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Objectives: To develop a score for assessment of patients' symptoms in primary Sjögren's syndrome (SS): the EULAR SS Patient Reported Index (ESSPRI)., Methods: Dryness, pain, somatic and mental fatigue were identified as the main symptoms of patients with primary SS, in studies developing the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI). It was suspected that a single 0-10 numerical scale for each domain was sufficient to assess these symptoms. These four scales were gathered to form the ESSPRI. 230 patients, from 12 countries completed the ESSPRI, SSI and PROFAD questionnaires and a 0-10 patient global assessment (PGA). Correlations between each symptom and PGA were obtained. Multiple regression modelling, using PGA as 'gold standard' was used to select domains and estimate their weights., Results: PGA had good correlation with dryness, limb pain, fatigue and mental fatigue (r=0.49-0.59, all p<0.0001), but correlated less well with individual dryness features. In multivariate analysis, dryness, limb pain and fatigue, but not mental fatigue, were significantly associated with PGA; weights derived from the regression were identical for these three domains. Thus, ESSPRI was redefined as the mean of the three scales: dryness, limb pain and fatigue. Lastly, ESSPRI significantly correlated with PGA (r=0.70), PROFAD (r=0.73) and SSI (r=0.66)., Conclusion: ESSPRI is a very simple index designed to measure patients' symptoms in primary SS. It has good construct validity and is well correlated with SSI and PROFAD. ESSPRI should now be validated for use as an outcome measure in clinical trials.

Abnormalities of memory B cells seem to be closely involved in the pathogenesis of primary Sjögrens Syndrome (pSS) and its malignant complication, B cell lymphoma. Recent studies on B cells in pSS add to our understanding of the distinct memory B cell subsets in pSS. Reduction of peripheral memory CD27(+) B cells, most strikingly of the CD27(+)IgM(+) subset, may indicate a lack of appropriate censoring mechanisms and incomplete differentiation processes within the ectopic lymphoid tissues in pSS. This ectopically formed lymphoid tissue might protect autoreactive memory B cells from deletion by physiological check-points and, thereby, may contribute to the perpetuation of the disease as well as to an enhanced lymphoma risk. Thus, B cells may be potential targets of direct or indirect treatment in pSS.

Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region (IgV) gene usage are also characteristic features of pSS. Comparison of B cells from the peripheral blood and salivary glands of patients with pSS with regard to their expression of the chemokine receptors CXCR4 and CXCR5, and their migratory capacity towards the corresponding ligands, CXCL12 and CXCL13, provide a mechanism for the prominent accumulation of CXCR4+ CXCR5+ memory B cells in the inflamed glands. Glandular B cells expressing distinct features of IgV light and heavy chain rearrangements, (re)circulating B cells with increased mutations of cmu transcripts in both CD27- and CD27+ memory B-cell subsets, and enhanced frequencies of individual peripheral B cells containing IgV heavy chain transcripts of multiple isotypes indicate disordered selection and incomplete differentiation processes of B cells in the inflamed tissues in pSS. This may possibly be related to a lack of appropriate censoring mechanisms or different B-cell activation pathways within the ectopic lymphoid structures of the inflamed tissues. These findings add to our understanding of the pathogenesis of this autoimmune inflammatory disorder and may result in new therapeutic approaches.

Purpose of Review: Recent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögren's syndrome. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as their implications for clinical handling and therapeutic options., Recent Findings: It becomes increasingly apparent that certain disturbances of the immune system (i.e. B-cell hyperreactivity and enhanced levels of B-cell-activating factor/B-lymphocyte stimulator) play a central role in this entity. Whether this is a primary abnormality or the result of predisposing factors or infectious, e.g. viral, agents remains uncertain. New insights into the pathogenesis also provide candidates for better diagnosis and classification of disease severity, such as flow cytometric analysis, measurement of soluble cell surface molecules, autoantibodies, cytokines, and ligands (B-cell-activating factor/B-lymphocyte stimulator). Whether B-cell-directed therapies (i.e. blocking B-cell-activating factor/B-lymphocyte stimulator, anti-CD20 therapy) will have an impact on primary Sjögren's syndrome needs to be shown in clinical trials. Alternative therapeutic approaches such as organ-targeted gene transfer are in development but must be carefully evaluated for safety and efficacy in preclinical models that resemble human primary Sjögren's syndrome., Summary: The pathogenesis of primary Sjögren's syndrome is complex and the factors initiating and driving autoimmunity in this entity are largely unknown. Recent studies provide new insights into potential pathogenetic mechanisms of the disease and, thereby, the chance for improved strategies in disease management and therapy.

