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Journal ArticleDOI

Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary Sjogren's syndrome

TL;DR: A parotid biopsy has a diagnostic potential comparable with that of a labial biopsy in the diagnosis of pSS, and may be associated with less morbidity.
Abstract: Objective. To assess the value of the parotid biopsy as a diagnostic tool for primary Sjogren's syndrome ( pSS), and to compare the parotid biopsy and the labial biopsy with regard to diagnostic value and biopsy-related morbidity. Methods. In 15 consecutive patients with pSS and 20 controls, the parotid biopsy was assessed as a diagnostic tool based on the presence of lymphocytic foci, benign lymphoepithelial lesions and lymphoid follicles. These new histological criteria were compared with established diagnostic criteria for the labial biopsy in 35 consecutive patients suspected for pSS who underwent simultaneous biopsies from both sites. In addition, both biopsies were compared for morbidity. Results. The first analysis revealed a focus score of >= 1 or lymphocytic infiltrates ( not fulfilling the criterion of a focus score of 1) combined with benign lymphoepithelial lesions as diagnostic criteria for pSS. When comparing the parotid biopsy with the labial biopsy sensitivity and specificity were comparable (sensitivity 78%, specificity 86%). Level of pain was comparable and no loss of motor function was observed. No permanent sensory loss was observed after parotid biopsy, while labial biopsy led to permanent sensory loss in 6% of the patients. Malignant lymphoma was detected in one parotid biopsy by chance, without involvement of the labial salivary gland. Conclusion. A parotid biopsy has a diagnostic potential comparable with that of a labial biopsy in the diagnosis of pSS, and may be associated with less morbidity.
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Journal ArticleDOI
TL;DR: Rituximab treatment is an effective and safe treatment strategy for patients with primary Sjögren's syndrome and significant improvements were found in comparison with baseline values.
Abstract: Objective. To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjogren's syndrome (SS) in a double-blind, randomized, placebo-controlled trial. Methods. Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of >= 0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2: 1 (rituximab: placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. Results. Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. Conclusion. These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.

427 citations

Journal ArticleDOI
TL;DR: It is found that WS contains more informative proteins, peptides, and mRNA, as compared with gland-specific saliva, that can be used in generating candidate biomarkers for the detection of primary SS.
Abstract: Sjogren’s syndrome (SS), which was first described in 1933 by the Swedish physician Henrik Sjogren (1), is a chronic autoimmune disorder clinically characterized by a dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). The disease primarily affects women, with a ratio of 9:1 over the occurrence in men. While SS affects up to 4 million Americans, about half of the cases are primary SS. Primary SS occurs alone, whereas secondary SS presents in connection with another autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus (SLE). Histologically, SS is characterized by infiltration of exocrine gland tissues by predominantly CD4 T lymphocytes. At the molecular level, glandular epithelial cells express high levels of HLA–DR, which has led to the speculation that these cells are presenting antigen (viral antigen or autoantigen) to the invading T cells. Cytokine production follows, with interferon (IFN) and interleukin-2 (IL-2) being especially important. There is also evidence of B cell activation with autoantibody production and an increase in B cell malignancy. SS patients exhibit a 40-fold increased risk of developing lymphoma. SS is a complex disease that can go undiagnosed for several months to years. Although the underlying immune-mediated glandular destruction is thought to develop slowly over several years, a long delay from the start of symptoms to the final diagnosis has been frequently reported. SS presumably involves the interplay of genetic and environmental factors. To date, few of these factors are well understood. As a result, there is a lack of early diagnostic markers, and diagnosis usually lags symptom onset by years. A new international consensus for the diagnosis of SS requires objective signs and symptoms of dryness, including a characteristic appearance of a biopsy sample from a minor or major salivary gland and/or the presence of autoantibody such as anti-SSA (2–4). However, establishing the diagnosis of primary SS has been difficult in light of its nonspecific symptoms (dry eyes and mouth) and the lack of both sensitive and specific biomarkers, either body fluid– or tissue-based, for its detection. It is widely believed that developing molecular biomarkers for the early diagnosis of primary SS will improve the application of systematic therapies and the setting of criteria with which to monitor therapies and assess prognosis (e.g., lymphoma development). Saliva is the product of 3 pairs of major salivary glands (the parotid, submandibular, and sublingual glands) and multiple minor salivary glands that lie beneath the oral mucosa. Human saliva contains many informative proteins that can be used for the detection of diseases. Saliva is an attractive diagnostic fluid because testing of saliva provides several key advantages, including low cost, noninvasiveness, and easy sample collection and processing. This biologic fluid has been used for the survey of general health and for the diagnosis of diseases in humans, such as human immunodeficiency virus, periodontal diseases, and autoimmune diseases (5–8). Our laboratory is active in the comprehensive analysis of the saliva proteome (for more information, see www.hspp.ucla.edu), thus providing the technologies and expertise to contrast proteomic constituents in primary SS with those in control saliva (9–11). Thus far, we have identified over 1,000 proteins in whole saliva (WS). In addition, we have recently identified and cataloged ~3,000 messenger RNAs (mRNA) in human WS (12). These studies have provided a solid foundation for the discovery of biomarkers in the saliva of patients with primary SS. We have previously demonstrated proteome- and genome-wide approaches to harnessing saliva protein and mRNA signatures for the detection of oral cancer in humans (13,14). There have been continuous efforts in the search for biomarkers in human serum or saliva for the diagnosis of primary SS. Some gene products were found at elevated levels in SS patient sera or saliva, including β2-microglobulin (β2m), soluble IL-2 receptor, IL-6, anti-Ro/SSA, anti-La/SSB, and anti–α-fodrin autoantibodies (15–20). However, none of them individually is sensitive or specific enough to use for the confirmative diagnosis of SS (15). Therefore, it is crucial to use emerging proteome- and genome-wide approaches to discover a wide spectrum of informative and discriminatory biomarkers that can be combined to improve the sensitivity and specificity for the detection of primary SS.

