azumi K, Kubota H, Inaba M, Saegusa J, Kon Y. Identification of a quantitative trait locus regulating B cell-dominant infiltration into autoimmune sialitis lesions of the IQI mouse model of primary Sjögren's syndrome. Immunogenetics 2007; 59:853-9. [PMID: 17938903 DOI: 10.1007/s00251-007-0244-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2007] [Accepted: 07/12/2007] [Indexed: 10/22/2022]
Abstract
Sjögren's syndrome (SS) is caused by an autoimmune sialodacryoadenitis, and up to 5% of patients with SS develop malignant B cell growth. The IQI mouse is a spontaneous model of primary SS in which B cells are the dominant cellular subpopulation among mononuclear infiltrates in sialitis lesions. Understanding the genetic control of aberrant B cell growth in IQI mice may help elucidate the genetic mechanisms involved in B-lineage hyperplasia leading to malignant transformation in human SS. B cell-dominant infiltration in the submandibular glands of 6-month-old IQI and C57BL/6 (B6) mice and their F1 and F2 progenies was quantified as B-lymphocytic sialitis score, and a genome-wide scan of 179 (IQI x B6) F2 females was performed to identify a quantitative trait locus (QTL) controlling this phenotype. A QTL significantly associated with variance in B-lymphocytic sialitis score was mapped to the D6Mit138 marker (position of 0.68cM) on proximal chromosome 6, with a logarithm of odds score of 4.3 (p = 0.00005). This QTL, named autoimmune sialitis in IQI mice, associated locus 1 (Asq1), colocalized with Islet cell autoantigen 1 (Ica1), which encodes a target protein of the immune processes that define the pathogenesis of primary SS in humans and in the nonobese diabetic mouse model.
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Affiliation(s)
- Akihiro Konno
- Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
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Hansen A, Lipsky PE, Dörner T. B-cell lymphoproliferation in chronic inflammatory rheumatic diseases. ACTA ACUST UNITED AC 2007; 3:561-9. [PMID: 17906611 DOI: 10.1038/ncprheum0620] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2007] [Accepted: 07/31/2007] [Indexed: 01/12/2023]
Abstract
Patients with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and especially primary Sjögren's syndrome (SS), are at higher risk than the general population of developing B-cell non-Hodgkin lymphoma (NHL). Analyses of the association between various lymphoma subtypes and specific disease entities suggest that this association might be mediated by disease-specific mechanisms, as well as by mechanisms unique to lymphoma subtype. These specific associations can provide important information about abnormal B-cell stimulation in these conditions. Patients with primary SS, SLE and RA are at high risk of developing diffuse large B-cell lymphomas, a group of high-grade NHLs with remarkable heterogeneity. Patients with primary SS are at particularly high risk of developing marginal-zone B-cell lymphomas. The risk factors of lymphoma development in primary SS seem to be closely related to the underlying mechanisms of abnormal stimulation and/or impaired censoring mechanisms of B cells. In patients with RA and SLE, more intense disease activity and/or long-lasting disease might be indications of a higher risk of lymphoma development. This Review will focus on the risk of lymphoma, common and disease-specific mechanisms of B-cell lymphoma development, and on the clinical consequences of lymphoma in patients with inflammatory rheumatic diseases.
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Affiliation(s)
- Arne Hansen
- Outpatients Department of Medicine, Charité University Hospital, Berlin, Germany.
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Mackay F, Groom JR, Tangye SG. An important role for B-cell activation factor and B cells in the pathogenesis of Sjögren's syndrome. Curr Opin Rheumatol 2007; 19:406-13. [PMID: 17762603 DOI: 10.1097/bor.0b013e328277ef4c] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW This review provides an update on the specific, strong association between dysregulated production of the cytokine B-cell activation factor and Sjögren's syndrome, and offers new perspectives on potential pathogenic mechanisms. RECENT FINDINGS Excess B-cell activation factor in mice triggers Sjögren's syndrome-like symptoms, and elevated serum B-cell activation factor in humans correlates with Sjögren's syndrome. B-cell activation factor is produced locally by activated monocytes, T cells and dendritic cells, and by epithelial cells and infiltrating B cells. Moreover, recent data in humans suggest that the innate immune system plays a role as an initiator of immune disorders in inflamed tissues. SUMMARY Recent data have demonstrated the critical role of B-cell activation factor and B cells in the pathogenesis of Sjögren's syndrome, and its association with B lymphomas. Moreover, B-cell depleting treatments have confirmed the critical role of B cells in Sjögren's syndrome. Excess B-cell activation factor possibly corrupts B-cell tolerance and allows the emergence of self-reactive B cells that efficiently present antigen to T cells. In addition, B-cell activation factor may stimulate T-cell independent activation of B cells via Toll-like receptors; this recently identified mechanism could also play a separate, detrimental role in autoimmunity.
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Affiliation(s)
- Fabienne Mackay
- The Autoimmunity Research Unit, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
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Iwanaga N, Kamachi M, Fujikawa K, Aramaki T, Izumi Y, Arima K, Tamai M, Aratake K, Nakamura H, Origuchi T, Ida H, Kawakami A, Taguchi T, Eguchi K. Membraneous glomerulonephritis and non-Hodgkin's lymphoma in a patient with primary Sjögren's syndrome. Intern Med 2007; 46:191-4. [PMID: 17301515 DOI: 10.2169/internalmedicine.46.1835] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The most common renal manifestation of Sjögren's syndrome is tubulointerstitial nephritis, and glomerular disease is rare (3). A 62-year-old woman with primary Sjögren's syndrome developed nephrotic syndrome. Kidney biopsy was consistent with membraneous glomerulonephritis. Steroid pulse therapy was not effective. Three months later she was diagnosed with non-Hodgkin's lymphoma of the tongue, and she was given CHOP therapy and radiation. Both the lymphoma and membraneous glomerulonephritis were resolved.
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Affiliation(s)
- Nozomi Iwanaga
- First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki, University, Nagasaki, Japan.
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