Objective: To assess whether abnormal chemokine receptor expression and/or abnormal responsiveness to the cognate ligands might underlie some of the disturbances in B cell homeostasis characteristic of primary Sjögren's syndrome (SS)., Methods: Chemokine receptor expression by CD27- naive and CD27+ memory B cells from patients with primary SS and healthy control subjects was analyzed using flow cytometry, single-cell reverse transcriptase-polymerase chain reaction (RT-PCR), and migration assays., Results: In contrast to healthy subjects, significantly higher expression of both surface CXCR4 and CXCR4 messenger RNA (mRNA) was seen in peripheral blood B cells from patients with primary SS. These differences were most prominent in CD27- naive B cells (P < or = 0.0006). In addition, significantly higher frequencies of CD27- naive B cells from patients with primary SS expressed mRNA for the inhibitory regulator of G protein signaling 13 (P = 0.001). Expression of CXCR5 by peripheral CD27+ memory B cells was moderately diminished in patients with primary SS compared with healthy controls (P = 0.038). No significant differences were noted in the expression of CXCR3, CCR6, CCR7, and CCR9 between B cells from healthy controls and those from patients with primary SS. Transmigration assays of blood B cells from patients with primary SS and healthy controls showed comparable responses of CD27- naive B cells but significantly diminished responses of activated primary SS CD27+ memory B cells to the ligands of CXCR4 and CXCR5, CXCL12 (P = 0.032), and CXCL13 (B lymphocyte chemoattractant; B cell-attracting chemokine 1; P = 0.018), respectively, when compared with those from healthy controls. Finally, compared with controls, peripheral reduction but glandular accumulation of CXCR4+,CXCR5+,CD27+ memory B cells was identified in patients with primary SS., Conclusion: In primary SS, overexpression of CXCR4 by circulating blood B cells does not translate into enhanced migratory response to the cognate ligand, CXCL12. This migratory response may be modulated by intracellular regulators. Retention of CXCR4+,CXCR5+, CD27+ memory B cells in the inflamed glands seems to contribute to diminished peripheral CD27+ memory B cells in primary SS.

Objective: To delineate disturbances in peripheral B cell memory in primary Sjögren's syndrome (SS)., Methods: Isotype-specific immunoglobulin (Ig) heavy-chain transcripts were analyzed in single-sorted CD19+,CD27- naive and CD19+,CD27+ memory B cells from patients with primary SS and normal healthy control subjects., Results: A significantly higher frequency of B cells expressing mu-, alpha-, and/or gamma-chain transcripts were found in patients with primary SS compared with controls (58.0% versus 14.3%; P < 0.0001). Notably, 30.5% of individual B cells (for primary SS, 38.7%; for controls, 12.7% [P < 0.0001]) simultaneously expressed transcripts for different Ig heavy-chain isotypes using identical V(H)-D-J(H) rearrangements. However, these cells lacked surface expression of more than one of the respective Ig heavy-chain isotypes as well as messenger RNA (mRNA) transcripts for 2 germinal center markers, activation-induced cytidine deaminase, and Bcl-6. In contrast with the findings in normal healthy controls, peripheral B cell memory in patients with primary SS was characterized by 1) circulating CD27+ B cells expressing heavily mutated Ig V(H) transcripts (mutational frequency 8.6% versus 4.3%; P < 0.0001), 2) significantly enhanced mutational frequencies of C mu transcripts (9.6% versus 2.5%; P < 0.0001), 3) a high proportion (61.2%) of CD27+ B cells expressing transcripts for multiple Ig heavy-chain isotypes, and 4) a CD27- memory-type B cell subpopulation expressing mutated C mu transcripts., Conclusion: Altogether, both B cell hyperactivity and striking abnormalities in peripheral B cell memory are indicated at the single-cell mRNA level in patients with primary SS. Detection of multiple Ig heavy-chain transcripts in peripheral CD19+,CD27+ memory B cells of patients with SS may represent the abnormal retention of pre-switch mRNA transcripts in circulating post-switch B cells.