355 citations

Journal ArticleDOI
TL;DR: SS has a large impact on HR-QOL, employment and disability, and employment was lower and DC rates were higher in SS patients compared with the Dutch population.
Abstract: Objective. To compare health-related quality of life (HR-QOL), employment and disability of primary and secondary SS (pSS and sSS, respectively) patients with the general Dutch population. Methods. HR-QOL, employment and disability were assessed in SS patients regularly attending the University Medical Center Groningen (n=235). HR-QOL, employment and disability were evaluated with the Short Form-36 questionnaire (SF-36) and an employment and disability questionnaire. Results were compared with Dutch population data (matched for sex and age). Demographical and clinical data associated with HR-QOL, employment and disability were assessed. Results. Response rate was 83%. SS patients scored lower on HR-QOL than the general Dutch population. sSS patients scored lower on physical functioning, bodily pain and general health than pSS patients. Predictors for reduced HR-QOL were fatigue, tendomyalgia, articular involvement, use of artificial saliva, use of anti-depressants, comorbidity, male sex and eligibility for disability compensation (DC). Employment was lower and DC rates were higher in SS patients compared with the Dutch population. Conclusion. SS has a large impact on HR-QOL, employment and disability.

189 citations

Journal ArticleDOI
TL;DR: Standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials is provided and areas where further research is required to achieve evidence-based consensus are identified.
Abstract: Labial salivary gland (LSG) biopsy is used in the classification of primary Sjogren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

178 citations

Journal ArticleDOI
TL;DR: Current knowledge and gaps in understanding of ELS formation and function are discussed including their prevalence in the above rheumatic autoimmune diseases; the mechanisms underlying their formation, maintenance and function, including positive and negative regulatory pathways; their functional relevance in the perpetuation of autoimmunity; their relationship with disease phenotypes, clinical outcomes and response to treatment.
Abstract: Ectopic lymphoid structures have been identified in the target organs of a subset of patients with rheumatic autoimmune diseases. This Review describes these structures and summarizes our current understanding of how they form, function and contribute to autoimmunity.

139 citations

References
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Journal ArticleDOI
TL;DR: These classification criteria for Sjögren's syndrome have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.
Abstract: Classification criteria for Sjogren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

4,914 citations


"Parotid gland biopsy compared with ..." refers background or methods in this paper

  • ...The diagnosis of pSS was based on the US–EU criteria, leaving out the histological criterion [2]....

    [...]

  • ...A diagnosis of pSS was made according to the US–EU criteria (including labial histopathology) [2]....

    [...]

  • ...A diagnosis of SS was made according to the US–EU criteria, without histology [2]....

    [...]

  • ...SS, Sjögren’s syndrome; non-SS, negative for SS (diagnosis according to US–EU criteria [2]); SS-A/B, anti-SSA or SSB antibodies; Pos, positive; Neg, negative; positive outcome of labial biopsy determined the definite diagnosis of pSS; parotid biopsy with focus score <1, but with the presence of LELs....

    [...]

  • ...[5] A focus score of 1 is required for the diagnosis of SS by the latest US–EU criteria [2]....

    [...]

Journal ArticleDOI
TL;DR: The experience of developing the WHO Classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.
Abstract: PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms. DESIGN: Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification. RESULTS: The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of ea...

3,338 citations

Journal ArticleDOI
Robert I. Fox1
TL;DR: It is suggested that the term Sjögren's syndrome be used to describe one subset of patients with sicca symptoms who exhibit particular major histocompatibility complex antigens, the presence of T cell lymphoid infiltrates on glandular biopsy, and specific autoantibodies in their sera.

1,436 citations

Journal ArticleDOI
TL;DR: These data show that statins can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation.

789 citations

Journal ArticleDOI
TL;DR: The clinical and laboratory features of patients referred for evaluation of sicca symptoms are reviewed, and the need for care in choosing the site for minor salivary gland biopsy is emphasized, and histologic features that aid in the evaluation of these biopsy specimens are described.
Abstract: The term "Sjogren's syndrome" (SS) is frequently used to describe the occurrence of keratoconjunctivis sicca and xerostomia in association with an autoimmune disorder. However, well-defined criteria for the classification of SS have not been established, and this diagnosis is being applied to a wide spectrum of conditions, ranging from clear "autoimmune" disease in some patients, to sicca complaints without evidence of a systemic immune process in elderly patients. Here, we review the clinical and laboratory features of patients referred for evaluation of sicca symptoms. In particular, we emphasize the need for care in choosing the site for minor salivary gland biopsy, and we describe the histologic features that aid in the evaluation of these biopsy specimens. In an attempt to identify a population of patients whose conditions might have a common etiopathogenesis and, thus, a common treatment program, we propose the following criteria for a diagnosis of SS: 1) objective evidence of keratoconjunctivis sicca, as documented by rose bengal or fluorescein dye staining; 2) objective evidence of diminished salivary gland flow; 3) minor salivary gland biopsy, obtained through normal mucosa, with the specimen containing at least 4 evaluable salivary gland lobules, and having an average of at least 2 foci/4 mm2; 4) evidence of a systemic autoimmune process, as manifested by the presence of autoantibodies, such as rheumatoid factor and/or antinuclear antibody. The diagnosis of "definite SS" would be made when all 4 criteria are met; the diagnosis of "possible SS" would be made when 3 criteria are present. Specific exclusions for this diagnosis are preexisting lymphoma, graft-versus-host disease, sarcoidosis, and acquired immunodeficiency disease.(ABSTRACT TRUNCATED AT 250 WORDS)

676 citations