Although a modified European-American consensus classification of Sjögren syndrome has been introduced during the last year, the etiopathogenesis of this disease characterized by chronic lymphocytic inflammation, impaired function, and, finally, destruction of the salivary and lacrimal glands as well as systemic manifestations remains to be elucidated. Recent insights into the pathogenesis of Sjögren syndrome resulting from immunogenetic, hormonal, and epidemiologic evaluations as well as animal and in vitro studies are highlighted by this review. Evidence confirms that lymphocytic disturbances, including ectopic germinal center formation and aberrations of cellular signaling play a significant role in Sjögren syndrome. Although some of these features are unique to Sjögren syndrome, others are also found in a number of systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. The underlying cause of Sjögren syndrome remains largely enigmatic. However, distinct characteristics may provide the basis for the classification of the disease entities. Finally, an enhanced risk of lymphomagenesis is a well-known hallmark of primary Sjögren syndrome, indicating the central role of derangement of lymphocyte regulation. As demonstrated by the introduction of the new targeted therapeutic approaches in rheumatoid arthritis, solid insights into the pathogenesis of Sjögren syndrome may pave the way toward new therapeutic approaches.

Objective: To delineate the mechanism of the abnormalities in B cell biology found in patients with primary Sjögren's syndrome (SS)., Methods: The distribution of peripheral B cell subpopulations in 21 patients with primary SS was analyzed by immunofluorescence labeling and flow cytometry. Immunoglobulin rearrangements were analyzed in single B cells isolated from the peripheral blood and parotid glands by fluorescence-activated cell sorting., Results: A significant reduction in the number of peripheral CD27+ memory B cells was found in SS patients, including a significantly reduced number of CD27+/IgD+/IgM+/CD5+ memory B cells. Remarkably, SS patients with secondary lymphoma uniquely exhibited an increase in CD27-expressing peripheral B cells, including CD27(high) plasmablasts. Molecular analysis for mutated Ig gene rearrangements confirmed that CD27 expression distinguished naive and memory cells in SS. In contrast to the peripheral blood, the majority of parotid B cells from 1 patient examined exhibited both the mutational status and phenotype of memory B cells. Accordingly, the mutational frequencies of V(H) rearrangements were significantly greater in parotid B cells than in peripheral blood B cells, whereas the V(H) gene repertoire appeared to be very similar between the compartments., Conclusion: These data indicate that there is an accumulation/retention of memory B cells in the inflamed salivary glands of SS patients. It is possible that preferential accumulation of CD27+ memory B cells in the inflamed parotid gland explains their reduction in the peripheral blood.

This review focuses on the use of immunglobulin (Ig) variable region genes by B cells from patients with primary Sjögren's syndrome (pSS) and the biologic insights that this provides. Comparison of the Ig repertoire from the blood and parotid gland of pSS patients with that of normal donors suggests that there are typical disturbances of B cell homeostasis with depletion of memory B cells from the peripheral blood and accumulation/retention of these antigen-experienced B cells in the inflamed tissue. Although there are clonally expanded B cells in the parotid gland, generalized abnormalities in the B cell repertoire are also found in pSS patients. The vast majority of the current data indicate that there is no major molecular abnormality in generating the IgV chain repertoire in patients with pSS. In contrast, disordered selection leads to considerable differences in the V(L) gene usage and V(H) CDR3 length of the B cell Ig repertoire in pSS patients. The nature of the influences that lead to disordered selection in pSS remains to be determined, but should provide important clues to the etiology of this autoimmune inflammatory disorder.

Patients with Sjögren's syndrome (SS) have characteristic lymphocytic infiltrates of the salivary glands. To determine whether the B cells accumulating in the salivary glands of SS patients represent a distinct population and to delineate their potential immunopathologic impact, individual B cells obtained from the parotid gland and from the peripheral blood were analyzed for immunoglobulin light chain gene rearrangements by PCR amplification of genomic DNA. The productive immunoglobulin light chain repertoire in the parotid gland of the SS patient was found to be restricted, showing a preferential usage of particular variable lambda chain genes (V lambda 2E) and variable kappa chain genes (V kappa A27). Moreover, clonally related V(L) chain rearrangements were identified; namely, V kappa A27-J kappa 5 and V kappa A19-J kappa 2 in the parotid gland, and V lambda 1C-J lambda 3 in the parotid gland and the peripheral blood. V kappa and V lambda rearrangements from the parotid gland exhibited a significantly elevated mutational frequency compared with those from the peripheral blood (P < 0.001). Mutational analysis revealed a pattern of somatic hypermutation similar to that found in normal donors, and a comparable impact of selection of mutated rearrangements in both the peripheral blood and the parotid gland. These data indicate that there is biased usage of V(L) chain genes caused by selection and clonal expansion of B cells expressing particular V(L) genes. In addition, the data document an accumulation of B cells bearing mutated V(L) gene rearrangements within the parotid gland of the SS patient. These results suggest a role of antigen-activated and selected B cells in the local autoimmune process in SS.

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. [ABSTRACT FROM AUTHOR]